Nanotechnology and nanobiotechnology have gained much momentum in recent years. The term nanotechnology mostly refers to the fabrication of new materials with at least one dimension in a size range between 1 and 100 nanometres (nm), that is one billionth (or 10–9) of a meter. It is already used in a variety of products across various industries such as agriculture, cosmetics, electronics, textiles, recycling, energy, chemicals, as well as healthcare. Nanobiotechnology is defined by science’s growing ability to work at the molecular level, atom by atom, combining biological materials and the rules of physics, chemistry, and genetics to fabricate synthetic structures such as biosensors, nanosized microchips and even tissue analogs for growing skin, bones, muscle, and other organs of the body [1, 2]. The development of a wide range of nanoscale technologies currently enables new scientific approaches in disease diagnosis, treatment, monitoring and prevention. These technological innovations of nanotechnology within medicine are referred to as “nanomedicine” by the National Institutes of Health in USA .
Nanoparticles with ~100 nm have been widely used to improve the drug accumulation, internalization and therapeutic efficacy. As shown in Figure 1, the physicochemical and biological properties of the nanoparticles can also be finely adjusted by tailoring their chemical properties, sizes, shapes, structures, morphologies, and surface properties . The conjugation chemistry strategy of the drug molecule and surface modification is very important for drug delivery. Drug molecules may be adsorbed or attached covalently to the surface of nanocarrier. Besides, the interior core can also entrap drug molecules. The surface coating of nanocarriers with molecules, for instance, hydrophilic and/or hydrophobic polymers [e.g. polyethylene glycol (PEG) and poly(ε-caprolactone) (PCL)] or surface modifications with targeting ligands such as antibodies, aptamers, peptides or small molecules determine the mechanism of uptake for the nanocarriers by the cells. Nanoparticles can be modified by active and passive targeting to enhance the concentration of the drug molecule inside the specific area. Once the drug loaded nanocarriers reach the diseased tissue, the therapeutic agent is released through changes in physiological environment such as temperature, pH, osmolarity, or via an enzymatic activity .
Delivering of therapeutic compound to the target site is a major problem in the treatment of many diseases. A conventional application of drugs may have limited effectiveness, poor biodistribution and lack of selectivity . It has been established that nanocarriers can become concentrated preferentially in tumors or at inflammatory sites, and this is due to antigen sampling by virtue of the enhanced permeability and retention (EPR) effect of the vasculature . The current treatment options for most solid tumors are surgical intervention combined with chemotherapy or radiation therapy. However, today’s therapy in its very general and systemic application form damages healthy tissues and causes unwarranted toxicity to the patient [8, 9]. In recent years, nanoparticle based delivery systems have been exploited in various medical applications. Their attractive features are that they are made from biocompatible, well-characterized and easily functionalized materials . On the basis of these materials’ properties, nanomaterials exhibit a highly differential targeting and uptake efficiency in a cell- or tissue-specific manner. Furthermore, the drug molecule on the nanocarrier is protected from harsh conditions before it can reach the target. In contrast to conventional drug delivery, using nanomaterials a prolonged and controlled drug release can be achieved [11, 12]. Thus, nanomedicine represents an innovative field with enormous potential for treatment by combination of smart nanoparticles with small molecules carrying a wide range of functions.
Liposomes, polymeric nanoparticles, dendrimers, metal nanoparticles, and quantum dots are versatile molecules with a variety of biomedical uses, such as diagnostic assays [13, 14], radiotherapy enhancement [15, 16], as well as drug and gene delivery [17, 18]. Liposomes are artificially prepared vesicles composed of lipid bilayers. They are biocompatible and their size can be varied in broad ranges (50–500 nm). Both hydrophobic and hydrophilic drugs can be encapsulated in the hydrophobic lipid bilayer and hydrophilic aqueous core, respectively . An alternative approach to liposome is the use of niosomes which are composed mainly of non-ionic surfactants . Polymeric nanoparticles made of natural polymers (e.g. chitosan, collagen) and synthetic polymers [e.g. poly(lactide-coglycolide) (PLGA) and (PCL)] are colloidal solid platforms for controlled and sustained release of drug molecules and gene delivery. Natural polymers are less toxic and more biodegradable than synthetic polymers. The majority of these compounds are synthesized through a spontaneous self-assembly process using block polymers of two or more polymeric chains with different hydrophilicity . Dendrimers are synthesized from branched monomers by stepwise a repetitive reaction sequence and it is possible to control of their structural and chemical properties, including size, shape and number of branches. Poly(amidoamine) (PAMAM) and poly-L-lysine are largely used dendrimers in drug and gene delivery. Low polydispersity and biocompatibility are the main problems using these nanoparticles as a tool in nanomedicine . Semiconductor quantum dots are utilized as fluorescent probes for imaging and labeling of the molecules due to their unique photophysical characteristics such as broad excitation and tunable emission. Nevertheless, the main components of the quantum dots are hazardous heavy metals such as cadmium and selenium, which are highly toxic in living organisms. The heavy metal core can be coated with shell and a further surface coating can be carried out to make quantum dot more biocompatible . Researchers are interested to study tracking of these nanoparticles and to investigate their physical and biological properties for their cellular uptake and delivery.
Physical properties and applications of nanoparticle based drug carriers
Size and shape
The physicochemical properties of nanoparticles, size, shape, and surface chemistry play a critical role in determining tissue penetration, cellular delivery, and therapeutic efficacy. Nanoparticles with varying size and shape are taken up to the cells at different rates. Cell membrane is composed of lipids, carbohydrates and proteins that mediate cellular functions. The nanoparticle surface can interact with these molecules and may activate the cell’s uptake mechanisms. Nanoparticle cell interactions can be remarkably different from that of small or large sized particles at nanoscale . As nanoparticles with a smaller size have larger surface areas available to adhere and interact with cell membranes, the decrease of nanoparticle size may lead to an increase in mobility and interaction with cell membranes, which can result in enhanced cellular uptake of nanoparticles . Besides, because of their small size, nanoparticles are often not recognized as a foreign agent by macrophages and consequently do not enter macrophages through membrane pores to be led to the digestion apparatus for such microparticles, the reticuloendothelial system . Donkor and Tang showed that, the cellular and nuclear internalization of 30 nm sized single-walled carbon nanotubes (SWCNT) was higher than 50 nm SWCNT . In a subsequent study, Jiang et al. reported that relatively small sizes of 2, 4 and 6 nm core gold nanoparticles (AuNP) were sufficient to induce dramatic changes in nanoparticle internalization efficiency and mechanism .
The shape of nanoparticles also plays a direct role for their function in biological systems . Li and coworkers investigated the influence of nanoparticle shape on the cellular uptake. To clarify its on cellular uptake of the nanoparticles, sphere, rod, cube, and disk shaped polymer-coated nanoparticles were compared. Based on a detailed free energy analysis, the effect of the nanoparticle shape was found to be mainly induced by the different membrane bending energies during endocytosis. The spherical nanoparticles needed to overcome a minimal membrane bending energy barrier, compared with non-spherical particles. The spherical nanoparticles thus demonstrated the fastest internalization rate, followed by cubic-, then rod- and disk-like nanoparticles .
Even though nanoparticles show a certain size and shape after synthesis, they might induce aggregation into larger clumps during the in vitro and in vivo applications. The formation of these aggregates complicates the interpretation of the results . Besides, although both size and shape are essential features, surface charge and functionality are also significant for the interaction of nanoparticles with the physiological system.
In addition to their size and shape, the surface chemistry of nanoparticles is an important factor for their interaction with the biological environment. Nanoparticles should ideally have a hydrophilic surface to escape macrophage capture . Generally, that can be achieved by coating the surface of nanoparticles with a hydrophilic polymer such as PEG, which has favorable inherent physicochemical properties and is biocompatible (e.g. it possesses high flexibility, but a low toxicity and immunogenicity). For this purpose, nanoparticles can also be fabricated from block copolymers with hydrophilic and hydrophobic parts [33, 34]. A surface modification of nanoparticles with PEG was found to reduce nanoparticle accumulation in off-target organs such as liver and spleen. PEG-coated nanoparticles have a high solubility in a number of solvents and exhibit a reduced adsorption of blood proteins, leading to prolonged circulation half-life compared to non-PEGylated nanoparticles [35–37]. In this way, it reduces the aggregation. PEG chains can be functionalized with alcohols, carboxylic acids amines and thiols to conjugate small molecules or targeting ligands. Yoon et al. demonstrated that tumor-targeting ability of hyaluronic acid nanoparticles (HANPs) could be optimized by chemical conjugation of amine-functionalized PEG, which might help escaping the unintended accumulation in liver .
The charge of nanoparticle’s surface is commonly characterized using the zeta potential, which variably reflects the electrostatic potential of particles and is influenced by the composition of the particles as well as by the medium in which the nanoparticles are suspended . Particles with a zeta potential more positive than +30 mV or more negative than −30 mV are normally considered to be physically stable [39, 40]. The negative membrane of cells interact differently with positively/negatively charged nanoparticles, whereby positively charged nanoparticles are generally known to be more easily internalized than neutral and negatively charged nanoparticles [41, 42]. Remarkably, some nanoparticles such as polymeric nanocomplexes and AuNP, which have the same size range, but different surface charges yielded marked discrepancies in both distribution and uptake efficiency. The particles also showed different levels of toxicity depending on their surface charges [43–46].
Nanoparticle surfaces are often bioconjugated with small molecules and/or targeting ligands to enable both in vitro and in vivo cell specific targeting . Proteins and peptides, carbohydrates, vitamins, aptamers, antibodies, and antibody fragments are the mostly used molecules that bind specifically to an overexpressed target on the cell surface . Immunogenicity, stability, and difficulties in site-specific conjugations with nanoparticles are the major obstacles in targeting ligands. Monoclonal antibodies (mAbs) are widely preferred targeting ligands because of their availability to research and their high affinity and specificity for molecular targets [49, 50]. Several mAbs have been used in clinics for cancer therapy, such as bevacizumab (against colorectal cancer) and trastuzumab (against breast cancer) . However, they are large, complex molecules and may cause immunogenicity.
Aptamers are small synthetic nucleic acid oligomers that can bind to targets with high sensitivity and high specificity. Aptamers are selected through an in vitro process called systematic evolution of ligands by exponential enrichment (SELEX) to be most specific for a particular target . They have potential advantages as targeting ligands. Aptamers can be synthesized with a specific functional moiety, such as a carboxylate, amino or sulfhydryl at only one end of the nucleic acid sequence of the aptamer. They are small in size and non-immunogenic [50, 53]. Peptides are an attractive alternative as targeting molecule due to several advantages, including a smaller size, a lower immunogenicity, a higher tissue penetration capability, a higher stability and a relatively easy production process. Phage-displayed peptide libraries are a valuable screening resource for identification of the peptides that target a specific receptor [54, 55]. The most widely used peptide in targeted delivery is the integrin targeted arginine-glycine-aspartic acid (RGD) peptide. This peptide has been extensively studied by combining various nanoparticles . A promising approach for overcoming the barrier of the cell membrane in drug delivery are cell penetrating peptides (CPPs). Arginine rich CPPs such as transactivator of transcription (TAT), penetratin and polyarginine are often used for intracellular delivery of the cargo conjugates . It has been hypothesized that the positively charged CPPs provide a strong electrostatic interaction with anionic species presented at the extracellular surface of cell membranes, including lipid head groups, proteins such as nucleolin, and proteoglycans like heparin sulfate [58, 59].
Passive and active targeting
Targeting of the nanoparticles is performed via two different strategies: passive and active targeting, as schematically shown in Figure 2. Nanoparticles can enhance the intracellular concentration of the drugs in cancer cells while avoiding unwarranted toxicity towards healthy cells. Malignant tumors release angiogenic growth factor proteins that stimulate new blood vessels or demand rerouting of existing vessels to supply them oxygen and nutrients [61, 62]. Tumor tissue is characterized by highly disorganized vascular architecture, irregular blood flow, reduced lymphatic drainage, and vessels are leaky [63, 64]. Because of the reduced lymphatic drainage, the permeating nanocarriers are not removed efficiently, and thus are retained in the tumor tissue . These features provide an EPR effect, which constitutes an important mechanism for the passive targeting and the selective accumulation of nanoparticles in the tumor and also in its surrounding tissue . Gabizon et al. showed that a PEGylated liposomal doxorubicin (Dox) formulation had a long circulation time in plasma, enhanced accumulation in murine tumors and a high therapeutic activity over free (unencapsulated) Dox .
The objective of the active targeting strategy is to overcome specificity limitations of drug conjugate by using targeting moieties. Nanoparticles are typically conjugated with targeting ligands that was described in the previous section, thereby allowing preferential accumulation of the drug within selected tissues or intracellular organelles . Fabricated nanoparticles may enter the cells via different endocytic pathways such as receptor-mediated endocytosis depending on their size, shape, and surface properties (Figure 3).
Drug loading and release
High drug loading capacity is essential for a successful drug delivery system. The surface chemistry of the nanoparticles and the properties of the drug as well as some environmental factors such as release conditions have a strong influence on both drug loading and release. The loading of drug molecules into the nanoparticles can be performed by two methods. Within the incorporation method, the drug should be incorporated at the time of nanoparticle formation. In the adsorption/absorption method, the nanocarrier should be incubated with the concentrated drug solution . Drug loading and entrapment efficiency is determined by the properties of the drug and the carrier molecule. Biomolecules, drugs or proteins show the greatest loading efficiency when they are loaded at or near their isoelectric point (pI), comprising a minimal solubility and a maximal absorption. Prior studies showed, that the use of ionic interactions between the drug and the matrix material can be an effective way to increase drug loading for small molecules [70, 71].
Summarizing, while designing a nanoparticle based drug delivery system, subsequent biodegradation and drug release should be considered. Loading the drug molecules inside or on the surface of nanoparticle carrier allows controlled release of the drug. This method bears many advantages such as improving biodistribution, reducing unwarranted side toxicity for healthy tissue and protecting the drug from physiological degradation compared to conventional free drugs administration . Desorption of the drugs, drug diffusion from the nanoparticle matrix, matrix erosion or degradation of nanoparticles determine the release rate of the drug [3, 69].
Utilization of nanoparticles as drug carriers offer promising improvements in drug delivery. The loading of drug molecules into or on top of the nanocarriers can improve the pharmacokinetic properties of the drug and can protect the drug against early degradation enabling targeted and controlled drug release. Thus, accumulation of the drugs in targeted size can be increased and in this way occurrence of undesired drug effects can be prevented in healthy tissues. Furthermore, multifunctional nanoparticles with simultaneously useful capabilities such as targeting and imaging contrast enhancement can be synthesized. These nanoparticles combine both diagnostic and therapeutic features within a single formulation and therefore are denoted as “theranostic” agents [72–74].
Despite the fact that there are several nanoparticle based drug delivery systems, being developed or being currently under preclinical and/or clinical evaluation, still only a few such nano-drugs are in use on the market . This is due to the fact that some problems in clinical usage encountered such as low drug loading capacity and a low circulation half-life, leading to low release and diagnostic features. Furthermore, the still relatively low physical stability and scale up problems bring along limitations for therapeutic applications of nanoparticle based drug delivery systems. Besides, the studies show that ultrafine particles (UFPs; diameter <100 nm) are more toxic and induce more severe inflammation than larger particles in their effects . Within the field of nanotoxicology, safe nanomaterials will be designed and new methods and techniques for analyzing these nanostructures in in vitro test platforms will be developed.
The greater part of the fabricated drug delivery systems work well in vitro, however many systems fail in in vivo testing because of excessive accumulation and toxicity in the kidneys and liver . In the last decade, three-dimensional (3D) cell culture systems have drawn great attention because they often offer levels of cell differentiation and tissue organization not observed in conventional two-dimensional (2D) culture systems . In recent years “organ-on-a-chip” systems are useful as an in vitro approach to test drugs and nanoparticles by mimicking the specific physiological environment found in certain organs. But both these technologies are relatively new and require further validation to predict clinical responses in human.
Consequently, smart multifunctional nanoparticles will be the most promising candidates as drug carriers in nanomedicine after identification on relevant targets and production of novel molecules. This molecules will enable the development of personalized drug delivery systems by improving the life quality and duration of the patients.
Konrad Adenauer Foundation is acknowledged for the financial support to Didem Ag Seleci. Rebecca Joncyzk thanks to Niedersächsische Krebsgesellschaft e.V. for funding support.
McNeil SE. Nanotechnology for the biologist. J Leukoc Biol. 2005;78:585–94. Google Scholar
Fortina P, Kricka LJ, Surrey S, Grodzinski P. Nanobiotechnology: the promise and reality of new approaches to molecular recognition. Trends Biotechnol. 2005;23:168–73. Google Scholar
Singh R, Lillard JJ. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009;86:215–23. Google Scholar
Xia Y. Are we entering the nano era? Angew Chem Int Edit. 2014;53:12268–71. Google Scholar
Panzarini E, Inguscio V, Tenuzzo BA, Carata E, Dini L. Nanomaterials and autophagy: new insights in cancer treatment. Cancers. 2013;5:296–319. Google Scholar
Nevozhay D, Kanska U, Budzynska R, Boratynski J. Current status of research on conjugates and related drug delivery systems in the treatment of cancer and other diseases. Postepy Hig Med Dosw. 2007;61:350–60. Google Scholar
Ge H, Hu Y, Jiang X, Cheng D, Yuan Y, Bi H, et al. Preparation, characterization, and drug release behaviors of drug nimodipine-loaded poly (epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) amphiphilic triblock copolymer micelles. J Pharm Sci. 2002;91:1463–73. Google Scholar
Sunderland CJ, Steiert M, Talmadge JE, Derfus AM, Barry SE. Targeted nanoparticles for detecting and treating cancer. Drug Dev Res. 2006;67:70–93. Google Scholar
Orive G, Gascon AR, Hernandez RM, Dominguez-Gil A, Pedraz JL. Techniques: new approaches to the delivery of biopharmaceuticals. Trends Pharm Sci. 2004;25:382–7. Google Scholar
Tiwari A, Patra HK, Choi J-W, editors. Advanced theranostic materials. Beverly: Wiley-Scrivener Publishing, 2015. Google Scholar
Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano. 2009;3:16–20. Google Scholar
Ai J, Biazar E, Jafarpour M, Montazeri M, Majdi A, Aminifard S, et al. Nanotoxicology and nanoparticle safety in biomedical designs. Int J Nanomedicine. 2011;6:1117–27. Google Scholar
Qiu X, Hildebrandt N. Rapid and multiplexed microRNA diagnostic assay using quantum dot-based Förster resonance energy transfer. ACS Nano. 2015;9:8449–57. Google Scholar
Donolato M, Antunes P, Bejhed RS, Zardan Gomez de la Torre T, Osterberg FW, Strömberg M, et al. Novel readout method for molecular diagnostic assays based on optical measurements of magnetic nanobead dynamics. Anal Chem. 2015;87:10613–8. Google Scholar
Kim K, Oh KS, Park DY, Lee JY, Lee BS, Kim IS, et al. Doxorubicin/gold-loaded core/shell nanoparticles for combination therapy to treat cancer through the enhanced tumor targeting. J Control Release 2016;228:141–9. Google Scholar
Cifter G, Chin J, Cifter F, Altundal Y, Sinha N, Sajo E, et al. Targeted radiotherapy enhancement during electronic brachytherapy of accelerated partial breast irradiation (APBI) using controlled release of gold nanoparticles. Phys Med. 2015;31:1070–4. Google Scholar
Hwang AA, Lu J, Tamanoi F, Zink JI. Functional nanovalves on protein-coated nanoparticles for in vitro and in vivo controlled drug delivery. Small. 2015;11:319–28. Google Scholar
Look J, Wilhelm N, von Briesen H, Noske N, Günther C, Langer K, et al. Ligand-modified human serum albumin nanoparticles for enhanced gene delivery. Mol Pharm. 2015;12:3202–13. Google Scholar
Suzuki R, Omata D, Oda Y, Unga J, Negishi Y, Maruyama K. Cancer therapy with nanotechnology-based drug delivery systems: applications and challenges of liposome technologies for advanced cancer therapy. In: Lu Z-R, Sakuma S, editors. Nanomaterials in Pharmacology. New York: Springer Science+Business Media, 2016:457–82. Google Scholar
Moghassemi S, Hadjizadeh A. Nano-niosomes as nanoscale drug delivery systems: an illustrated review. J Control Release. 2014;185:22–36. Google Scholar
Wang AZ, Langer R, Farokhzad OC. Nanoparticle delivery of cancer drugs. Annu Rev Med. 2012;63:185–98. Google Scholar
Parat A, Bordeianu C, Dib H, Garofalo A, Walter A, Begin-Colin S, et al. Dendrimer–nanoparticle conjugates in nanomedicine. Nanomedicine (Lond). 2015;10:977–92. Google Scholar
Al-Ali A, Singh N, Manshian B, Wilkinson T, Wills J, Jenkins GJ, et al. Quantum dot induced cellular perturbations involving varying toxicity pathways. Toxicol Res. 2015;4:623. Google Scholar
Nel AE, Maedler L, Velegol D, Xia T, Hoek EM, Somasundaran P, et al. Understanding biophysicochemical interactions at the nano–bio interface. Nat Mater. 2009;8:543–57. Google Scholar
Ha HK, Kim JW, Lee M-R, Jun W, Lee W-J. Cellular uptake and cytotoxicity of β-lactoglobulin nanoparticles: the effects of particle size and surface charge. Asian-Australas J Anim Sci. 2015;28:420–7. Google Scholar
Choi J, Zhang Q, Reipa V, Wang NS, Stratmeyer ME, Hitchins VM. Comparison of cytotoxic and inflammatory responses of photoluminescent silicon nanoparticles with silicon micron-sized particles in RAW 264.7 macrophages. J Appl Toxicol. 2009;29:52–60. Google Scholar
Donkor DA, Tang XS. Tube length and cell type-dependent cellular responses to ultra-short single-walled carbon nanotube. Biomaterials. 2014;35:3121–31. Google Scholar
Jiang Y, Huo S, Mizuhara T, Das R, Lee Y-W, Hou S, et al. The interplay of size and surface functionality on the cellular uptake of sub-10 nm gold nanoparticles. ACS Nano. 2015;9:9986–93. Google Scholar
Doane TL, Burda C. The unique role of nanoparticles in nanomedicine: imaging, drug delivery and therapy. Chem Soc Rev. 2012;41:2885–911. Google Scholar
Li Y, Kröger M, Liu WK. Shape effect in cellular uptake of PEGylated nanoparticles: comparison between sphere, rod, cube and disk. Nanoscale. 2015;7:16631–46. Google Scholar
Verma A, Stellacci F. Effect of surface properties on nanoparticle-cell interactions. Small. 2010;6:12–21. Google Scholar
Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res. 2003;42:463–78. Google Scholar
Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet. 2001;40:539–51. Google Scholar
Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copolymers for drug delivery. J Pharm Sci. 2003;92:1343–55. Google Scholar
Sperling RA, Parak WJ. Surface modification, functionalization and bioconjugation of colloidal inorganic nanoparticles. Phil Trans R. Soc A. 2010;368:1333–83. Google Scholar
Svenson S, Prud’homme RK, editors. Multifunctional nanoparticles for drug delivery applications: imaging, targeting, and delivery. In: Nanostructure Science and Technology. Boston: Springer Science+Business Media, 2012.Google Scholar
Ulusoy M, Jonczyk R, Walter J-G, Springer S, Lavrentieva A, Stahl F, et al. Aqueous synthesis of PEGylated quantum dots with increased colloidal stability and reduced cytotoxicity. Bioconjugate Chem. 2016;27:414–26. Google Scholar
Yoon HY, Koo H, Choi KY, Lee SJ, Kim K, Kwon IC, et al. Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapy. Biomaterials. 2012;33:3980–9. Google Scholar
Duman O, Tunc S. Electrokinetic rheological properties of Na-bentonite in some electrolyte solutions. Micropor Mesopor Mater. 2009;117:331–8. Google Scholar
Crooke ST, editor. Antisense drug technology: principles, strategies, and applications, 2nd ed. Boca Raton: CRC Press, 2008. Google Scholar
Yue ZG, Wei W, Lv PP, Yue H, Wang LY, Su ZG, et al. Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles. Biomacromolecules. 2011;12:2440–6. Google Scholar
Arvizo RR, Miranda OR, Thompson MA, Pabelick CM, Bhattacharya R, Robertson JD, et al. Effect of nanoparticle surface charge at the plasma membrane and beyond. Nano Lett. 2010;10:2543–8. Google Scholar
Jiang J, Oberdörster G, Biswas P. Characterization of size, surface charge, and agglomeration state of nanoparticle dispersions for toxicological studies. J Nanopart Res. 2008;11:77–89. Google Scholar
Asati A, Santra S, Kaittanis C, Perez JM. Surface-charge-dependent cell localization and cytotoxicity of cerium oxide nanoparticles. ACS Nano. 2010;4:5321–31.Google Scholar
Frohlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomed. 2012;7:5577–91.Google Scholar
Schaeublin NM, Braydich-Stolle LK, Schrand AM, Miller JM, Hutchison J, Schlager JJ, et al. Surface charge of gold nanoparticles mediates mechanism of toxicity. Nanoscale. 2011;3:410–20. Google Scholar
Zhang S, Gao H, Bao G. Physical principles of nanoparticle cellular endocytosis. ACS Nano. 2015;9:8655–71. Google Scholar
Narang AS, Mahato RI. Targeted delivery of small and macromolecular drugs. CRC Press; 2010. Google Scholar
Sun T, Zhang YS, Pang B, Hyun DC, Yang M, Xia Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed. 2014;53:12320–64. Google Scholar
Friedman AD, Claypool SE, Liu R. The smart targeting of nanoparticles. Curr Pharm Des. 2013;19:6315–29. Google Scholar
Milano A, Nasti G, Iaffaioli RV, Caponigro F. First line targeted therapies in breast cancer: focus on bevacizumab. Biologics. 2007;1:3–10. Google Scholar
Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science. 1990;249:505–10. Google Scholar
Wang AZ, Gu F, Zhang L, Chan JM, Radovic-Moreno A, Shaikh MR, et al. Biofunctionalized targeted nanoparticles for therapeutic applications. Expert Opin Biol Ther. 2008;8:1063–70. Google Scholar
Zhang X-X, Eden HS, Chen X. Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates. J Control Release. 2012;10:159:2–13. Google Scholar
Li ZJ, Cho CH. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery. J Transl Med. 2012;10:1–9. Google Scholar
Seleci M, Ag Seleci D, Ciftci M, Demirkol DO, Stahl F, Timur S, et al. Nanostructured amphiphilic star-hyperbranched block copolymers for drug delivery. Langmuir. 2015;31:4542–51. Google Scholar
Tabujew I, Marco Lelle M, Peneva K. Cell-penetrating peptides for nanomedicine – how to choose the right peptide. BioNanoMat. 2015;16:59–72. Google Scholar
Ziegler A, Blatter X, Seelig A, Seelig J. Protein transduction domains of HIV-1 and SIV TAT interact with charged lipid vesicles. Binding mechanism and thermodynamic analysis. Biochemistry. 2003;42:9185–94. Google Scholar
Goncalves E, Kitas E, Seelig J. Binding of oligoarginine to membrane lipids and heparan sulfate: structural and thermodynamic characterization of a cell-penetrating peptide. Biochemistry. 2005;44:2692–702. Google Scholar
Peer D. Harnessing RNAi nanomedicine for precision therapy. Moll Cell Ther. 2014;2:5. Google Scholar
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57. Google Scholar
Prabhu VV, Chidambaranathan N, Gopal V. A historical review on current medication and therapies for inducing and inhibiting angiogenesis. J Chem Pharm Res. 2011;3:526–33. Google Scholar
Escoffre JM, Bouakaz A. Therapeutic ultrasound, advances in experimental medicine and biology. Heidelberg, Germany: Springer, 2015. Google Scholar
Baronzio GF, Hager ED, editors. Hyperthermia in cancer treatment: a primer, medical intelligence unit. Berlin: Landes Bioscience and Springer Science+Business Media, 2006. Google Scholar
Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul. 2001;41:189–207. Google Scholar
Yu MK, Park J, Jon S. Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics. 2012;2:3–44. Google Scholar
Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res. 1994;54:987–92. Google Scholar
Sinha R, Kim GJ, Nie S, Shin DM. Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol Cancer Ther. 2006;5:1909–17. Google Scholar
Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70:1–20. Google Scholar
Chen Y, Mohanraj VJ, Parkin JE. Chitosan-dextran sulfate nanoparticles for delivery of an anti-angiogenesis peptide. Lett Pept Sci. 2003;10:621–9. Google Scholar
Mahapatro A, Singh DK. Biodegradable nanoparticles are excellent vehicle for site directed in-vivo delivery of drugs and vaccines. J Nanobiotechnol. 2011;9:55–66. Google Scholar
Cheng Z, Zaki AA, Hui JZ, Muzykantov VR, Tsourkas A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science. 2012;338:903–10. Google Scholar
Zheng SW, Huang M, Hong RY, Deng SM, Cheng LF, Gao B, et al. RGD-conjugated iron oxide magnetic nanoparticles for magnetic resonance imaging contrast enhancement and hyperthermia. J Biomater Appl. 2014;28:1051–9.Google Scholar
Pennakalathil J, Ozgun A, Durmaz I, Cetin A, Rengul T, Tuncel D. pH-responsive near-infrared emitting conjugated polymer nanoparticles for cellular imaging and controlled-drug delivery. Int J Polym Sci A1. 2015;53:114–22. Google Scholar
Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H. Nanoparticles as drug delivery systems. Pharmacol Rep. 2012;64:1020–37. Google Scholar
Oberdorster G, Ferin J, Gelein R, Soderholm SC, Finkelstein J. Role of the alveolar macrophage in lung injury: studies with ultrafine particles. Environ Health Perspect. 1992;97:193–9. Google Scholar
de Villiers MM, Aramwit P, Kwon GS, editors. Nanotechnology in drug delivery. In: Biotechnology: Pharmaceutical Aspects. New York: AAPS Press and Springer Science+Business Media, 2008. Google Scholar
Huh D, Hamilton GA, Ingber DE. From three-dimensional cell culture to organs-on-chips. Trends Cell Biol. 2011;21:745–54. Google Scholar
About the article
Published Online: 2016-04-28
Published in Print: 2016-05-01