Scheme 5.1 Schematic representation of the therapeutic approach by combining chemo- and photodynamic therapy
1.7 Membrane-based drug delivery systems
conjugating the targeting ligand on the surface by chemical modifications. The possible surface modification of the SeNPs are shown in Figure 1.7.
Transferrin conjugated SeNPs were prepared to target the cancer cells overexpressing the transferrin receptor. These TF-conjugated NPs selectively internalized through endocytosis in cancer cells avoiding the healthy cells.58 Similarly, Folic acid-conjugated SeNPs have also shown enhanced delivery to the folic acid receptor overexpressing cells.58 In another study, L-arginine capped drug-loaded NPs were used to deliver siRNA for MDR-1 inhibition. The fluorescent labeling of these NPs by ruthenium complexes renders the fluorescent NPs that can be tracked inside the cells.59 Multiple studies have shown that the synergistic response of the loaded drug and SeNPs making an effective treatment strategy. Recent studies have reported the synthesis of the stimuli-responsive nanocarriers for drug delivery after various stimuli, including temperature and pH.60
Additionally, PEG coating has also shown to induce the PEG-specific IgM antibodies.63 Addressing the insufficiency of nano-systems to serve as suitable nanocarriers, various biological membranes derived from red blood cells (RBC), platelet, and cancer cells are currently being explored by researchers to prepare or coat the nanocarriers.64,65 Merits of these membranes based carrier include their effective interaction with target cell surface, biocompatibility, non-immunogenicity and targeting efficiency without modification of the surface.66, Some of the membrane-based drug carriers are illustrated in Figure 1.8.
1.7.1 Stem cells as a drug carrier
Stem cells or stem cell membrane coated NPs have been reported for drug delivery applications. Stem cells have shown a migration and accumulation towards tumor mass.67 Also, stems cells can be genetically engineered for targeted therapeutic approach.68 A death receptor ligand, tumor necrosis factor apoptosis ligand (TRAIL) overexpressing stem cells induced apoptosis in the metastatic glioma cells.
Figure 1.8 Cell membrane‐coated nanoparticles. A variety of cell types have been used as sources of membranes to coat nanoparticles. [Reproduced from reference 65 with permission from John Wiley and Sons].
1.7.2 Tumor cell-derived particles
Tumor cell-derived particles are the natural mediators of distant cells. These natural carriers containing drugs can be used to treat cancer cells.69 Apart from these natural and signaling vesicles, artificial stimuli can induce to shred the cell-derived microparticles. For example, the microparticles were collected after treatment of cells with an anticancer drug (methotrexate) and ultraviolet irradiation. The apoptotic cells generated drug-loaded microparticles can be collected and used for therapeutic applications.70
1.7.3 Exosomes
Exosomes are similar to the cell-derived particles regarding the membrane composition. Exosomes are extracellular vesicles generated from cells, which plays an important role in cell-cell communication. Exosome released from cell possess information for target cells in the form of proteins, carbohydrates, lipids or nucleic acids.71 Due to this ability to carry the cargo, exosomes are being used to delivery therapeutic molecules. Another essential characteristic of the exosome is targeting specificity due to presence of proteins on surface.
Doxorubicin loaded exosomes have shown the cancer-specific drug delivery after conjugating ligand on exosome membrane for targeting.72
1.7.4 RBC membranes for drug delivery
Apart from the artificial and human-made nano-carriers, the human body has natural carriers like red blood cells (RBCs). A profuse amount of RBCs in body carries oxygen, carbon dioxide, and acts as a buffer system to maintain body pH. RBCs have unique properties like their flexibility, 7-8 µm size and biconcave shape, which allows them to maneuver through the network of capillaries of size less than their own diameter (Figure 1.9).73 Essential properties of the RBCs like non-immunogenicity, biocompatibility, their more prolonged circulation in the blood and larger volume has attracted the scientists to use these natural carriers for therapeutic payload delivery purpose. Researchers are utilizing these unique properties to prepare nanocarriers for different applications.74 Whole RBCs have shown potential for drug delivery applications. Loading of the cargos or even a bigger biomolecule can be achieved by directly incubating them with intact or lyzed RBCs.75 Once the cargo is encapsulated, these RBCs can be used for sustained release of the cargo in blood.76 Apart from using whole RBC as a carrier, researchers have
used RBC membrane to prepare nano-sized vesicles for anticancer drug delivery.
Figure 1.9 Morphology of the Red Blood Cells (RBC).
Isolated RBC membrane can be used to coat nanocarriers to augment the physicochemical properties. RBC membrane coated gold nanocages were prepared to target the 4T1 cancer cells. The membrane coated nanocages precisely delivered paclitaxel to the tumor cells, and the near-infrared irradiation-induced hyperthermia resulted in enhanced cell death.77 As shown in (Figure 1.10), upconversion NPs were coated with RBC membrane to achieve dual targeting of cancer cells and mitochondria.78 In-vivo experimental results showed excellent stability and RES escaping ability after RBC membrane coating. Dual targeting and delivery of the photodynamic agent to these tumors resulted in a reduction in tumor growth and increased the survival rate of tumor-bearing mice.78
Figure 1.10 UCNP based RBC membrane-coated NPs to target cancer and mitochondria. [Reproduced from reference 77 with permission from the Royal Society of Chemistry].
1.8 Some important anticancer drugs and signaling pathway blockers