Significant advances in the application of injectable drug delivery systems for cancer therapy have occurred in the last decades. These advancements include the use of liposomes and other nanoparticles as macromolecular conjugates. For instance, liposomal doxorubicin modified by poly (ethylene glycol) (PEG) (Doxil) was the first liposome with anti-cancer effects approved by the US Food and Drug Administration (FDA), whereas Abraxane [paclitaxel (PTX) loaded in albumin nanoparticles] was recently produced for the treatment of breast cancer. There are several challenges related to modification of liposomes and their effects on cancer tissues , , , , , , , , . As a typical class of nanomedicines, liposomes are nowadays prepared at the nano size range using different methods. In the nanomedicine field, the design of the nano-scaled devices and their interactions with cellular targets at the nano-scale are rapidly evolving. In this way, liposomes had been the first generation of nano-scale drug delivery systems approved for treatment of cancer (e.g. Doxil) and fungal infections (e.g. Ambisome) , , , , , . Liposomes have an aqueous interior part, surrounded by one or more concentric bilayers of phospholipid structure. The diameter of liposomes is variable ranging from 1 nm to several microns. In the case of injectable clinical utilization, all liposome formulations are in the submicron ultra-filterable range of less than 200 nm size and can be considered as nanostructure systems. When amphiphilic lipids such as phospholipids are dispersed in water, liposomes are spontaneously formed. These structures are physically stable, and unlike polymeric particles, they are not covalently bound. Depending on the water solubility properties of the drug, it can be encapsulated in the aqueous core or in surrounding bilayer of the liposome , , . Hydrophobic drugs are incorporated into the lipid membrane, whereas hydrophilic drugs are encapsulated within the central aqueous core , , , , , , . Cancer therapy may benefit from nanocarriers via two major approaches including passive and active targeting with liposomes being potentially useful in both cases. In this review, we attempt to present practical information regarding recent advances with respect to injectable liposomes and lipid nanoparticle (LNP)-based drug delivery systems with passive and active targeting abilities for cancer therapy.
Cancer disease and therapy hindrances
Abnormal growth (neoplasm) of a tissue to produce an abnormal population of cells is referred to as tumor, which can be found in two major forms: benign or malignant. Cancer is the malignant form of neoplasm resulting in cells without a normal morphology and/or function . These types of tissues have subdivisions of cells, interstitial and vascular. In the case of cellular type, cancers may be carcinoma, sarcoma, lymphoma, germ cells (pluripotent cells) tumors, and blastoma. This classification is based on the tissue of origin of the malignancy (Figure 1). Also, based on size and shape, cancer cells such as carcinoma type may be divided into small-cell, spindle cell, and giant cell carcinoma .
As illustrated in Figure 2, cancer therapy may be carried out by several approaches including chemotherapy, biological therapy, immunotherapy, hormone therapy, radiotherapy, stem cell transplant, using therapeutic vaccines, and surgery , , , , . In chemotherapy, cancer cells are often destroyed or treated by cytotoxic and genotoxic drugs. This type of therapy has several major side effects such as nausea, fatigue, diarrhea, hair loss, disruption of mouth, pharynx mucosa, and bone marrow , . In biological therapy, living organisms (mainly viruses and bacteria) or components of living organisms are utilized to treat cancer. Among viruses, anticancer properties of the mumps virus, Newcastle disease virus, reovirus, adenovirus, vaccinia virus, and the measles virus are approved by the US FDA . Also, vaccines of bacillus Calmette-Guérin, weakened form of the tuberculosis bacteria, have been applied against bladder cancer . Immunotherapy is one subtype of biological therapy. Application of monoclonal antibodies, adoptive cell transfer, cytokines, and vaccines in cancer treatment are located in the immunotherapy group . In this way, the effect of BATF3-dependent dendritic cells in improvement of antitumor efficiency by anti-PD-1 and anti-CD137 monoclonal antibodies against several types of cancer is approved . The side effects of immunotherapy are pain, soreness, redness, swelling, rash, itchiness, and flu-like symptoms.
Tumor receptors are a potential target for specific ligands or antibodies with or without delivery of a cytotoxic drug cargo. The pathophysiology of tumor neovasculature and the interaction of tumors with the stroma have a major role in tumor development. In fact, cancer is a disease caused by somatic mutations that result in the transformation of normal cells into malignant tumor cells. There are four major stages to phenotype progress of tumor cells: (1) appearance of abnormal cells, (2) high proliferation of tumor cells, (3) invasion to the surrounding tissues through angiogenesis, and (4) metastases. In stage 4 of cancer, there is abnormal migration of tumor cells from the primary tumor site through blood vessels or lymphatics to distant organs and formation of secondary tumors .
Competition for drug uptake by liver and kidneys, binding of protein with drug inactivation, glomerular filtration and urinary excretion of low molecular weight drugs, and low stability of drug in fluids (e.g. opening of the lactone ring of camptothecin analogs) are physiologic parameters that can seriously limit the drug distribution efficiency from plasma to tumors and neutralize their effects.
Liposomes and LNPs
Being one of the oldest while still promising drug carriers, liposomes are spherical structures made of a hydrophilic core surrounded by a bilayer made of some amphiphic lipid materials, mainly phospholipids. Generally, the size of liposomes can be in the range of 25 nm–2.5 μm with one or several bilayer membranes . Classification of liposomes is based on these two parameters, i.e. number of bilayers and size. In the case of bilayers number, there are unilamellar (with one phospholipid bilayer) and multilamellar (with several bilayers like an onion shape) liposomes with unilamellar type divided into two subtypes of small and large unilamellar liposomes (Figure 3) . These structures are important in encapsulating of various drugs with different size, shape, and solubility in water. By modification of these vesicles, it may be possible to target specific organs, tissues, and cells , . Also, based on the charge of the lipid constituents in the formation of liposomes, there are cationic and anionic liposomes. For example, cationic unilamellar liposomes can be synthesized by N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride to deliver nucleic acids including miRNA, DNA, and siRNA to cells of interest . In the case of anionic liposomes, mixtures of 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine as anionic and zwitterionic lipids, respectively, have been used to prepare carriers for the effective ion delivery of plasmid DNA molecules encoding green fluorescence protein .
Major disadvantages of liposomes include the lack of affordable preparation methods, low degree of drug loading capacity and stability, and rapid decomposition in the human body before the therapeutic effect can be achieved. Generally, there are four types of LNPs: solid lipid nanoparticles (SLN), nanostructured lipid carrier (NLC), lipid drug conjugate (LDC), and polymer-lipid hybrid nanoparticle (PLN). The first generation of LNPs was introduced in 1993–1996 as SLNs. High stability in the reticuloendothelial system (RES) at the physiologic temperature of 37°C and a practically acceptable drug encapsulation could be possible by using solid lipid instead of liquid lipid in the preparation method. These structures have other advantages including an easy large-scale production, simple sterilization, suitable bioavailability, biocompatibility, biodegradability, controlled release of drugs, higher shelf life, efficient drug targeting, and improved drug absorption and dissolution . NLCs are another type of LNPs with both solid and liquid lipids in their composition without perfect crystalline structure. A higher capacity to encapsulate a wide range of drugs with solubility in the liquid and solid phases of lipids is the advantage of these systems over the SLNs . Both SLNs and LNPs have limited capabilities with respect to loading of hydrophilic drugs. In this way, conjugation of hydrophilic drugs with hydrophobic molecules by covalent bonds and salt formation resulted in a new nanostructure named LDC. LDCs can be used for drugs with sensitivity to the acidic conditions of the stomach. For even better loading of hydrophilic drugs, PLNs were introduced as a linkage between ionic polymers and hydrophilic drugs such as gemcitabine . Several polymers such as polycaprolactone and polylactic-coglycolic acid can be utilized for conjugation with drugs in a core-shell structure .
Liposomes can target cancer tissues by both passive and active targeting strategies (Figure 4). Some mutations can cause uncontrolled division of cells in the body resulting in cancer disease. The basis for the passive targeting of the tumor tissues by liposomes is, mainly, the different pore sizes between the endothelial cells of the tumor microvasculature compared to the ‘tighter’ structures found in normal capillaries. Therefore, if one prepares liposomes with such a size that allows them to extravasate in the tumor tissues while prohibiting the carriers to exit the capillaries in normal tissues, an ideal targeting goal would be achieved , , . In addition to the increased permeability, there is a phenomenon in tumor sites commonly known as enhanced permeability and retention effect (EPR). This situation is characterized by the increased blood capillary permeability in the affected tissues with a much lesser return of the fluids to the lymphatic circulation. In this way, the drugs encapsulated in liposomes (up to the size of 400 nm) can be accumulated efficiently in tumor sites. Mechanistically, the overexpression of some regulating angiogenesis factors such as vascular endothelial growth factor (VEGF) may result in both chaotic tumor vessel architecture and increased vascular permeability. These factors, ultimately, lead to enhanced permeation and retention . Abraxane® (albumin-bound PTX) is a typical example of a drug delivery system which accumulates in tumors via EPR .
There are several reports of passive targeting by LNPs. For example, sclareol-SLNs with an average particle size of 88 ± 5 nm has shown significantly higher growth inhibitor effect on A549 human lung epithelial cancer cells after a period of 48 h compared to the free drug along with a sustained drug release . Conjugation of curcumin with SLN is another report for passive targeting of tumor tissues used in breast cancer with remarkably higher tissue availability . In a similar study, growth inhibition of Hodgkin’s lymphoma xenograft was observed by 50.5% in the case of curcumin-SLN receiving group . For passive targeting of glioblastoma and melanoma, temozolomide-SLN showed higher inhibition in proliferation of these types of cancer tissues and lower cytotoxicity in healthy cells compared to temozolomide without SLN .
There are several ways to target actively a specific site of body by a drug carrier (Figure 5). In order to achieve the active targeting of cancer sites, a variety of ligands are utilized to exploit any specific antigens expressed by cancer cells. The prostate-specific membrane antigen has been successfully targeted by conjugation of RNA A10 onto PLA-block-PEG co-polymers, which exhibited increased drug delivery to prostate tumor tissue compared to non-targeting nanoparticles . In the case of the active targeting by immunoliposomes, binding to target cells and uptake by the RES are two kinetically competing processes. PEG chains have shown a successful avoiding of the RES uptake of liposomes, thus leading to an elevated blood concentration and enhanced target binding of immunoliposomes. Also, the presence of free PEG did not interfere with the binding of the terminally linked antibody to the antigen in pendant-type immunoliposomes , .
Breast cancer is characterized by high expression of estrogen receptors including MAPK, HER2/neu, PI3K/Akt, and epidermal growth factor receptor (EGFR)/VEGFR which can be targeted actively by modified liposomes. In this way, the role of IL-6 growth factor is important specifically in complicating the biological situation. For targeting of IL-6, Diacerein encapsulation in Tyr-3-octreotide-PEG-liposomes has shown significant effect on cell division and angiogenesis of breast tumor cells via higher cleavage of caspase 3 and poly ADP ribose polymerase .
CD44 is a cell membrane glycoprotein that regulates interaction, adhesion, and migration of cells in the extracellular matrix. These regulations are related to the binding of hyaluronic acid to CD44. In the case of LNPs, hyaluronic acid coated-NLCs loaded by PTX were used to deliver PTX to cancer cells with overexpression of CD44. This nanostructure showed sustained drug release than the free drug, Taxol® . Modification of resveratrol-SLN with Apolipoprotein E demonstrated meaningful permeability through the blood brain barrier hCMEC/D3 cell line with lower cytotoxicity than unmodified resveratrol-SLN . Trans-activating transcriptional activator (TAT) peptide by 86 and 101 amino acids is one of the cell-penetrating peptides that can transfer through the cell membrane without damaging it. In this way, HeLa cells as cervical tumor cells were targeted effectively by TAT-functionalized-SLNs having two antitumor agents including α-tocopherol succinate-cisplatin prodrug and PTX . As mentioned, targeting of cancer tissues by antibody is an efficient way of active targeting approach. As a typical example, the receptor for advanced glycation endproducts was used to modify the surface of di-allyl-disulfide-loaded SLN for targeting of triple-negative breast cancer cells . Overexpression of epidermal growth factor receptor variant III (EGFR vIII) in many tumor tissues is another way for targeting. Using anti-EGFR vIII monoclonal antibody conjugated by DSPE-PEG2000-NHS (1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000-NHS) linker to doxorubicin (Dox)-loaded NLC has shown a meaningful inhibitor effect on the growth of HC2 20d2/c cells .
This review presents recent advances in two drug delivery systems of LNPs and liposomes in passive and active targeting of the cancer sites. Recent surveys have been approved with the great potential for widespread adoption of SLNs in the cancer treatment field. In this way, SLNs are significant candidates for the improvement of drug delivery systems. These structures have major characteristics including suitable biodegradability, higher biocompatibility, lower clearance rates by the RES, the ability for specific targeting of cancer tissues, and sustained controlled-release of drugs. Therefore, it can be concluded that SLNs demonstrate various advantages over conventional chemotherapy and liposomes nanostructures.
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About the article
Published Online: 2019-02-01
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Employment or leadership: None declared.
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Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.