Development of Anti-Cancer Therapeutic Strategy Using Synthetic Non-Viral Carriers for Gene and Drug Delivery in Targeted Cancers

Abstract

Despite significant advances in cancer therapy, cancer continues to be a leading cause of death in the world. One of the major hurdles in cancer therapy is abnormal cancer cell proliferation leading to metastasis. Traditional cancer therapies are based on the fact that rapidly proliferating cancer cells are more sensitive to anti-cancer drugs, but unfortunately, these anti-cancer drugs show non-specific toxicity to proliferating normal cells too. Therefore, apart from the understanding the molecular basis of cancer, it is now necessary to explore and develop new anti-cancer therapeutic strategy by using non-viral carrier for gene and drug delivery. In first study, lithocholic acid (LCA), a potent anti-cancer drug, is converted to two forms of poly(ethyleneglycol) PEG conjugates, PEG-LCA(PL) and lactobionic acid (LBA) conjugated PEG-LCA (LPL). HepG2 cancer cells and LO2 normal cells were used for in vitro experiments. We further confirmed C6-loaded PL and C6-loaded LPL nanoparticles were injected into in H-ras model mice through IV administration. In another study, we performed the gene therapeutic effect of short hairpin Rab25 RNA (shRab25) on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- induced lung tumorigenesis in female A/J mice. Mice were injected with single dose of NNK by intraperitoneal injection to induce the tumor. Eight weeks later, Glycerol proxylate triacrylate and spermine (GPT-SPE) which is used for non-viral cationic carrier that can deliver gene to lung via aerosol delivery. GPT-SPE/Rab25 using short hairpin RNA complexes delivered into tobacco-induced lung cancer model A/J mice through aerosol-only inhalation twice a week for 8 weeks. Aerosol mediated gene delivery performs a noninvasive alternative for the targeting genes to lungs. Repeated aerosol delivery of GPT-SPE/Rab25 shRNA complexes greatly suppressed lung tumorigenesis. Those results strongly provide the novel and potential therapeutic outcome for liver and lung cancer treatment.