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BY 4.0 license Open Access Published by De Gruyter January 9, 2020

Optically responsive delivery platforms: from the design considerations to biomedical applications

  • Irina Koryakina , Daria S. Kuznetsova , Dmitry A. Zuev , Valentin A. Milichko , Alexander S. Timin and Mikhail V. Zyuzin ORCID logo EMAIL logo
From the journal Nanophotonics


Drug carriers with intelligent functions are powerful therapeutic and diagnostic platforms in curing various diseases such as malignant neoplasms. These functions include the remote noninvasive activation of drug using physical impacts, e.g. light exposure. Combination of different therapeutic modalities (chemotherapy, photodynamic therapy, and so forth) with light-responsive carriers enables promising synergetic effect in tumour treatment. The main goal of this review article is to provide the state of the art on light-sensitive delivery systems with the identification of future directions and their implementation in tumour treatment. In particular, this article reviews the general information on the physical and chemical fundamental mechanisms of interaction between light and carrier systems (e.g. plasmonic and dielectric nanoparticles), the design of optically responsive drug carriers (plain and composite), and the mechanisms of light-driven controlled release of bioactive compounds in biological environment. The special focus is dedicated to the most recent advances in optically responsive bioinspired drug vehicles.

1 Introduction

Drug delivery systems are designed to enable more effective drug administration, particularly, to deliver drugs to specific organs, to provide sufficient drug pharmacokinetics, and to improve solubility of drugs. Particulate delivery systems composed of organic and/or inorganic materials have proven their efficiency as drug carriers with different release mechanisms. Controlled drug release upon external and internal stimuli is one of the most important properties of drug carriers such as nanoparticles (NPs) of organic or inorganic nature, as well as bioinspired delivery platforms. Typically, the drug activation occurs in response to environmental triggering, for example, changes in pH [1] and ionic strength [2] (chemical stimuli), temperature [3] (physical stimulus), enzymatic degradation [4] (biological stimulus), and others [5]. However, researchers and medical professionals have aspired to focus on mechanisms for noninvasive drug activation using physical stimuli. Regarding the implementation of physical approaches for drug release: ultrasound [6], light [7], and magnetic field [8] can be used. Light is the most biocompatible external impact that is widely used to activate drug carriers and induce the cargo release [9]. Therefore, penetration depth of light is an important parameter for an effective noninvasive drug activation. Penetration of light irradiation with the wavelengths less than 700 nm [ultraviolet (UV) and visible] is rather limited to 1 mm due to the scattering and absorption from skin layers [10]. Application of the near-infrared (NIR) light irradiation (700–1000 nm) to trigger release of the bioactive molecules (drugs) inside biological objects allows to overcome this penetration barrier due to the lowest absorption coefficients of hemoglobin, lipids, and water in the NIR region [10].

There are two common mechanisms of light activation of bioactive compounds from the carriers: thermal effects and photochemical triggering (reassembly of organic carrier-structure upon light irradiation, which includes hydrophobicity–hydrophilicity transition or photocleavage reaction). Photothermally responsive drug carriers are able to adsorb light energy and convert it into heat. This heat further stimulates intracellular drug release from the carrier either by phase change mechanisms or by disruption of its structure. High temperatures (hyperthermia) also can reduce the cell viability; therefore, photothermal therapy (PTT) can be applied for such carriers along with the chemotherapy.

Another photoinduced mechanism involves either disruption of the hydrophobic–hydrophilic formulations with embedded photochromic moieties (e.g. micelles, liposomes [11]) or disassembly of the organic delivery platforms due to photocleavage reactions [12]. It is worth highlighting that the photochemical oxidation reaction is a special case of photocleavage mechanisms of drug release as reported by Bédard et al. [13]. Based on the design of light-responsive drug carriers, their interaction with light can vary, which in turn involves different mechanisms of drug activation. The photorelease profiles of bioactive compounds from light-sensitive drug carriers can be regulated via the adjustment of a number of parameters, such as light wavelength, light power intensity, duration of light exposure, and beam diameter [14], [15]. The important issue that should be taken into account is the stability of drug carriers in biological fluids. It is worth mentioning that after the first introduction of particulate drug carriers into biological fluids, organic compounds from these fluids tend to bind carriers’ surface forming so-called protein corona [16]. This protein coating may undergo continuous adsorption and desorption, depending on the affinity of the surrounding proteins to the carrier’s surface [17]. Protein corona can significantly change physicochemical properties of the carriers [18]. Moreover, it can affect particles light sensitivity [19]. For example, aggregated gold (Au) NPs can seriously induce the shift of plasmon band and therefore the efficiency of the light absorption [20].

For the design of light-responsive drug carries, various types of nanostructured materials based on plasmonic/dielectric NPs [Au, silver (Ag), Fe2O3, Fe3O4, and others], photosensitizers (PSs), photochromic moieties [azobenzene (AZO), coumarin, spiropyran (SP), o-nitrobenzyl (NB), 4-bromo-7-hydroxycoumarin, and 2-diazo-1,2-naphthoquinone (DNQ)] have been considered. In addition, composite materials have gained interest as light-responsive components because they combine the merits of organic and inorganic components. As an example, micelle-, liposome-, and polymer-based materials modified with light-responsive parts can be fabricated [21], [22], [23]. Moreover, the inspiration from the biological side leads to the development of the cell-based delivery systems possessing light-addressable properties. Development of such delivery platforms usually involves the application of therapeutically relevant cells that can be naturally recruited in the tumour regions and deploy drugs upon laser irradiation. Various cell types have been reported as effective natural carriers, including mammalian cells [red blood cells (RBCs), neutrophils, leukocytes, phagocytes, stem cells (SCs), B lymphocytes, T lymphocytes, natural killer (NK) cells], bacteria, and viruses [24].

This review article aims to underline most recent advances of research on the light-sensitive drug delivery platforms. Special focus is dedicated to the consideration of the fundamental physical and chemical mechanisms describing light–matter interactions, which stimulate either conformational or thermal changes in the structure of the drug carriers. It further summarizes recent progress on the existing plain (individual plasmonic/dielectric materials) and composite (inorganic/organic nanostructured materials, as well as biomimetic platforms) drug delivery carriers, particularly on their design, drug loading/release possibilities, and biomedical applications (Figure 1).

Figure 1: Schematic overview of light-sensitive delivery systems, as well as drug release mechanisms.
Figure 1:

Schematic overview of light-sensitive delivery systems, as well as drug release mechanisms.

2 Fundamental principles of light interaction with plasmonic and dielectric NPs

2.1 Physical aspects of NPs’ heating

Resonant particulate nanophotonic structures are proven to be effective tools for precise optical heating of various systems at the nanoscale. This heating can be achieved by interaction of light with such plasmonic (Au, Ag) and dielectric (Si, Ge) nanometer-scale particles differently [25], [26], [27], [28], [29]. Indeed, different optical resonances (plasmonic and Mie-type resonance) of these NPs allow electromagnetic field localisation with further conversion to heat energy by different paths and efficiencies. Moreover, these resonances can be simply tuned to biological transparency region in the NIR optical range by varying their physicochemical parameters such as size, shape, and composition. This enables to precisely control the heating process at the depth of several centimeters inside a tissue. In this section, we consider these fundamental mechanisms of conversion of light energy to heat in plasmonic and dielectric NPs focusing on the nature of these processes and their dynamics.

2.1.1 Plasmonic heating

Photothermal therapy is one of the most remarkable examples of plasmonic heating application in biomedicine. This heating is based on the nature of plasmonic NPs’ optical properties and arises from the resonant interaction of the electromagnetic field at certain frequencies with the oscillations of electrons (plasmons). These plasmons provide considerable enhancement of electric field near the NP surface as well as rise of optical absorption at the resonant frequency [20]. Generally, plasmonic heating can be described as the temperature accumulation and temperature distribution around the NP.

2.1.2 Temperature accumulation

As mentioned above, plasmonic NPs convert some part of this energy into heat under light irradiation, which is mainly related to absorption process. When considering the uniformly polarised spherical NP with the diameter, which is smaller than an excitation wavelength, this NP can be represented as an electromagnetic dipole (for larger spheres, Mie theory should be applied). In this case, the computation of the heat energy absorbed by plasmonic spherical NP strongly depends on the absorption cross-section σabs, which can be calculated as follows [26]:


where α(ω)=4πR3ε(ω)εsε(ω)+2εs is NP polarisability, k is the angular wave number in the medium, ε(ω) is a complex relative permittivity of plasmonic NP, and εs=ns2 is a real relative permittivity of a medium around the spherical NP with a radius of R.

The plasmonic resonance takes place at the frequency ω when ε(ω)≈−εS. In turn, the absorption cross-section is related with scattering and extinction cross-sections (σscat and σext) as follows [26]:


where σscat=k46π|α|2.

The power absorbed by the NP (Q) during irradiation is directly related with σabs and intensity of the incident light I as follows [25], [28]:


In case of complicated geometry, the power generated by the NP can be calculated through the heat power density q(r) inside the NP with volume V at the position r as follows [25], [28]:


where E(r) is the electric field amplitude inside the NP, and ε0 is dielectric permittivity.

It is obvious that σabs plays an important role in the efficiency of conversion of light energy to heat. Table 1 represents the estimated values of σabs for different plasmonic materials, which can be used in PTT. Taking into account that Au is mostly nontoxic and biocompatible material [36], it allows to consider Au as the most suitable metal for plasmonic heating in nanomedicine. It is also important that the mechanisms of NP heating depend on laser modes, pulsed and continuous wave (CW). These processes are further discussed.

Table 1:

Comparison of the absorption cross-section for different plasmonic NPs.

Diameter of NPs (nm)ωp (nm)σabs (nm2)Ref.

2.1.3 Temperature distribution around the NP

The good example illustrating the heating process of plasmonic NP is described in the work [37], where a spherical Au NP with known radius (R) immersed in water and uniformly illuminated at a resonant frequency is studied. In this case, the initial increase in the instantaneous temperature (moderate case) is considered; therefore, the changes in physicochemical properties of the material, mass transfer, cavitation, convection processes in liquid, oxidation of NP, possible molecular coatings, and others are not taken into account. Some of these examples can be found in several works [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48].

It was established that the mode of laser irradiation (CW or pulsed) of plasmonic NP has a significant influence on the spatial extension of the temperature profile around the NP (Figure 2A), as well as temperature evolution (Figure 2B) [28], [37]. This effect can be utilised to control spatial region of heating and selectively start heat-activated chemical processes.

Figure 2: The modes of laser heating of Au NP in water.(A) Spatial extension of the temperature profile in CW and pulsed modes of laser irradiation. The normalised time τ=t/τtr is used in case of pulsed irradiation. Insets, 3D representation of the temperature profile around plasmonic NP under CW and single fs-laser pulse irradiation. (B) Comparison of the time-dependent temperature behaviour for the CW (dashed line) and single-pulse illumination (solid line) modes. Reprinted with permission from [28], [37]. Copyright 2013 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim; Copyright 2011 American Physical Society.
Figure 2:

The modes of laser heating of Au NP in water.

(A) Spatial extension of the temperature profile in CW and pulsed modes of laser irradiation. The normalised time τ=t/τtr is used in case of pulsed irradiation. Insets, 3D representation of the temperature profile around plasmonic NP under CW and single fs-laser pulse irradiation. (B) Comparison of the time-dependent temperature behaviour for the CW (dashed line) and single-pulse illumination (solid line) modes. Reprinted with permission from [28], [37]. Copyright 2013 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim; Copyright 2011 American Physical Society.

In the CW mode of irradiation and spherical shape of the NP, the steady-state temperature distribution δT(r) outside the NP can be described as follows [28]:


where δTNP is the uniform temperature increase of the NP; δT(r)≈δTNP when r<R.

In turn, for the nanostructures with axial symmetry (rods, ellipsoids, discs, and tori), the temperature increase can be set as follows [49]:


where β is a dimensionless value introduced to correct geometry and equals 1 in case of sphere; Req is the equivalent radius describing a sphere with the same volume as investigated for nonspherical NP; and κs is the thermal conductivity of the surrounding medium.

In the pulsed mode (picosecond and femtosecond scale), the interaction of laser radiation with a plasmonic NP can be generally described as step-by-step processes changing internal temperature of the NP and providing the temperature diffusion from heated NP to a surrounding media. These processes are schematically presented in Figure 3.

Figure 3: Schematic representation of processes taking place under pulsed (~100 fs) laser irradiation of Au NPs.The electronic temperature of the electronic gas (Te), temperature of the lattice (Tp), and surrounding media (Text), as well as room temperature (RT), are demonstrated on the scheme.
Figure 3:

Schematic representation of processes taking place under pulsed (~100 fs) laser irradiation of Au NPs.

The electronic temperature of the electronic gas (Te), temperature of the lattice (Tp), and surrounding media (Text), as well as room temperature (RT), are demonstrated on the scheme.

At first, the absorption of the laser energy by the free electron gas and its thermalisation (around 100 fs [37]) take place. At this stage, the temperature of the ions of the metal lattice Tp remains unchanged (nonequilibrium conditions). Then electron–phonon interaction starts and provides internal equilibrium in the NP volume with uniform temperature of the electron gas Te and metal lattice over a time scale of some units of ps (~1.7 ps in case of Au NP) [37]. At this point, the temperature of a surrounding media Text is still lower compared to the heated NP’s temperature. The subsequent diffusion of heat from the NP to a media starts and lasts from the 10th of picoseconds to nanoseconds. To estimate the heat diffusion, the parameter of time τtr should be introduced [28],


where L is the characteristic size of the NP (e.g. R for a sphere), and ρ and cp are the mass density of the NP and heat capacity at constant pressure, respectively.

It is worth mentioning that these processes are size-dependent. For example, electron–phonon thermalisation does not depend on the size of NPs larger than 5 nm [37], [50] and can overlap in time with the electron–phonon thermalisation process for NPs smaller than 20 nm [37], [38].

The pulse repetition rate f and laser fluence F have an important impact on the heating process, and (3) can be introduced as follows [28], [37]:


where I is average irradiance. In this case, the value of the initial temperature of the NP can be described as follows [37]:


where V is the volume of the NP.

It is important to note that the pulse repetition rate can be tuned to provide quasi-CW heating mode. In this case, heat will be delivered into the NP so fast that there will be no time for the NP cooling (f≳1/τtr). Pulse duration and its ratio to τtr are other parameters, which have significant influence on the heating/cooling dynamics in the pulsed mode [28]. When the small NP (less than 100 nm) is irradiated by the picosecond or femtosecond laser pulses, the interaction of the laser pulse with the NP can be observed in Figure 3, and the time of heating equals τtr (due to magnitude). Otherwise, under nanosecond pulses, the duration of heating is determined only by the duration of the laser pulse (the processes in Figure 3 time overlap) [28], [37].

An example of the different heating processes is shown in the recent work of Halas and coworkers, where authors experimentally revealed the variations in heating mechanisms under the investigation of light-triggered deoxyribonucleic acid (DNA) release from Au NPs [15]. Indeed, CW laser illumination drives the photothermal release of dehybridised single-stranded DNA, whereas femtosecond excitation results in negligible local heating followed by DNA release by breaking of the thiol bond. The authors underlined the importance of application of such NPs irradiated by different laser modes in the development of NIR-triggered gene or drug delivery.

2.1.4 Heating of dielectric NPs

Another approach of the nanoscale heating is based on the utilisation of resonant NP made of high refractive index materials [26], [29], [51]. Initially, such NPs were not considered as effective heating tools. Indeed, metal NPs can provide high temperatures due to significant ohmic losses, which makes them very efficient for optically induced heating. The main drawback of heating in metal NPs is that this process is poorly controlled. Moreover, it can harm the nanostructure itself or/and lead to undesirable chemical reactions in surrounding media [29]. In contrast, high-index (dielectric) materials possess low optical losses (no charged carriers) and therefore at the first sight cannot provide significant optically induced heating. However, recently it has been demonstrated that it is possible to achieve high light-to-heat conversion in these systems [26]. In particular, magnetic quadrupole resonances in silicon (Si) NPs have been employed to generate highly efficient optical heating.

To compare the heating process in a resonant NP (metal or dielectric), (3) can be introduced [26],


where σ=ε0ωIm(ε) is electric conductivity, F=⟨|E|2⟩/|E0|2 is spatially averaged field enhancement factor, and Veff is the effective mode volume inside the NP.

Therefore, these three components contribute to NP heating. Taking into account optical losses, the impact of the first two components (σF2) can be considered, including the radiative and ohmic components. At the resonant frequency,


In this case, the maximum value of σF2 can be achieved when γOhmicγrad [28]. This requirement is satisfied for small metallic and big dielectric NPs (Figure 4).

Figure 4: Calculated resonant heating maps for a spherical NP with diameter D in the air for different real and imaginary parts of permittivity made for various ratios of wavelength λ to D.In the calculations, λ is fixed, green lines depict dispersion for materials studied, and direction of arrows shows the wavelength increase (in micrometers). Reprinted with permission from [26]. Copyright 2017 American Chemical Society.
Figure 4:

Calculated resonant heating maps for a spherical NP with diameter D in the air for different real and imaginary parts of permittivity made for various ratios of wavelength λ to D.

In the calculations, λ is fixed, green lines depict dispersion for materials studied, and direction of arrows shows the wavelength increase (in micrometers). Reprinted with permission from [26]. Copyright 2017 American Chemical Society.

According to (10), the effective mode volume inside the NP Veff has also influence on the NP heating and can be calculated as follows [26]:

(11)Veff=πD2δ(plasmonic NP),
(12)VeffπD3/6(dielectric NP),

where δ is a skin depth (less than 20 nm in the visible range).

Thus, increase in the NP size for efficient optical-induced heating is more reasonable in case of resonant dielectric NPs, which, at appropriate sizes, can provide comparable heating with plasmonic ones and sometimes even exceed it (Figure 5A).

Figure 5: Optically induced heating and thermometry in high-refractive index NPs.(A) Comparison of temperatures achieved in plasmonic and dielectric NPs. The results of theory (solid lines) and experiment (circles) are represented. Heating conditions, λ=633 nm, I0=2 mW/μm2. (B) Results of calculation of the temperature-dependent Raman shift on the temperature for Si NP from (13) (solid line) and its approximation (dotted line). Reprinted with permission from [26], [52]. Copyright 2017 American Chemical Society; Copyright 2017 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Figure 5:

Optically induced heating and thermometry in high-refractive index NPs.

(A) Comparison of temperatures achieved in plasmonic and dielectric NPs. The results of theory (solid lines) and experiment (circles) are represented. Heating conditions, λ=633 nm, I0=2 mW/μm2. (B) Results of calculation of the temperature-dependent Raman shift on the temperature for Si NP from (13) (solid line) and its approximation (dotted line). Reprinted with permission from [26], [52]. Copyright 2017 American Chemical Society; Copyright 2017 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Another interesting feature of dielectric materials is that many of them demonstrate Raman signal, which is not observed in plasmonic materials. This effect can be employed for developing the all-in-one system based on resonant dielectric NPs, which unifies optically induced heating with the thermometry at the nanoscale. Moreover, it has been demonstrated that resonant properties of such NPs can also be applied for the enhancement of Raman signal (e.g. 140 times at the magnetic dipole resonance in spherical Si NPs) [53].

The dependence of the Raman line shift Ω on dielectric NP temperature can be considered on the example of crystalline Si NP. The temperature can be calculated as follows [26], [52]:


where Ω0=528 cm−1, x=Ω02kBT,y=Ω03kBT,A=−2.96 cm−1, B=−0.174 cm−1 for crystalline Si, and kB is the Boltzmann constant.

The plotted temperature dependence of Raman signal shift can be approximated in Figure 5B with simple analytical equation [52],


Thus, the opportunity of the Raman nanothermometry combined with the high temperatures, which can be achieved at optical resonances in dielectric NP under optically induced heating, makes them an attractive platform for a wide range of applications [54], [55], [56]. The optical thermometry at the nanoscale available in these materials can be effectively used in the field of drug delivery to precisely control the temperature of drug release inside cell and avoid undesirable overheating. However, it is worth to mention that under high values of laser fluence or temperatures, thermooptical nonlinear effects can change refractive index and thermal conductivity of heated materials.

Compared to plasmonic NPs, the key difference of heating of dielectric NPs is the ability to heat them to higher temperatures up to 1000 K and more with less pumping laser intensity [52], [54]. This opens up the possibility of utilisation of such NPs for drug delivery without phototoxicity [51], as well as for high-temperature photochemistry and catalysis at the nanometer scale. Indeed, Si quantum dots were proven to be effective nanosystems for applications in cell biology and medicine [57]. In turn, application of optically resonant high-refractive index nanoparticles (e.g. Si, Ge, Fe2O3, etc.) makes it possible to add another opportunity related with optical-induced heating and control of chemical reactions in different systems at the nanoscale. For example, Zograf et al. employed resonant dielectric NPs to induce release of antitumour drug from biocompatible polymer microcontainers upon pulsed NIR-laser irradiation with less applied power density. Noninvasive intracellular release was probed on two cell types, carcinoma cells and SCs. The developed systems based on polymer containers decorated with dielectric resonant particles were found to have a high potential as drug delivery platforms [51].

2.2 Chemical aspects of light–NP interaction

The electron ejection from the metal surface by light, so-called photoelectric effect, was discovered by Heinrich Hertz [58] in 1887 during the study of the interaction between UV light and metals. Afterwards, Albert Einstein provided the explanation of this effect in 1905 by the following statement [59]: light consists of a set of photons with a discrete energy allowing electron ejection from a metal surface with a certain threshold, i.e. a minimum photon energy equals the metal’s work function. These discoveries induced the quantum revolution and stimulated research in different fundamental directions, including complex physical (discussed above) and chemical processes that can be excited by light.

In this section, we discuss the process of light–NP interaction from the chemical point of view. Figure 6 illustrates photodissociation, decomposition, desorption, and quenching of chemical environment adsorbed to the surface of the NPs, as well as phototherapy. Interestingly, regardless of the metallic or dielectric nature of the NPs, these processes are the result of heating the NPs by light and light-induced transfer of charges or energy (Figure 6).

Figure 6: Schematic illustration of the light–NP interaction. (A) Local heating of NPs and adsorbates, (B) electron and/or hole transfer to adsorbates, and (C) energy transfer from/to NPs. These three mechanisms allow observing chemical transformation of surroundings including photodissociation, photodecomposition, photodesorption, and other. The green arrows represent the incoming light, while the red arrows correspond to electron relaxation with the loss of its energy and re-emission of the light. The heat distribution is represented as hemispheres.
Figure 6:

Schematic illustration of the light–NP interaction. (A) Local heating of NPs and adsorbates, (B) electron and/or hole transfer to adsorbates, and (C) energy transfer from/to NPs. These three mechanisms allow observing chemical transformation of surroundings including photodissociation, photodecomposition, photodesorption, and other. The green arrows represent the incoming light, while the red arrows correspond to electron relaxation with the loss of its energy and re-emission of the light. The heat distribution is represented as hemispheres.

As discussed above, the light-induced heating of metallic (plasmonic) and dielectric NPs includes different mechanisms and involves a cascade of complex processes [60]. In the former case, the excited plasmons can relax within tens of femtoseconds by nonradiative way and excite energetic charge carriers (electrons and holes). Afterwards, the relaxation from non-Fermi to Fermi electron distribution occurs through electron–electron scattering. Cooling of this electronic gas takes picoseconds due to electron–phonon interaction with the following heat dissipation from the NP to surrounding media through phonon–phonon scattering. In case of dielectric NPs, after excitation of the charged carriers from the valence to conduction band, the relaxation of electrons occurs also through electron–phonon interaction with following heat dissipation from the NP surface. As a result, the energy transfer from photons to thermal energy of NP adsorbates (nuclear motion of atoms) takes from picoseconds to microseconds and activates the chemical bonds and chemical transformations with the following consequences.

2.2.1 Desorption (photons to thermal energy)

In some cases, the light-induced heating of the NPs with different adsorbates is applied for remote on-demand optical delivery/release of bioactive compounds with high spatial resolution [61]. Here we discuss the important issues of desorption from the chemical point of view – the unbinding between adsorbates and NPs. It should be noted that desorption of organic compounds from the NP surface requires different energy depending on bonding. On the one hand, noncovalent bonding as hybridisation (hydrogen bonds, which, for example, results in formation of double-stranded DNA) [15] or electrostatic interaction (as an example, the interaction between cationic polymers and negatively charged single-stranded and double-stranded nucleic acids) requires a little (up to several meV) thermal or electronic energy for desorption [62]. This interaction is also important for protein corona formation around NPs [16], [54]. On the other hand, the covalent bonding is generally achieved by coupling with amino acid residues as -NH2, -SH, and -COOH. In the case of covalent bonding, the dissociation of the bonds as thiol group, amine-carboxylate coupling, and complex of azide-tagged NP and alkyne-tagged adsorbate [63] requires much higher energy at least 0.1 eV by heating or electronic injection [15], [62], [64].

2.2.2 Photodissociation and decomposition (photons to thermal energy)

The catalytic reactions such as ammonia synthesis, hydrocarbon reforming, oxidation, hydrogenation, and others are generally triggered by heating at relatively high temperatures (500°C or greater). This process involves the excitation of phonons of the NP and their coupling to vibrational modes of the adsorbates [65]. For instance, heating of Au NPs dispersed in water–ethanol mixture results in decomposition of ethanol to CO2, H2 and CO, whereas dicumyl peroxide can be decomposed by light on the surface of Au NP into 2-phenyl-2-propanol and acetophenone [66], [67].

2.2.3 Phototherapy (photons to thermal energy)

The electron–phonon scattering in plasmonic NPs can result in significant heating to the melting temperature of NPs. As discussed, the tuning of the NP shape and size can shift the plasmon resonance to NIR range, where the light absorption of tissues is limited. In case of therapy with plasmonic NPs, the illumination results in local efficient heating of these NPs with following cellular hyperthermia, cell death, and tumour remission, as well as treatment of epithelial carcinoma SK-BR-3, photothermal destruction of malignant squamous cell, and others [68], [69], [70]. Moreover, owing to local heating, plasmonic NPs can be used for modulation of thermosensitive ion channels without cell damage [71], [72].

The photothermal mechanism described above assumes the energy conversion of photons to phonons of the NPs, which triggers the chemical transformation. An alternative mechanism involves the energy conversion of photons to energetic charge carriers. These carriers can transfer from the NP to adsorbate before their interaction with phonons and following energy dissipation. The efficiency of this process depends on overlapping of electronic states of the NPs and adsorbates as well as lifetime of exited carriers. In case of efficient excitation of charges, their spatial separation and following transfer to the adsorbates should occur. The injection of electrons or holes to adsorbates should be considered separately; nevertheless, it results to the same effect mentioned above.

2.2.4 Desorption (photons to energetic charge carriers)

Similar to the desorption caused by light-induced heating and utilised for drug and gene delivery, the electron-induced mechanism demonstrates less efficiency, but higher stability of the adsorbates. For example, pulsed laser radiation can break thiol Au-SH bonds by hot-electron transfer for double-stranded DNA release from the NP surface [15]. We omit here the detailed discussion, as this process is well described in [73], and the corresponding mechanism (desorption induced by electronic transition) is also discussed in previous works [65], [74], [75].

2.2.5 Photodissociation and decomposition (photons to energetic charge carriers)

In general, after electron and hole separation by light and before their collision, these energetic charges can be transferred to the adsorbates, which can result in different effects. Energetic holes of the NPs serve as principal oxidants and are involved in different processes as generation of reactive hydroxyl radicals (OH·) [76], [77], water splitting (H2O+2h+ → 2H++½O2), and reactive oxygen species (ROS) (H2O+h+ → H++·OH) [78], [79], [80], as well as oxidation of citrate molecules and ethylene adsorbed on the NPs [81], [82], [83] and many others. In contrast, energetic (hot) electrons participate in hydrogen evolution (2H++2e → H2), generation of superoxide anion ·O2 [80], dissociation of oxygen to O2 ions [82], hydrogen dissociation, reduction of nitroaromatic compounds, ammonia decomposition (2NH3 → N2+3H2) [84], hydrogen production from ammonia borane, and esterification of benzaldehyde with alcohol to produce ethyl benzoate [74], [85], [86], [87], [88]. Moreover, for the most complex systems such as Saccharomyces cerevisiae functionalised by indium phosphide NPs, the electron injection from the illuminated NPs to such heterotrophs stimulates cytosolic regeneration of redox cofactor nicotinamide adenine dinucleotide phosphate [89], whereas the complex of Moorella thermoacetica–CdS NPs represent the electronic transfer from the NPs to bacteria for photosynthetic reduction of CO2 to produce acetic acid [90]. However, in case of dielectric NPs, such catalytic activity is limited due to the large band gaps (several eV) of common semiconductors as titanium dioxide (TiO2) and very low mobility of their charge carriers. Additionally, it should be noted that, in contrast to the heat-induced dissociation and decomposition, where the NPs and adsorbates are in thermal equilibrium, the charge-induced reaction allows exciting specific vibrational modes of the adsorbates, selectively increases its temperature, and triggers specific reaction.

Finally, resonant interaction between light and the NPs can result in electromagnetic field localisation near the NP surface [91]. In this case, plasmonic NPs demonstrate unprecedented values of field localisation on their surface or in the gaps, whereas dielectric NPs demonstrate the electromagnetic field localisation mostly inside their volume with slight dissipation of energy to their surface [52], [92]. In any case, the enhancement of electric field |E|2 on the surface increases the rate of electron–hole pairs formation in adsorbates that stimulate their chemical transformation [93] via the generation of singlet oxygen 1O2 on the surface of metallic and dielectric NPs [80]. Moreover, the energy transfer can be carried out both from the NP to adsorbates, and vice versa [62]. In the latter case, the energy transfer is described by NP surface energy transfer mechanism [94], where an optically excited organic fluorophore acts as a donor, which transfers its energy by dipole–dipole interaction to acceptor (NPs) through a nonradiative path. The efficiency of this process directly depends on overlapping of donor emission spectrum and acceptor absorbance. The distance between donor and acceptor [94] and the size of acceptor [95] also play a critical role in the energy transfer efficiency.

3 Light-responsive plain delivery systems: recent applications in nanomedicine

3.1 Plain plasmonic NPs

As described above, plasmonic NPs (e.g. Au and Ag) have proven to show strong scattering and absorption of light in visible and NIR region owing to their localised surface plasmon resonances (SPRs). The absorbed light is then transformed into thermal energy [96]. Being a good nanoheaters, the Au and Ag NPs provide a versatile and multifaceted platform for a broad range of biomedical applications such as drug delivery.

3.1.1 Au NPs

Among various light-responsive delivery platforms, Au NPs have attracted tremendous interest as drug carriers due to their particular features; simple synthetic manipulation; enabling precise control over the physicochemical properties of particles; and strong binding affinity to thiols, disulphides, and amines, which allow performing surface coating [97]. At present, various synthetic conditions have been developed for the fabrication of anisotropic Au NPs with different sizes and shapes. Based on dimensions, Au NPs can be divided into three categories: (i) one-dimensional Au NPs (e.g. nanorods, nanowires, nanotubes, etc.); (ii) two-dimensional Au NPs (e.g. stars, pentagons, squares/rectangles, dimpled nanoplates, hexagons, truncated triangles), and (iii) three-dimensional Au NPs (e.g. nanotadpoles, nanodumbbells, nanopods, nanostars, and nanodendrites). As mentioned above, the SPR band of Au NPs depends on the morphology (e.g. shape, size, core charge, etc.) of Au NPs. A variety of Au NPs with different morphologies and sizes were fabricated to manipulate the visible and NIR spectrum. As an example, recently developed anisotropic popcorn-shaped Au NPs possessed tunable SPR, high colloidal stability, and high biocompatibility [98].

The effective SPR absorption of Au NPs allows employing these NPs in photodynamic therapy (PDT). Moreover, the modification of Au NPs with PSs allows enhancement of the PDT efficiency in cancer treatment. For instance, in the recent work, generation of singlet oxygen was effectively tuned by manipulating the physical location between Au NPs and PSs [99]. Usually, the synergy of Au NPs and PSs occurs in the following manner: the energy transferred from the Au NPs to the PSs enhances the photodynamic effect with higher stability. After administration of Au NPs in vivo and reaching the tumour cells, ROS are released from the PSs attached to the surfaces of Au NPs under irradiation. The released ROS demonstrate phototoxic features, whereas nonphototoxic effects are usually observed in the blood circulation without exposure to light. Thus, this synergy of plasmonic NPs with attached PSs demonstrates selectivity of the used therapy.

As mentioned above, the heating abilities of Au NPs make it possible to utilise them also in PTT. It was demonstrated that the heat causes the death of malignant tumours [100]. In general, based on many reports, spherical solid Au NPs with diameter greater than 50 nm are the most commonly used platform in PTT. Recently, Au NPs were combined with other nanostructures. For example, Chen et al. [101] combined Au NPs with NaYF4,Yb3+/Er3+ nanomaterials and coated the resulted structure with silica shell. The surfaces of these nanocomposites were then decorated with folic acid through multiple steps to impart the Au NPs properties of selectivity in vivo. The NaYF4,Yb3+/Er3+ nanostructures acted as light converters and emitted green and red light under 980 nm laser excitation. The additional silica coating improved biocompatibility of the developed systems. This system exhibited significantly enhanced therapeutic efficiency as demonstrated in vitro and in vivo.

The Au NPs can be also employed as effective nanocarriers that are capable of carrying various drugs such as peptides, proteins, plasmid DNAs, small interfering ribonucleic acids, and chemotherapeutic agents [97]. Various surface modification strategies of Au NPs were developed, which allow controlling the penetration and retention of NPs in tumours. For instance, polyethylene glycol (PEG) coating is one of the widely used methods for Au NP modification to prolong the blood circulation time of NPs and enhance their accumulation into tumour cells. Also, the surface of Au NPs can be modified with antibodies that allow performing targeted delivery of drugs to the area of interest. This enables the combination of the targeted properties of Au NPs with the therapies (e.g. PDT, PTT). In the recent work, Au NPs were loaded with a variety of antitumour agents, including paclitaxel, methotrexate, daunorubicin, gemcitabine, platinum complexes, doxorubicin (DOX), etc. [102]. In this case, loading was performed by simple physical adsorption of antitumour agents on Au NPs or by using alkanethiol linkers. The successful loading of antitumour drugs was probed both in vitro on tumour cell cultures and in vivo using mice bearing implanted tumours of various natures and localisations (Lewis lung carcinoma, pancreatic adenocarcinoma, and so forth) [102].

The light sensitivity of Au NPs allows controlling the release process of the drugs. In many works, the light stimuli were used to release drug molecules from Au NPs. For example, Sreejivungsa et al. [103] developed a novel monolayer of Au NPs for the controlled release of a model drug using UV light. Wang and colleagues fabricated multifunctional Au NPs loaded with DOX for the treatment of metastatic breast cancer [104]. Upon laser irradiation, the local temperature of Au NPs was increased substantially and efficiently released DOX from the Au NP surface. In another work, Zhang and colleagues developed a core-shell NPs that consisted of Au nanoshell and 10-hydroxycamptothecin for the treatment of breast cancer [105]. After the introduction of the developed NPs in vivo and their irradiation at power density of 1 W cm−2 with the exposure time of 10 min, full tumour remission in a 4T1 breast syngeneic mouse model was observed. It is important that no significant weight loss of mouse and tumour recurrence were indicated. Park and coworkers [106] designed PEGylated multifunctional hollow Au NPs for delivery of DOX against A549 lung cancer. Upon NIR irradiation, the Au NPs efficiently released DOX. Furthermore, these NPs were capable of sensitising A549 cells to X-ray radiation. The effective combination of chemotherapy (DOX), PTT (high temperature), and radiation resulted in the highest cytotoxic effect of the developed systems. In another study, Si phthalocyanine 4 (a drug for the treatment of rabies) was linked to PEGylated Au NP conjugates. After reaching the tumour site and further passive accumulation of NPs, the molecules of phthalocyanine 4 were released from the surface of the NPs under irradiation with light at 670 nm [107]. Recently, Zhang et al. [108] developed a new Au NP with immunological properties that possessed core-shell structure. These NPs could release heat (PTT) and tumour antigen-based immunotherapeutic agent. The obtained results clearly demonstrated the accumulation of Au NPs in the tumour area, for example, in tumour-bearing mice in 24 h after administration (Figure 7B) and, therefore, improved antitumour effect from both PTT and immune therapy (Figure 7C).

Figure 7: In vivo characterisation and antitumour effect of immunological Au NPs combined PTT and tumour antigen-based immunotherapy.(A) Schematic diagram of PTT using Au NPs. (B) In vivo distribution of Au NPs labeled with fluorescent marker in tumour-bearing mice at different time points. IR thermal images with corresponding temperature profiles. (C) The photographs of tumours from the sacrificed mice at the 21st day. Tumour growth curves after different treatments with and without laser irradiation of 2.0 W cm−2. Tumour weight of the sacrificed mice at the 21st day. Adapted with permission from [108]. Copyright 2019 American Chemical Society.
Figure 7:

In vivo characterisation and antitumour effect of immunological Au NPs combined PTT and tumour antigen-based immunotherapy.

(A) Schematic diagram of PTT using Au NPs. (B) In vivo distribution of Au NPs labeled with fluorescent marker in tumour-bearing mice at different time points. IR thermal images with corresponding temperature profiles. (C) The photographs of tumours from the sacrificed mice at the 21st day. Tumour growth curves after different treatments with and without laser irradiation of 2.0 W cm−2. Tumour weight of the sacrificed mice at the 21st day. Adapted with permission from [108]. Copyright 2019 American Chemical Society.

When speaking about Au NPs, photoporation should be mentioned as a valuable approach to deliver various bioactive molecules in a controlled manner. The mechanism of photoporation is based on the large absorption cross-section of Au NPs and their ability to raise temperature upon irradiation. After incubation of Au NPs with cells, Au NPs absorbed onto cell membranes can permeabilise membranes upon laser irradiation through thermally induced phenomena, local heating, acoustic waves, or formation of water vapour bubbles. Indeed, Xiong et al. [109] used 70 nm Au NPs, which were adsorbed onto cell plasma membrane after 30 min. Afterwards, compound of interest was added, and cells were irradiated in a controlled manner with laser in pulsed regime. The formation of vapour bubbles induced nanopores in cell plasma membrane and allowed compound of interest to diffuse inside cells. This approach enables selective delivery of bioactive molecules in a spatially resolved manner using Au NPs [109].

Overall, Au NPs are the most widely studied drug carriers because of low inherent toxicity, high surface area, and tunable stability. However, some issues still need to be addressed such as engineering of Au NP’s surface in order to improve Au NP’s bioavailability and immunogenicity. Moreover, Au NPs are not able to protect cargo from degradation in biological fluids, as bioactive compounds are usually attached to the NP’s surface, and to keep these molecules intact, additional organic coatings are required.

3.1.2 Silver NPs

Silver NPs are also a widely studied plasmonic material that can be used in biomedical applications. An advantage of Ag NPs is simple and low-cost chemical synthesis. Silver NPs can be obtained in various shapes, such as spherical, rod, octagonal, triangle, flower-like, etc. As a drawback, Ag NPs have low biocompatibility and, therefore, cytotoxicity to healthy cells. The smaller-sized Ag NPs cause enhanced cytotoxic effects compared to the larger counterparts due to the increased surface reactivity of NPs. The shape of Ag NPs also contributes to overall toxicity. As the size and shape of Ag NPs are directly related to the SPR, it is important to optimise the Ag NP morphology in order to achieve the sufficient biocompatibility and effective light sensitivity. As for Au NPs, the surface of Ag NPs can be coated with biopolymers, which can reduce their cytotoxicity. By varying the size and shape, it is possible to tune the plasmon peak of Ag NPs in the range of 393–738 nm and 500–1000 nm, which leads to strong visible and NIR scattering and absorption enabling employment Ag NPs in PTT and PDT [110].

Similar to Au NPs, Ag NPs are also good nanoheaters, and this can be effectively employed in PTT. In the recent work, Ag-based NPs were developed with the improved ability to absorb NIR irradiation. The developed systems could perform PTT therapy against A549 cells at a low irradiation power density (0.20 W cm−2) without any damage to the normal healthy cells and the surrounding tissues [111]. Another study reported that DOX-loaded Ag-based NPs demonstrated excellent chemophotothermal therapeutic efficiency and possessed NIR-laser–controlled drug-releasing functions [112].

Several researchers developed Ag NP-based PSs for PDT [113]. In general, to fabricate Ag NP-based PSs, bovine serum albumin (BSA) is used [113]. The functional groups of BSA (e.g. amino, imidazolyl, and thyol) interact with Ag ions forming stable Ag–BSA complexes. For example, Cui and colleagues synthesised Ag nanodots using BSA via biomineralisation method [114]. The diameter of Ag nanodots was 5.80 ± 0.5 nm, which corresponded to the most optimal photothermal properties. Later, Vankayala et al. [115] showed that singlet oxygen can be formed through direct sensitisation using Ag NPs without presence of any organic PSs under light irradiation.

Some studies reported that the fast biodegradation of Ag NPs on the cellular level and within a whole organism can significantly limit the application of Ag NPs for drug delivery applications. Motivated by the high plasmonic potential of Ag NPs, several strategies were suggested to preserve Ag nanostructure from the fast degradation [116]. These strategies mostly focus on surface modification of Ag NPs with an extra protecting layer of inorganic or organic coating, such as Si [117], graphene oxide (GO) [118], self-assembled monolayers of organic thiols [119], etc. Another approach to protect the unstable Ag NPs involves Au coating. As discussed above, the Au NPs possess own plasmonic resonances in combination with slow biodegradation in the biological environment. The result of Ag modification with Au nanostructures can lead to the enhanced plasmonic properties. Up to now, there are only few studies employing Ag–Au NPs as light-sensitive drug delivery carriers [120], [121]. Nevertheless, the PTT potential and fate in the biological environment of Ag-based NPs are not fully explored. Recently, Espinosa et al. [116] fabricated anisotropic hybrids composed of Ag NP cores coated with Au shell, which possessed efficient NIR absorption. For this synthesis, Au nanostars and Ag nanoplates were used (Figure 8A). The evaluation of the photothermal efficiency and intracellular biodegradation of the developed Ag–Au-based NPs was tested on the tissue-mimetic model in vivo. According to the obtained results, almost total tumour regression was observed on the example of mice model. Moreover, in the comparative study, it was demonstrated that the cellular heating was much more efficient in case of Ag–Au NPs compared to individual Ag NPs. This indicated the high potential of Ag–Au NPs in PTT due to improved heating properties of the developed carriers (Figure 8B). Thus, the surface modification of Ag NPs by Au coating provides new functional properties for developing efficient drug delivery platform.

Figure 8: Structure and photothermal efficiency of Ag, Au, and Ag–Au NPs.(A) Transmission electron microscopy (TEM) images and UV-visible/NIR spectra of Au NPs, Ag NPs, and Ag–Au NPs. (B) Infrared (IR) thermal images of mice injected with Ag NPs and Ag–Au NPs exposed under NIR-laser irradiation (680 nm, 1 min, 1 W cm−2) with corresponding analysis of average temperature after 1 min of 680 nm NIR-laser exposure and effect on tumours. Reprinted with permission from [116]. Copyright 2018 American Chemical Society.
Figure 8:

Structure and photothermal efficiency of Ag, Au, and Ag–Au NPs.

(A) Transmission electron microscopy (TEM) images and UV-visible/NIR spectra of Au NPs, Ag NPs, and Ag–Au NPs. (B) Infrared (IR) thermal images of mice injected with Ag NPs and Ag–Au NPs exposed under NIR-laser irradiation (680 nm, 1 min, 1 W cm−2) with corresponding analysis of average temperature after 1 min of 680 nm NIR-laser exposure and effect on tumours. Reprinted with permission from [116]. Copyright 2018 American Chemical Society.

3.2 Plain dielectric NPs

Despite wide applicability of plasmonic NPs as light-sensitive drug delivery carriers, Au and Ag NPs have finite conductivities at optical frequencies. This can lead to the inherent dissipation of the electromagnetic energy [122]. Moreover, fluorescent compounds placed near plasmonic NPs experience quenching effects. To overcome this, the additional spacer on plasmonic NP’s surface is needed to increase the distance between the fluorescent molecule and surface of NP [123]. Alternatively, the high refractive index dielectric NPs are under intensive investigation. Owing to their better resonant properties, dielectric NPs such as Si, Ge, and Fe2O3 can be more efficient heaters compared to plasmonic counterparts [26]. Therefore, resonant dielectric NPs have a great potential to be used as drug delivery carriers, enabling remote controlled activation of drugs under optical irradiation.

3.2.1 Si NPs

One of the most abundant light-sensitive materials that can be also used in nanomedicine is Si. The most common approach to fabricate crystalline Si NPs is laser ablation, resulting in an effective nanoheater with excellent resonant properties [26], [124]. Alternatively, electrochemical etching approach for the Si NP synthesis leads to the formation of porous Si NPs, which can be effectively loaded with drugs. Xia et al. [125] demonstrated an increased delivery of the commercially available drug DOX into cancer cells using light-sensitive porous Si NPs. These carriers were loaded with a transducer (indocyanine green), which can effectively convert light into heat. NIR irradiation of the internalised carriers resulted in the increased release of DOX compared to the pH-induced release in the acidic microenvironment of lysosomes [125]. Another study reported on the excellent heat generation abilities of porous Si NPs under NIR irradiation itself enabling PTT. In vivo animal tests on the Balb/c mice revealed murine colon carcinoma (CT-26) tumours were completely resorbed within 5 days after porous Si NP treatment in combination with NIR laser [126]. Apart from PTT, porous Si NPs can provide efficient PDT, which involves the conversion of ground-state molecular oxygen (3O2) to singlet oxygen (1O2) by energy transfer. As mentioned, the 1O2 is highly reactive and can cause the lethal damage of target cells [127]. When excited with visible light, the quantum-confined domains in porous Si NPs generate 1O2, and due to extremely long exciton lifetime, 1O2 generation is efficient [128]. Indeed, Xiao et al. [129] demonstrated an improved PDT from porous Si NPs prepared by electrochemically etched Si wafers in cancer cells (HeLa and NIH-3T3). According to the obtained data, 45% of cells were dead after PDT treatment compared to the less than 10% cytotoxicity in control experiments [129]. Si NPs can be also used as carriers for the PSs that are designed to generate ROS. Secret et al. [130] covalently linked porphyrin to the Si NPs in order to demonstrate imaging and PDT in vitro under two-photon excitation (TPE) conditions. The authors demonstrated that PDT occurred under TPE conditions, where Si NPs transferred light energy to porphyrin, resulting in MCF-7 breast cancer cell death [130]. Other PSs can be used to modify Si NPs for PDT. Knežević et al. [131] employed ruthenium (Ru) (II) complexes that can adsorb visible and UV to functionalise Si NPs. The surface of Si NPs was additionally linked with targeting moieties to enable selective targeting to tumour tissues. The developed systems demonstrated increased cytotoxicity under exposure to blue and NIR light [131]. The fluorescent small-sized (4 nm) Si quantum dots (QDs) were also applied as PSs (chlorin e6) carriers for PDT. Additionally Si QDs were modified with MnO2, which is known to produce oxygen in the reaction with the endogenous excess metabolites (H2O2) in acidic tumour microenvironment. The developed Si-based carriers enabled enhanced loading capacity with PSs and dual-imaging properties [fluorescence and magnetic resonance tomography, magnetic resonance imaging (MRI)], which resulted in significant inhibition of HeLa-bearing tumour in vivo [132].

3.2.2 Titanium dioxide NPs

Another light-responsive material that can be used as drug delivery carriers is TiO2. An important feature of TiO2 NPs is its photocatalytic properties, which can be activated under visible or UV light. This results in generation of cytotoxic ROS such as hydrogen peroxide and peroxy radicals, which can be harmful for targeted cells [133]. Unlike Si NPs, TiO2 NPs are mostly synthesised using chemical methods, such as solvothermal method, sol–gel methods, and so forth [134]. This allows precise controlling size and shape of TiO2 NPs, which is essential in biomedical applications. Liu et al. [135] probed photocatalytic activity of TiO2 NPs, which were attached onto the surface of TiO2 nanotubes in Streptococcus mutans and Porphyromonas gingivalis bacteria. The developed photosensitive material demonstrated improved antimicrobial properties under UV light due to decreased size of TiO2 NPs and therefore increased surface area and greater amount of released toxic ROS [135]. In another study, Yadav et al. [136] realised the combined cancer therapy using coral-shaped TiO2 NPs loaded with anticancer drug DOX. The increased surface area of TiO2 NPs resulted in increased payload of DOX onto the NPs. The developed delivery systems provided synergetic cytotoxic effect in cancer MCF7 cells from the released DOX (under biological stimuli inside cells) and generation of ROS from the TiO2 NPs (under UV-light irradiation) [136]. From clinical perspective, the photoactivation of TiO2 NPs with UV light has several limitations, such as low tissue penetration depth [137], and UV-mediated ROS production lasts for a short time and is not enough to provide a sustained and prolonged tumour destruction [138]. To address it, the drug delivery systems based on TiO2 NPs, which generate ROS under UV-light irradiation, can be loaded with visible light-responsive PSs. Indeed, TiO2 NPs were loaded with Ru complexes, which are already in clinical trials as anticancer agents [139]. Ruthenium complexes are able to generate 1O2 under visible light irradiation. The developed systems showed sensitivity to UV and visible (green) light as demonstrated in melanoma cells [140]. Another way to overcome the limitation of UV light is represented by the X-ray–responsive mesoporous TiO2 NPs that can be also employed for PDT. In the recent study, Guo et al. [141] designed an effective drug delivery platform that possessed combined cancer therapy (PDT and chemotherapy) based on mesoporous TiO2 NPs. These carriers were loaded with anticancer drug DOX. Additionally, surface of mesoporous TiO2 NPs was modified with targeting moieties [hyaluronic acid (HA) and cyclic pentapeptide]. The developed systems demonstrated an increased selectivity to CD44-overexpressing tumour cells and improved cytotoxicity [141]. Another approach to avoid irradiation with UV light of biological objects and induce generation of ROS is to combine TiO2 NPs with upconverting NPs (UCNPs) such as rare earth–based NPs [142], [143], [144]. As mentioned above, NIR light is able to penetrate deeper into cells and tissues and has minimal photodamage [145]. One of the main features of the UCNPs is their ability to absorb light energy in NIR region and convert it into UV light due to the unique ladder-like structure of energy levels of lanthanide ions [144]. Yin et al. [146] developed NaGdF4, Yb, Tm NPs as a core, with the TiO2 as a shell for NIR-mediated combined anticancer therapy. The chemotherapy was achieved by loading of the developed carriers with DOX, and PDT was provided by TiO2 shell, which expressed ROS under irradiation of whole system with NIR light, which was subsequently converted into UV light. As a result, the developed systems demonstrated an increased cancer cell (MDA-MB-231) death [146]. To shift the activation of TiO2 NPs into the visible light spectrum, TiO2 NPs can be grafted with some transition metal oxides such as iron oxide NPs (IONPs). Therefore, the nanocomposites (TiO2–IONPs) can be applied as visible light–sensitive PSs for PDT. Zhang et al. [147] developed TiO2–Fe3O4 complexes, which generated ROS under visible light. Additionally, these complexes were loaded with Fe2+-dependent drug artemisinin, and the surface was modified with HA to induce HA-mediated endocytosis. According to the obtained results, the developed systems induced an improved tumour inhibition in vitro and in vivo (Figure 9B) [147].

Figure 9: Example of light-treatment with inorganic NPs.(A) Schematic diagram of employment of silica NPs as light-sensitive drug carriers. (B) In vivo NIR imaging of tumour-bearing mice intravenous injected with free NIR-dye (IR783) solution (upper row) and IR783-loaded HA–TiO2–IONPs (lower row) at different times after injection. (C) Thermal images obtained with the IR camera in mouse, after intratumoural injection IONPs, in the left-hand tumour, and after 10-min application of AMF, NIR-laser irradiation, or DUAL (both effects). Reprinted with permission from [125], [147], [148]. Copyright 2015 John Wiley and Sons; Copyright 2017 Impact Journals; Copyright 2016 American Chemical Society.
Figure 9:

Example of light-treatment with inorganic NPs.

(A) Schematic diagram of employment of silica NPs as light-sensitive drug carriers. (B) In vivo NIR imaging of tumour-bearing mice intravenous injected with free NIR-dye (IR783) solution (upper row) and IR783-loaded HA–TiO2–IONPs (lower row) at different times after injection. (C) Thermal images obtained with the IR camera in mouse, after intratumoural injection IONPs, in the left-hand tumour, and after 10-min application of AMF, NIR-laser irradiation, or DUAL (both effects). Reprinted with permission from [125], [147], [148]. Copyright 2015 John Wiley and Sons; Copyright 2017 Impact Journals; Copyright 2016 American Chemical Society.

3.2.3 Iron oxide NPs

Magnetic IONPs are widely used particles (some of them are already clinically approved) in biology and medicine as MRI contrast agents, in magnetic hyperthermia applications, and others [149], [150], [151]. Despite the magnetic properties of IONCs, recent studies demonstrated that highly crystalline IONPs possess also thermal response on NIR light [152], which can be effectively used in PTT. The mechanism of photothermal energy conversion has not been fully understood. This phenomenon can be explained by high density of defects in the electronic structure of Fe3O4 NPs. These defects can be attributed to the mixed valences of neighbouring cation ions (Fe2+ and Fe3+) of the inverse spinel-structured Fe3O4 NPs [153]. Therefore, the narrowing of the band gap takes place with the consequence formation of oxygen vacancies. The heating then subsequently occurs under NIR light, when optically excited electrons exchange transitions from the different defects, which is related to the different band gap energies [154]. The highly crystalline IONPs are usually synthesised by thermal decomposition method with further coating of NPs with polymers to make them water-soluble, which is essential for biomedical applications. Chen et al. [152] reported on the concentration-dependent temperature increase up to 56°C [0.5 mg(Fe)/ml] when Fe3O4 NPs were irradiated with light. After intravenous administration into SUM-159 tumour-bearing mice, IONPs could effectively accumulate within the tumour (5.3% of injection dose) due to enhanced permeability and retention effect. After NIR irradiation of the tumour zone, complete tumour regression was observed [152]. In another study, Oh et al. [155] showed combined PTT and chemotherapy after administration of highly crystalline Fe3O4 NPs loaded with DOX. The enhanced cytotoxicity of human breast cancer cells (MDA-MB-231) was induced by synergetic effect from heat under NIR-laser irradiation and released DOX [155]. Shen et al. [156] developed temperature-responsive drug carriers based on IONPs. In this work, Fe3O4 NPs were coated with temperature-sensitive polymer, which was postloaded with DOX. The NIR irradiation of Fe3O4 induced increase in the temperature, which resulted in the polymer shrink with the subsequent release of DOX. These NIR-light–responsive drug delivery systems were tested in vitro and in vivo. The revealed data demonstrated tumour inhibition rate of up to 91.5% [156]. Apart from MRI, the additional functionalisation of IONPs with carbon can provide fluorescence properties enabling dual-modal imaging. Wang et al. [157] developed multifunctional carriers that comprised Fe3O4 as a core material and carbon as a shell material. These carriers exhibited NIR, upconverted, and wavelength-tunable fluorescence properties. The multimodal imaging and PTT were probed on mice bearing C6 glioblastoma and resulted in improved tumour therapy [157]. In another study, Wang et al. [158] combined magnetic and upconversion properties in one particulate system for PDT. Optically and magnetically responsive liquid marbles based on NaYF4 nanocrystals and doped with Yb3+/Er3+/Gd3+ were loaded with protoporphyrin IX to produce ROS. In the developed system, UCNP outer layer acted as a light transducer to introduce photons with higher energy that are necessary to activate PSs [158]. As mentioned above, highly crystalline IONPs are capable of being heated under alternating magnetic field and NIR irradiation. This feature of IONPs was examined by Espinosa et al. [148], where iron oxide nanocubes were injected into the tumour of 8-week-old female immunodeficient athymic nude NMRI mice. Laboratory animals were treated simultaneously with alternating magnetic field and NIR-laser irradiation. The revealed data showed the twofold to fivefold amplification of heat in the tumour area compared with magnetic stimulation alone. These dual-mode treatment resulted in complete tumour regression (Figure 9C) [148].

3.2.4 Lanthanide-doped UCNPs

Recently, UCNPs doped with lanthanide ions have emerged a great potential as drug delivery carriers due to possibility to control carrier fate inside cells and laboratory animals with optical microscopy (deep optical bioimaging). Indeed, UCNPs are able to absorb light with lower energies (NIR) and convert in high-energy radiation (UV/visible). Detailed explanation of this phenomenon can be found in the studies of Escudero et al. [144] and Bagheri et al. [159]. Therefore, remarkable advantages that include enhanced biological tissue penetration depths, less photodamage, and good biocompatibility make UCNPs preferable as light-responsive delivery carriers. Lanthanide-doped UCNPs of different sizes and shapes can be synthesised with wet chemical methods. These methods are generally based on precipitation reactions. In order to obtain monodisperse uniform NPs, the controlled release of cations and/or anions, as well as appropriate reaction kinetics, is required [142], [143].

Apart from bioimaging, UCNPs can be used as a source to induce drug release through photodegradation of PSs that should be incorporated into drug carrier. Indeed, Yao et al. [160] demonstrated light-induced release of anticancer drug from carriers based on UCNPs incorporated into AZO amphiphilic molecules, which are sensitive to NIR to UV/vis upconversion luminescence. They can transform the trans-isomer into the cis-isomer under UV light and conversely the cis-isomer into the trans-isomer under visible light. Authors probed release of DOX using NIR light (980 nm) on the model of MCF-7/ADR tumour borne by nude mice [160]. In another study, photocleavable moieties were conjugated to the surface of UCNPs to release chemotherapeutic upon light irradiation. For this, UCNPs were coated with o-phosphorylethanolamine ligands and coupled to an NB derivative of 5-fluorouracil. Upconverting NPs absorbed NIR light and emitted blue photoluminescence that was in resonance with the absorption band of NB derivative of 5-fluorouracil. This resulted in photocleavage with subsequent release of drug [161]. Another photocleavable delivery system was developed by Xing et al. [162]. Photoresponsive copolymer modified with folic acid was conjugated with UCNPs (NaYF4,Yb3+,Tm3+). The developed carriers were then exposed to NIR light with subsequent release of DOX in a sustained manner [162]. Jalani et al. [163] developed NIR-sensitive delivery systems based on UCNPs (LiYF4,Yb3+,Tm3+) coated with chitosan hydrogel cross-linked with a photocleavable cross-linker. Under 980 nm excitation, UV emission cleaved cross-linked and released loaded fluorescent BSA. The efficiency of the remote drug release was tested in vitro [163]. Upconverting NPs can be also used for multiple-drug loading. In the recent study, NaYbF4,Er UCNPs were used as core element for loading of several compounds: (i) antitumour drug DOX and (ii) tocopheryl polyethyleneglycol 1000 succinate to overcome multidrug resistance. Both compounds were liberated from the developed carriers in a prolonged manner in physiological conditions. Moreover, upconversion abilities of carriers and strong X-ray attenuation enabled dual-imaging modalities (luminescence and X-ray computed tomography), which made the developed carriers good candidates for imaging-guided cancer agents [164].

4 Light-responsive composite delivery systems: recent applications in nanomedicine

Recent developments in material science enable fabrication of light-sensitive drug delivery systems with complex architecture taking advantages from individual delivery system. The main goal of composite systems is to design materials that possess novel functional properties such as enhanced drug loading, prolonged circulation times in vivo, multimodal imaging, and others [22], [165]. In this section, we discuss the recent advances in the development and application of light-sensitive drug delivery systems based on polymers and on biological systems.

4.1 Composite delivery platforms based on organic NPs

Organic-based NPs are one of most attractive delivery systems, which can be easily modified with light-sensitive moieties. Light sensitivity of organic NP-based delivery systems is usually achieved through incorporation of specific chemical moieties or nanostructured materials into the polymer structure. There are several organic-based materials, including lipids and polymers, which are usually used for NP fabrication [166]. The advantages of these materials are determined by their reduced toxicity, easy synthesis, and suitability for the drug encapsulation [167]. In this part, we review the most extensively used light-sensitive composite carriers based on (4.1.1) amphiphilic macromolecules, (4.1.2) liposomes, and (4.1.3) polymeric particles.

4.1.1 Amphiphilic macromolecules (micelles)

Hydrophobic bioactive compounds can be encapsulated into the cavity of amphiphilic macromolecules, so-called micelles, due to the hydrophilic heads and hydrophobic tails. This leads to the formation of vesicle-like structure with hydrophobic cores [168], and on-demand delivery of drugs occurs by disrupting the hydrophilic–hydrophobic balance of the carriers. Micelles are usually synthesised out of biocompatible materials [169] with the incorporated PSs in its structure, which convert photoirradiation into a chemical signal. This conversion occurs through the different types of photoreactions such as isomerisation, rearrangement, cleavage, dimerisation, and heating, which are comprehensively described by Huang et al. [168] (Figure 10).

Figure 10: Schematic illustration of different release mechanisms of photo-responsive micelles.Reprinted with permission from [168]. Copyright 2014 Royal Society of Chemistry.
Figure 10:

Schematic illustration of different release mechanisms of photo-responsive micelles.

Reprinted with permission from [168]. Copyright 2014 Royal Society of Chemistry. Isomerisation

This process is accomplished by the structural changes in the micellar structure upon light irradiation. The typical photoisomerisation molecules, which are used to design polymeric micelles, include AZO, SP, and dithienylethene [157]. Molla et al. [170] fabricated AZO-containing photoisomerisation micelles using b-PEG-azoB-PLA. The developed systems allowed encapsulation of hydrophobic and hydrophilic molecules and their further release upon UV light [170]. Yuan et al. [171] also designed novel amphiphilic AZO-containing micelles for an effective light-induced destruction of micelles upon UV light (360 nm). Rearrangement

Upon light irradiation, the hydrophobic part of amphiphilic polymers converts into hydrophilic ones, which results in disassembly of polymeric micelles. An example of such molecule involved in this process is hydrophobic DNQ molecule, which can be changed into a hydrophilic 3-indenecarboxylic acid upon UV-light irradiation (Figure 10) [168]. Li et al. [172] developed novel DNQ-containing multifunctional light-responsive micelles, where DNQ groups can undergo Wolff rearrangement under UV/NIR light irradiation. Cleavage

This mechanism is based on the break of photocleavage groups located in the side chain of the micelles. Photocleavage reaction usually occurs using photochromic NB and coumarin-incorporated copolymers, which are employed in fabrication of light-responsive micelles. As an example, Ji et al. [173] showed photoresponsive poly(ethylene glycol)-block-poly(o-nitrobenzyl-l-glutamate) diblock copolymers. These copolymers can self-assemble into spherical micelles in aqueous solution. The obtained micelles demonstrated photoinduced transition of their morphology from spheres to cylinders under UV light. This phenomenon arises from the disruption of amphiphilicity induced by the cleavage of NB groups on the side chains [173]. Dimerisation

This mechanism of conformational changes in micellar structure is based on temperature-dependent photoinduced chemical bonds, which turn into the swollen state above the lower critical solution temperature (LCST). This results in the release of the pre-encapsulated drug. In the recent study, dual-responsive polymeric micelles were designed using photodimerisation process, which were capable of tuning the LCST of the polymer by attaching photosensitive moieties [174]. Heating

The heating process is associated with the conversion of light energy into heat. For this, the polymeric micelles are usually modified with inorganic particles (Au, Ag, and other), which possess NIR absorption. Ma et al. [175] reported on Au nanoshell nanomicelles with light-triggered release mechanism for PTT. Authors demonstrated an efficient NIR-induced stepwise release behaviour of DOX in vitro.

Therefore, by the application of each previously mentioned mechanism, one can control the stabilisation of the micellar structure, formation/disruption of micelles, or cross-linking.

4.1.2 Liposomes

The great step forward in preclinical and clinical studies was made in employment of liposomes as drug delivery carriers. The synthesis of liposomes is rather straightforward and can be achieved in size-controlled manner [176]. Liposomes usually comprised of naturally derived phospholipids, which can mimic the biological membranes [172]. Unlike micelles, hydrophilic and hydrophobic molecules can be loaded into the structure of liposomes because of its lipid bilayer structure. Regarding the synthesis and loading of liposomes with bioactive compounds, we refer to the following review articles [176], [177], [178].

Liposomes can be further engineered with functional moieties to be light-sensitive. The most common way to do this is to include PSs that transfer the light energy to molecular oxygen with further formation of ROS. Generally, PSs are hydrophobic; therefore, encapsulation of these compounds in the liposomes increases their solubility, as well as delivery to the targets [179]. The mechanisms of the light-triggered release of cargo from the liposomes can be different and are similar to the micelles. They mostly include photoisomerisation, photocleavage of lipids upon exposure to light-mediated formation of ROS, and photopolymerisation of lipids containing double or triple bonds. Another way to stimulate release of bioactive compounds from liposomes under light is incorporation of plasmonic nanostructures. Au NPs can be embedded into the liposomal structure either via thiol bonding or via electrostatic interactions, when mixing formed liposomes with Au NPs [180]. Under laser irradiation, because of the large temperature gradients, the surrounding medium produces bubbles, which induce rupture of liposomal structure with the consequent release of cargo into the surroundings [181]. However, Palankar et al. [182] demonstrated that apart from rupture transient pores in liposomal membrane can occur upon localised laser irradiation of Au NPs embedded into the structure of liposomes. This transient opening of liposomal membrane was monitored by ion current. Another mechanism of cargo release from liposomes modified with Au NPs is the thermic effects, which lead to the disintegration or melting of liposomal structure. For instance, Luo et al. [183] showed controlled release upon NIR irradiation from chitosan-coated oleic acid liposomes with outer layer of Au NPs. The mechanism of the release in this case was activation of the gel to liquid crystalline phase transition of the liposomes [183]. In another study, Lajunen et al. [184] demonstrated light-triggered release of fluorescence probes from liposomes that contained DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and modified either with Au nanorods or Au nanostars. The release of cargo was temperature dependent, proving that with the increase in temperature disintegration/melting rate of liposomes also increases [184]. Light-responsive liposomes can be additionally designed for addressable delivery of bioactive compounds. For this, apart from functionalisation with Au NPs (for light sensitivity), surface of liposomes can be modified with targeting molecules (antibodies, peptides). Indeed, Li et al. [185] conjugated human epidermal growth factor receptor 2 antibody to the surface of liposomes. As a result, authors observed approximately twofold increase in accumulation of carriers in vivo near the tumour region. The targeted delivery did not cause systemic toxicity after injection [185]. In another study, peptides were applied to improve cellular uptake of light-sensitive liposomes. For this, SPACE (skin-penetrating-and-cell-entering) peptides were conjugated onto the surface of liposomes, which were in turn modified with Au NPs. Fluorescence molecules and nucleic acids were delivered with the developed carrier systems, and the release was triggered upon NIR irradiation. The authors claimed the mechanism that induced the intracellular release was the vapour bubble formation, which led to the mechanical disruption of liposomes [186]. In the recent in vivo study, Li et al. [187] combined PDT and chemotherapy in one light-responsive liposomal carrier. For this, PSs (ICG-ODA) as well as DOX were incorporated into the structure of liposomes. The combined therapy led to the significant inhibition of tumour growth compared to the PDT or chemotherapy alone [187].

4.1.3 Polymers

Light-responsive polymeric delivery systems are under extensive investigation in the past decade. The basic principle of polymer carriers’ synthesis is comprehensively described in the recent review article [22] and based on so-called layer-by-layer technique, which consists of deposition of oppositely charged polymers onto the sacrificial template [188]. After the dissolution of template, hollow polymer capsules can be produced, which in turn can be loaded with various bioactive compounds, such as drugs [189], nucleic acids [190], macromolecules [9], fluorescent moieties [191], and other. Generally, to impart polymer capsules properties of light sensitivity, their shell should be modified with plasmonic/dielectric NPs. These NPs can be simply attached onto the polymeric shell via electrostatic interactions. The main mechanism of intracellular cargo release from the polymer capsules upon laser irradiation is the temperature increase, which leads to the change of the permeability of the polymer shell and thus the triggered release of cargo [9], [192], [193]. The detailed description of thermodynamics and temperature rise inside polymer capsules modified with plasmonic NPs is provided in the recent works [194], [195]. In the pioneer works, aggregated Au NPs were employed as heat agents embedded into the polymeric shell [196]. Indeed, Skirtach et al. [197] used Au and Au sulphide NPs for modification of polymer capsule wall. Activation of capsules was achieved using NIR-laser irradiation (830 nm) with the subsequence release of loaded fluorescent dye inside cancer cells [197]. Initial size of Au NPs was 15 nm in diameter, which has the maximum of plasmon band at approximately 520 nm. However, the aggregation of 15 nm NPs results in red shift and broadening of plasmon band of Au NPs [198], which is more sufficient for NIR-light irradiation. In this study, fluorescence molecules were delivered into cytosol of individual A549 cell upon laser irradiation. The similar Au NP aggregates, embedded into the polymeric shell of capsules, were used for the in vivo release of adenosine triphosphate in order to activate Wnt signalling pathway in the small freshwater polyp Hydra vulgaris (Figure 11A) [199]. In another study, polymer capsules with outer silica layer were also modified with Au NP aggregates in order to deliver pH-sensitive fluorescent molecules upon laser irradiation. Additional layer was introduced to encapsulate low-molecular-weight cargo, which was not able to diffuse through the dense Si layer [200]. The synthesis procedure of polymer capsules with embedded Au aggregates cannot be fully controlled, as the induction of NP aggregates is a statistical process. Therefore, in this case, it is not always possible to achieve a good match of applied wavelength of laser irradiation with the maximum peak of the plasmon band. For this reason, other types of heating agents were applied to achieve more efficient NP heating at the same laser power density. In the recent study, Au nanostars with the narrow size distribution and the absorption maximum at approximately 800 nm were employed to functionalise polymeric capsules. Kantner et al. [9] demonstrated successful cell-by-cell laser-induced staining, which were realised with polymer capsules modified with Au nanostars. As fluorescence markers, DAPI (4′,6-diamidino-2-phenylindole), propidium iodide, phalloidin conjugated with dye, and wheat germ agglutinin conjugated with dye were used. Authors additionally performed intracellular staining of cells with polymer capsules loaded with different cargoes upon laser irradiation (Figure 11B) [9]. As an alternative to Au nanostars, Au nanorods can be used as heating agents in the polymer capsules wall, as Au nanorods possess two plasmon peaks (transversal and longitudinal) [201]. One of these peaks is situated in the NIR region, which is suitable for biomedical applications. In the recent work, polymer capsules modified with Au nanorods were employed to functionalise surface of scaffolds, which can be used as a frame for the new tissue formation. Capsules were loaded with hormone (dexamethasone), which in combination with β-glycerophosphate stimulates differentiation of mesenchymal stem cells (MSCs) in osteogenic direction in vitro. Burst-like release of bioactive compounds onto the scaffolds surface was probed using NIR-laser irradiation [202]. In recent studies, Au nanorods were also employed to induce noninvasive release of drugs from polymer capsules in vivo. Upon NIR irradiation at used laser power density 0.54 J cm−1 DOX was released inside bearing nude mice [203], [204]. Unusual shape of light-sensitive drug carriers was reported by Wu et al. [205], where polymer tubes were functionalised with Au NPs. Theoretical and experimental study demonstrated the explosion of developed systems upon laser irradiation. Authors claimed that mechanism of tube explosion is based on rapid evaporation of water inside tubes caused by photothermal effects [205]. Not only plasmonic NPs can be employed as nanoheaters into the capsules wall. Kurapati and Raichur [206] embedded GO into polymer capsules, which possesses superior optical absorption and photothermal conversion. Thus, GO-modified polymer capsules were also developed to be NIR light–sensitive [206]. Diversity of polymer capsules enables encapsulation of different nanostructures at the same time. For instance, Yashchenok et al. [207] incorporated Au NPs and single-walled carbon nanotubes (SWCNs) into the polymer capsule wall in order to perform thermometry at the nanoscale. Au NPs were employed as nanoheaters, and SWCNs as Raman nanothermometers. The obtained results demonstrated that upon NIR light irradiation the temperature of composite polymer capsule destruction was 348 K for a power density of 31.8×104 W·cm−2 [207]. It is worth mentioning that incorporation of nanostructured materials (e.g. plasmonic NPs) into the polymer capsule shell enables not only noninvasive light-induced drug delivery but also imaging of intracellular environment with e.g. photoacoustic imaging technique. This results in theranostic platform for an effective therapy and diagnosis [208], [209].

Figure 11: Light-induced release of bioactive compounds from composite polymer carriers.(A) NIR-triggered activation of Wnt signalling pathway, (top) schematic diagram of experimental procedure, (left bottom) untreated animal, irradiated, (right bottom) animal treated with light-sensitive capsules and irradiated. Scale bars correspond to 500 μm. (B) Fluorescence and overlay (fluorescence+bright field channel) images of cells incubated with light-sensitive capsules. In (2–4), images are shown after three illumination steps. The scale bar corresponds to 20 μm. Reprinted from [9], [199]. Copyright 2016 American Chemical Society; Copyright 2018 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Figure 11:

Light-induced release of bioactive compounds from composite polymer carriers.

(A) NIR-triggered activation of Wnt signalling pathway, (top) schematic diagram of experimental procedure, (left bottom) untreated animal, irradiated, (right bottom) animal treated with light-sensitive capsules and irradiated. Scale bars correspond to 500 μm. (B) Fluorescence and overlay (fluorescence+bright field channel) images of cells incubated with light-sensitive capsules. In (2–4), images are shown after three illumination steps. The scale bar corresponds to 20 μm. Reprinted from [9], [199]. Copyright 2016 American Chemical Society; Copyright 2018 by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

4.2 Composite light-sensitive bioinspired delivery platforms

Most of organic and inorganic drug carriers, which are responsive to light, do not reach clinical trials. Only some of them are officially approved by the Food and Drug Administration [24]. The main barrier between the development of the light-sensitive drug carriers and their translation into clinics is attributed to the ability of the organism to recognise and remove foreign biomaterial. Therefore, the novel design of the drug delivery platforms is required to protect the carriers from the cell immune system [24], [210]. Therefore, biomimetic-based approaches that attempt to imitate the real biological situation in cells and tissues are of great interest. Such delivery systems transfer specific biological functionalities to synthetic drug carriers [24], [211]. Light-responsive biological (bioinspired) drug carriers can be considered as one of the most attractive delivery systems, replicating features that are similar to the biological objects [212]. The main advantages of bioinspired carriers are their ability to interact with specific sites of the body, their cell/tissue entering mechanisms, capability to avoid the immune responses, and prolonged circulation times in biological fluids [212], [213]. Light-responsive bioinspired carriers include the use of (4.2.1) mammalian cells, (4.2.2) bacteria, and (4.2.3) viruses (Figure 12).

Figure 12: Schematic illustration of implementation of bioinspired light-sensitive carriers.
Figure 12:

Schematic illustration of implementation of bioinspired light-sensitive carriers.

4.2.1 Cell-based drug carriers

Cell-based delivery systems attract tremendous attention because of the treatment ability of various diseases including oncology, diabetes, hemophilia, and cardiomyopathy. At the same time, cell engineering in combination with the designed nanoparticles and microparticles enables fabrication of biomimetic light-responsive platforms for the delivery of different bioactive compounds. Among different therapeutically relevant cells, RBCs, immune cells, SCs are widely employed as bioinspired drug delivery platforms and will be further discussed in details [214], [215]. Red blood cells

After in vivo administration, therapeutic formulations rely predominantly on the vascular system for the effective biodistribution and accumulation at the target site. RBCs or erythrocytes are the most abundant cells in the human blood system (approximately 99% of the total amount of blood cells). RBCs have an average lifespan of 120 days without being cleared by macrophages. In comparison, the lifespan of the PEGylated drug carriers, which is known to have prolonged circulation times, is approximately 10 h [216], [217]. RBCs have a diameter of 7–8 μm and an average volume of 90 fl oz; they lack a nucleus and can change their shape to fit through the blood vessels. Erythrocytes confine the unintended extravasation and extend the circulation time in the body, which in combination with high cargo loading capacity, excellent biocompatibility, and low immunogenicity makes them as excellent drug delivery systems [216], [218]. RBCs can be reversibly opened under hypotonic conditions to inject exogenous compounds upon resealing of membrane pores. Another method of RBC drug loading involves the attachment of drug molecules to the cell surface through biotin, affinity ligands, or nonspecific interactions such as van der Waals forces, hydrogen bonding, or electrostatic or hydrophobic forces [215], [216].

For the controlled therapy, the RBC membranes can be modified with light-responsible agents. Delcea et al. [219] reported on RBCs modified with aggregates of Au NPs with high NIR absorbance. The attachment of Au NPs to RBCs was verified with Raman spectroscopy. The mechanism of the drug release was the heating of the lipid bilayer and/or transmembrane proteins. The developed system demonstrated improved drug release from the RBC biocarriers upon NIR-laser irradiation. Gao et al. [220] developed a cell-based delivery system composed of RBCs modified with the PS chlorin e6, which was incorporated into the membrane of erythrocytes upon mixing without disturbing the membrane structure. To achieve chemotherapeutic effect, DOX was introduced into the inner aqueous cavities of RBCs. The mechanism of photoinduced release of the drug was the break of cells’ membrane upon laser irradiation. The resulted drug delivery platform possessed synergetic therapeutic effect from generation of ROS (PDT) and chemotherapy upon exposure to the 660-nm light [220]. However, the RBC-based delivery systems have some limitations. The main disadvantage of the RBC implementation as drug carriers is their ex vivo modifications including hemotransfusion (transferring of blood or blood products intravenously), which limit their wide application. Another challenge of the RBC employment as delivery carriers is their loading with drugs, which can sometimes lead to the change of their structural and functional properties [216], [221]. Immune cells

Another promising type of cell-based drug delivery platform is immune cells or white blood cells (WBCs). The main feature of immune cells is the response to injuries. Damage tissues produce signalling molecules such as chemokines and cytokines, which attract immune cells that infiltrate into the damage sites, e.g. infection, inflammation, tissue injury, and cancer. Immune cells are capable of deep penetration into tissues compared to the conventional drugs [222], [223]. The size of WBCs varies from 7 μm (small lymphocytes) to 20 μm (monocyte) [224]. The WBCs derived from the body can be loaded in vitro with drugs without any apparent toxic effects and reinjected into the blood. Immune cells can be also modified with light-responsive agents for the noninvasive therapy of cancer [225], [226].

There are different types of WBCs (leukocytes) such as neutrophils, lymphocytes, and macrophages, which can be employed as cell-based drug delivery vehicles to mediate the delivery across the biological barriers. The modification of leukocytes with light-responsive agents enables the release the drugs to targeted sites upon laser irradiation. The key feature of leukocytes is their migration abilities towards inflammatory area and adhesion to endothelial wall tissues with tumour cells [212], [223], [227].

Neutrophils present the most abundant leukocyte in the human organism. They are the first cell type that appears at the damage sites and secrete cytokines to recruit other cells. Neutrophils have a short lifespan (approximately 5 days) in blood circulation and only a few hours after isolation from the body. On the one hand, their shorter lifespan limits neutrophil applications in drug delivery. However, their ability to be instantly recruited makes these cells attractive as drug vehicles [228]. Chu et al. [229] showed a drug delivery system based on fluorescent polystyrene NPs coated with anti-CD11b antibodies via biotin–neutravidin binding that target activated neutrophils. The migration of the developed platforms was induced by neutrophils with the following infiltration into tumour. To achieve PTT, neutrophils were decorated with Au NPs. The neutrophil uptake of NPs did not alter neutrophil activation and transmigration. The developed cell-based delivery system possessed features of combined PTT and PDT under 660 nm light [229].

Lymphocytes are primarily presented in the blood circulation and lymphoid organs (spleen, tonsils, lymph nodes). T and B cells are the main types of lymphocytes that are responsible for the adaptive immune system. T cells play a key role in cell-mediated immunity, whereas B cells are involved in humoural immunity. Both T and B cells present multiple functions in the organism and are involved in numerous processes such as detecting antigens, infiltrating damage tissues, and attacking abnormal cells [228]. The advantages of drug delivery by lymphocytes are their migration and accumulation inside the tumour areas. Moreover, such delivery system can detect and attack metastases that are hard to be diagnosed [215], [230]. Another type of lymphocytes, so-called NK cells, can more effectively attack infections and tumours [231]. They constitute approximately 10% of circulating lymphocytes and, unlike T lymphocytes, can eliminate target cells spontaneously without antigen-specific stimulation. Deng et al. [232] designed NK cell membranes decorated with NPs loaded with PSs. Photosensitizers [4,4′,4″,4‴-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid)] loaded into NK carriers enhanced NK cell immunotherapy and eradicated primary tumour cells through PDT [232].

Macrophages are mononuclear phagocytes that play a crucial role in eliminating pathogens and cellular debris. They can act as antigen-presenting cells and secrete various types of bioactive compounds to communicate with other immune cells [233]. Macrophages can engulf different molecules based on specific receptor interactions and their phagocytic capabilities [216]. Choi et al. [234] used macrophages to deliver Au nanoshells to the tumour hypoxic regions. After application of NIR light, cancer cells were destroyed within these tumour areas [234]. Other works demonstrated the migratory potential of drug-loaded macrophages in glioma both in vitro (tumour spheroids) and in vivo (mice models) [225], [235]. In the first work, Au nanoshells were used to modify macrophages and to suppress tumour spheroid growth upon NIR-laser irradiation. As the NPs are not able to cross the patent blood-brain barrier, macrophages can overcome this limitation. In the second work, authors demonstrated that macrophages readily traverse the blood-brain barrier, where residual glioma cells were found after surgery. Macrophages have the potential to increase NP delivery to different types of tumours including glioblastoma multiforme [225].

Overall, immune cells have a quick response and intrinsic homing properties with respect to damaged tissues and tumours. The sensitive detection of target sites and abilities to overcome biological barriers can facilitate drug delivery. However, among the available immune cells, leukocytes are difficult to cultivate and handle. They have relatively short lifespans, which hinder the manipulation processes for the drug loading [215]. Stem cells

Stem cells, in particular, MSCs, have attracted great interest because of their properties of intrinsic inflammation and tumour tropism. Because of the property of active migration towards tumours and penetration tumours, SCs are applied as bioinspired carriers with wide possibilities of drug loading such as apoptosis-inducing and antiangiogenic factors, cytotoxic chemotherapy, immunomodulatory agents, oncolytic viruses, drug-loaded microparticles and NPs, and tissue- or tumour-specific prodrugs [236], [237]. The cytokine release in the tumour stroma and the interaction of MSCs with cytokine and chemokine receptors present on the cell surfaces are mainly responsible for their migration towards tumours [238], [239]. Xu et al. [240] developed a synergistic treatment platform based on MSCs loaded with light-responsive plasmonic–magnetic hybrid NPs containing lipids, DOX, Au nanorods, and Fe3O4 nanocluster (MSCs–LDGI) for photoacoustic imaging, targeted PTT, and chemotherapy against triple-negative breast cancer. Mesenchymal stem cells–LDGI maintained good bioactivity to migrate towards cancer cells both in vitro and in vivo. The disassembly of the developed nanostructures with the subsequence drug release was probed upon light irradiation. In vitro and in vivo experiments showed that the MSCs–LDGI efficiently inhibited cancer cell growth and implemented good therapeutic effects via both local and intravenous injection routes [240]. In recent work, Muslimov et al. [241] developed the light-sensitive MSCs-based delivery system. Antitumour drug was encapsulated into composite capsules functionalised with Au nanorods. In turn, capsules were used to modify MSCs. Upon NIR-laser irradiation, composite capsules were disintegrated because of the thermal effects. The efficiency of the developed MSC-based delivery system was probed on model of melanoma spheroids. NIR–triggered drug release indicated the higher antitumour efficiency of bioinspired platform compared to the free drug (Figure 13) [241].

Figure 13: Addressable drug delivery using light-sensitive MSCs-based delivery platform.(A) Schematic diagram of the experimental procedure. (B) Confocal microscopy images of tumour spheroids with and without NIR-laser irradiation incubated with (left) free antitumour drug, (middle) polymer light-sensitive particles loaded with antitumour drug, (right) MSC-modified polymer light-sensitive particles loaded with antitumour drug. Living cells were stained with calcein AM (green); nuclei of dead cells were stained with propidium iodide (red). Scale bars correspond to 100 μm. Reprinted with permission from [241]. Copyright 2019 Royal Society of Chemistry.
Figure 13:

Addressable drug delivery using light-sensitive MSCs-based delivery platform.

(A) Schematic diagram of the experimental procedure. (B) Confocal microscopy images of tumour spheroids with and without NIR-laser irradiation incubated with (left) free antitumour drug, (middle) polymer light-sensitive particles loaded with antitumour drug, (right) MSC-modified polymer light-sensitive particles loaded with antitumour drug. Living cells were stained with calcein AM (green); nuclei of dead cells were stained with propidium iodide (red). Scale bars correspond to 100 μm. Reprinted with permission from [241]. Copyright 2019 Royal Society of Chemistry.

4.2.2 Bacteria-based drug carriers

Pathogens such as bacteria have developed unique strategies to avoid the immune response and induce favourable interactions with host target cells [71]. Bacteria can penetrate even nonphagocytic mammalian cells by specific surface molecules. Bacteria can successfully grow in tumour sites because of the impaired blood circulation and large necrosis area of solid tumours [242]. Bacteria have the full complement of ribonucleic acid (RNA) polymerases, and they are able to deliver or produce these proteins at the target site [243]. Bacteria-based engineering strategies for drug delivery include recombinant bacteria, microbots, and bacterial ghosts.

Recombinant bacteria are carriers that are genetically modified by the expression systems encoding proteins and antigens [71]. Hosseinidoust et al. [243] developed an optogenetic and light-sensitive delivery system based on recombinant bacteria using an engineered bacterial light-oxygen-voltage protein that bonded DNA when illuminated with blue light. The system showed a high dynamic range of protein expression, rapid activation, and deactivation kinetics in vitro. The recombinant bacteria were employed to activate transcription in different eukaryotic systems (mammalian cell lines and zebrafish embryos) upon stimulation with blue light [243], [244], [245].

Microbots are bacteria that transfer drug agents attached onto their surface. Microbots do not require genetic modifications for the drug delivery. This approach employs the invasive properties of bacteria that are able to migrate into the tumours, which cannot be reached by conventional chemotherapy. The genetically unmodified bacteria can be conjugated with the NPs via biotin–streptavidin interactions or different chemical-labile linkers [246] (Figure 14A). Luo et al. [248] reported on the bacteria-mediated targeting hypoxia (oxygen reduced tumour) to offer the expandable spectra for cancer theranostics. The authors developed two drug delivery approaches including a cargo-carrying method and an antibody-directed method. These approaches allowed delivering upconversion nanorods for imaging and Au nanorods for PTT ablation upon NIR light excitation. The antibody-directed strategy demonstrated more effective treatment giving high-level bioimaging, longer retention period, and effective therapy of tumours [248].

Figure 14: Drug delivery using light-sensitive bacteria and viruses.(A) Schematic diagram of the bacterial microbots to load, deliver, and release active drugs for cancer therapy. (B) Cellular uptake mechanisms of viruses. Reprinted with permission from [246], [247]. Copyright 2018 Elsevier, Copyright 2017 Ivyspring.
Figure 14:

Drug delivery using light-sensitive bacteria and viruses.

(A) Schematic diagram of the bacterial microbots to load, deliver, and release active drugs for cancer therapy. (B) Cellular uptake mechanisms of viruses. Reprinted with permission from [246], [247]. Copyright 2018 Elsevier, Copyright 2017 Ivyspring.

Bacterial ghosts are empty cell envelopes of Gram-negative bacteria. In bacterial ghosts, plasma components with all genetic material are removed. They can be produced by controlled expression of the cloned lysis gene E from bacteriophage species, generating a lysis tunnel structure within the envelope of the living bacteria [249]. Bacterial ghosts keep cellular morphology similar to native bacteria, where the entire surface structures including adhesins, membrane proteins, lipopolysaccharides, and the peptidoglycan layer are preserved [250]. Drug carriers can be also obtained from bacterial outer membrane vesicles [251]. Gujrati et al. [252] developed bioengineered bacteria vesicles for both contrast enhancement in photoacoustic imaging and PTT. These bacterial vesicles demonstrated several advantages, as they possessed a rigid membrane with high stability and reduced leakage in the systemic circulation. The authors obtained bacteria vesicles with encapsulated melanin using an Escherichia coli strain. This bacterial strain was previously modified to be less endotoxic and to overexpress tyrosinase, which produces melanin that is passively incorporated into the cytosol and membrane of vesicles. The obtained results indicated that upon NIR light irradiation bacteria vesicles with melanin generated strong optoacoustic signals appropriate for bioimaging applications. In addition, the developed bacteria vesicles released heat upon NIR-laser irradiation, which resulted in photothermal effects both in vitro and in vivo [252].

4.2.3 Viruses-based drug carriers

Viruses are infectious microorganisms consisting of nucleic acids in a protein coating (capsid). Viruses possess several properties that can be effectively used for the development of bioinspired drug delivery carriers. As previously discussed, an ideal drug carrier should avoid host cell immune response, and target cells of interest with further release of the loaded cargo into the cytoplasm. These processes fully describe the early stage of the virus infection. Viruses naturally evolved to deliver genetic material into target cells. Moreover, viruses can evade host body protection and reach specific tissues or cells. Once viruses are taken up by host cells, they colonise the intracellular space and release the DNA or RNA to replicate themselves (Figure 14B). Viruses utilise their protein components to overcome cellular barriers. Drug delivery technologies can learn a great deal from viruses [247].

Viral vectors were one of the first systems to deliver specific genes. Such vectors included inactivated adenoviruses, adeno-associated viruses, retroviruses, and lentiviruses. Viral vectors had to transfer only the required genes to the target cells. For this, they were modified to minimise the risk of their expansion. The process of inactivation involved the deletion of a part of the viral genome critical for the viral replication. Such vectors can infect cells but are not able to produce the new virions without a helper virus [24], [253], [254]. Viral vectors can be also modified for an effective PTT. Everts et al. [255] covalently bound adenoviral vectors with Au NPs, so that the developed engineered systems successfully retargeted a tumour-associated carcinoembryonic antigen without losing the viral vector infectivity. Jung et al. [256] explored the combination of oncolytic adenovirus and Au nanorod–mediated hyperthermia to improve antitumour effect against head and neck cancer. Exposure of the virus–Au nanorods system to light improved endocytosis of oncolytic adenovirus, transgene expression, and subsequent cytolysis of head and neck cancer cells [256]. In another study, Pandori et al. developed light-responsive viruses-based delivery system by conjugating photocleavable moieties to viral components, which possessed no infectivity. The exposure of the modified viruses to the UV light induced the modification of photocleavable moieties, which resulted in restoration of the virus infectivity [257].

5 Conclusion and outlook

Light-responsive nanostructured materials are successfully employed in the field of nanomedicine for the delivery of drugs. Given the nature of particles, different mechanisms can be employed for the release of bioactive compounds. In this review article, we considered two major groups of light-sensitive carriers, plain and composite. Each group consisted of either plasmonics and dielectric NPs, or organic and bioinspired drug carriers.

5.1 Plasmonic NPs

As discussed above, plasmonic NPs (Au and Ag) and their combination open up a great potential for the development of optically responsive drug delivery platforms. The rational design and fabrication of anisotropic Ag and Au NPs with different morphology (e.g. shape and size) provide various strategies for light-induced cancer treatment. The fundamental, careful, and accurate investigations of Ag/Au NP morphology on cellular toxicity and behaviour are highly demanded. Also, chemical stability of Ag or Au NPs in biological fluids is required. The surface coating of Au/Ag NPs with biopolymers or proteins significantly increases their application in medicine for drug delivery. At present, the main stream in application of plasmonic NPs as drug carriers is devoted to the development of combinational Au- or Ag-based nanocarriers.

5.2 Dielectric NPs

Compared to plasmonic NPs, dielectric NPs are not widely used as drug delivery carriers. However, similar to plasmonic NPs, Si NPs are excellent nanoheaters, and based on their size and shape, they can be excited in the wide-range spectrum [26]. This feature of Si NPs in combination with an effective field enhancement [123] can be successfully used in PTT of malignant neoplasms with simultaneous visualisation of NP biodistribution in vivo with optical fluorescence microscopy. For this, Si NPs should be modified with fluorescence molecules, which requires additional synthetic steps. Bioimaging of TiO2 NPs is also not straightforward, and it requires additional surface modification. With the progress in material science, the limitations of the employment of UV light for biological tissues to induce generation of ROS can be overcome by the doping/modification of TiO2 NPs with other materials (rare earth, magnetic); therefore, irradiation wavelength can be shifted to areas with lower energies. Iron oxide NPs can also act as nanoheaters, which in combination with external alternating magnetic field (AMF) significantly improves PTT providing synergetic effect from magnetic field and light energy. Upconverting NPs are currently under an extensive investigation, as they are nonphototoxic with wide surface functionalisation possibilities. However, there are some limitations that still need to be improved. First is the relatively low quantum yield of the converted light, which requires higher power excitation. Moreover, stability of lanthanide dopants, as well as photoresponsive moieties, needs to be further investigated prior to in vivo applications. All discussed types of dielectric NPs are promising drug delivery carriers with certain benefits and drawbacks; however, IONPs are closer to the real clinical applications, as this material is clinically approved, and clinical trials on humans were already conducted [258], [259].

5.3 Composite delivery systems based on organic NPs

To combine therapeutic and diagnostic properties in one carrier, composite delivery systems are under intensive investigation. Indeed, composite organic NPs are often utilised to optimise delivery of bioactive compounds, to prolong circulation time, to enable bioimaging, and to provide combined therapy (e.g. chemotherapy and PDT). Easy modification of micelles and liposomes with light-sensitive moieties enables controllable drug release upon laser irradiation. However, prior to complete implementation of micelles and liposomes in clinics, some issues should be addressed. First, biodegradability and biocompatibility of these carriers, as well as their products after photoreaction, should be improved. Another issue that needs to be solved is NIR-sensitive micelles and liposomes that are of urgent need. For this, multiphoton-reaction mechanisms are required, which will result in a wider application of micelles and liposomes in nanomedicine. Despite biocompatibility, easy synthesis, wide functionalisation possibilities, polymer capsules are also still not introduced into clinics because of the short circulation time and large size, which are not always optimal for in vivo applications. Therefore, light-sensitive bioinspired drug delivery platforms can help to overcome the abovementioned limitations of composite carriers based on organic polymers.

5.4 Bioinspired delivery platforms

These delivery systems based on cells, bacteria, or viruses loaded with the pharmaceuticals (or contrast agents for imaging) retain their biological functions: their distribution will mimic their natural movement to the disease areas. However, despite all the advantages of light-responsive bioinspired delivery platforms, large size of cells can be a significant physical barrier that prevents complete dispersion of these cells in small vessels of the vascular network. This fact limits access of exogenously introduced cells to many target sites, including tumour tissues [236], [240]. Despite the advantages of discussed bacteria-based drug systems, there are several challenges in their development and utilisation. First, the toxicity of bacterial drug carriers still remains a serious limitation. The bacteria-induced toxicity at the therapeutic efficacy dose can cause a rapid bacteria clearance or autoimmune response. The second challenge is drug loading. Loading of agents with average sizes of hundreds nanometers affects the motion of bacteria, diffusion from blood vessels, and migration into tumours. The third concern is the lack of tissue distribution profile of bacterial carriers. Moreover, anaerobic bacteria can selectively infect and break hypoxic regions but leave a well-oxygenated outer rim of the tumours that can lead to tumour regrowth [242], [246]. The viruses-based delivery systems also suffer from limitations such as a potential immunogenicity, pathogenicity, and the broad tropism of viruses.

5.5 Future perspectives

Nevertheless, it seems that the development of composite light-responsive carriers consisting of individual parts of organic and inorganic nature is the direction of future research in the field of nanomedicine. This will make it possible to take advantage of each component of the developed smart delivery platform and enable, e.g. enhanced loading with drugs, multimodal imaging, targeted properties, prolonged circulation times in blood, and so forth. Moreover, the application of light-sensitive composite carriers will be able to provide noninvasive activation of therapeutics in combination with PTT at the target sites in vivo.



singlet oxygen


molecular oxygen

Ag NPs

silver nanoparticles

Au NPs

gold nanoparticles




bovine serum albumin


murine colon carcinoma


continuous wave




deoxyribonucleic acid










graphene oxide


hyaluronic acid


iron oxide nanoparticles




lower critical solution temperature


amphiphilic macromolecules


magnetic resonance imaging


mesenchymal stem cells





NK cells

natural killer cells




photodynamic therapy


polyethylene glycol




photothermal therapy


quantum dots


red blood cells


ribonucleic acids


reactive oxygen species


room temperature




stem cells


surface enhanced Raman spectroscopy

Si NPs

silicon-based NPs






surface plasmon resonance


single-walled carbon nanotubes


transmission electron microscopy

TiO2 NPs

titanium dioxide nanoparticles


two-photon excitation


upconverting nanoparticles




white blood cells


The part of this work related to the physical principles of light interaction with NPs was supported by the Ministry of Education and Science of Russian Federation (project 2.2267.2017/4.6). The part of this work related to the chemical mechanisms of light interaction with delivery carriers was supported by the Russian Foundation for Basic Research (project 18-32-20089). The part of the work about bioinspired delivery platforms was supported by a grant from the Russian Science Foundation (project 19-75-10008). M.V.Z. thanks the President’s Scholarship SP-1576.2018.4.


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Received: 2019-10-15
Revised: 2019-11-24
Accepted: 2019-12-10
Published Online: 2020-01-09

©2020 Mikhail V. Zyuzin et al., published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 Public License.

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