Construction Of Co-delivery Systems Of Anti-cancer Drugs And MiRNA Based On PLGA Microparticles And PLA Nanoparticles

The increasing incidence and mortality of cancer have made it a primary disease of human, and developing a safe and efficient therapeutic strategy is urgent necessary. Recently, tumor-targeted systems for co-delivery of anti-cancer drugs and genes have been widely investigated, and are potentially to be an effective technique for cancer treatment.Here, we first developed a porous microparticle harboring doxorubicin and PEI25K/miRNA-34 a for lung cancer treatment via a pulmonary inhalation. The intravenous administration could not achieve an effective concentration in lungs and meanwhile cause severe side effects on normal tissues. In contrary, porous PLGA microparticle could realize the accumulation and sustained release of drugs in the alveoli, due to its porous surface and degradable properties. In the system, miRNA-34 a was encapsulated as it is an endogenous p53-inducing miRNA and plays a key role in inhibiting the tumorigenesis and further development. The efficiency of inhibiting the tumor proliferation and migration, and the detailed mechanism were systematically evaluated, using A549 cell line as a model. The results clearly showed that porous PLGA microparticle could inhibit the tumor proliferation and migration due to the synergistic effect of doxorubicin and miRNA-34 a.Further, PLA nanoparticles for co-delivering doxorubicin and mi R-519 c were constructed using aptamer AS1411 as a ligand, which can specifically bind to necleolin over-expressed on the surface of most tumor cells. The miR-519 could silence the expression of efflux pump ABCG2 in tumor cells, thereby enhancing the sensitivity of tumor cells toward the chemotherapeutics. From the results, we can obviously observe that the tumor-targeted endocytosis of nanoparticle was mediated by AS1411, and the proliferation of tumor cells could be inhibited due to an improved sensitivity to doxorubicin, using Hep G2 cell line as a model. In the future research, the nude mice bearing tumors will be constructed for evaluating the in vivo tumor-targeted mechanism and anti-cancer efficiency of the system.In summary, we constructed two types of systems for achieving the co-delivery of drug and gene, based on PLGA microparticle and PLA nanoparticle. The two systems could realize the tumor-targeting delivery for achieving the accumulation of drugs in lung cancer and hepatocarcinoma cells, respectively. Meanwhile, enhanced anti-proliferative and anti-migration effects could be obtained due to the synergy of miRNA and chemotherapeutics. Thus, these two carriers are potential to be widely used as safe and efficient systems in tumor treatment through an improved anti-tumor efficiency and reduced side effects.