A major obstacle for cancer therapies is the lack of targeted delivery of therapeutics. To compensate, existing drug treatments rely on high dosages and frequent administrations. This results in adverse effects in the patient due to the drugs failure to discriminate between normal body cells and tumor cells. The discovery of RNAi (RNA interference) has radically opened possibilities to the advancement of cancer treatments. Intensive research on RNAi and its applications has led to the study of promising siRNA (short interfering RNA) candidates from in vitro tests to clinical trials. As with other curative agents, targeted intracellular delivery is not a guarantee. To increase specificity, anti-cancer agents have been packaged in nanoparticles bound to targeting moieties to promote uptake in infected cells. Even with these advancements, delivery of siRNA to the cytosol remains incomplete due to sequestration in endosomes, and further degradation in lysosomes. An approach to trigger endolysosomal escape of nanoparticles is under development known as photochemical internalization (PCI). PCI is partially derived from photodynamic therapy (PDT) in use today, which makes use of ligand bound photosensitizers, which will undergo a photochemical reaction when illuminated. This reaction causes the formation of reactive oxygen species as well as other cytotoxic effects, inducing necrosis of the targeted tissue. PCI utilizes the sequestration of photosensitizers and nanoparticles within endocytic vesicles to release siRNA in a temporally and spatially controlled manner. Amphiphillic photosensitizers when illuminated will cause a photochemical reaction disrupting the endolysosmal membrane, which in turn will allow for escape of siRNA nanoparticles. This novel approach allows the endolysosome to serve as a depot from which siRNA can be released into the cytoplasm. The use of photosensitizers specifies the release in cells, which have only internalized photosensitizers in the presence of light only. This also allows for a sustained release of siRNA into the cytoplasm from an original dosing. In order for PCI to be introduced as a mainstream clinical treatment, improvements must be made on current nanoparticle delivery systems, siRNA half-life in the cytosol, and standardization of associated treatment parameters such as illumination duration, frequency, and concentrations of photosensitizers. In addition, further research is required in regards to the RNAi mechanism to further fine tune PCI to allow for its clinical approval.
Key words: RNAi, siRNA, endolysosomal escape, photochemical internalization (PCI), nanoparticle, photosensitizer, cytotoxicity, illumination.
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