Construction Of Porous Microparticles And Phenylboronic Acid-functionalized System For Small Nucleic Acid Delivery Based On The Multidrug Resistance Mechanism

Multidrug resistence(MDR) could confer a simultaneous resistance to different chemotherapeutics with different targets and structures, thus it has been one of the major obstacles to the successful clinical cancer treatment. Many key regulators including efflux pump proteins and anti-apoptotic proteins are responsible for MDR. Small nucleic acid based therapeutic approaches, especially small interfering RNA(si RNA) and micro RNA(mi RNA), are able to knock down some specific genes by targeting the m RNAs, which serve as powerful tools in reversing the MDR. Developing efficient systems for small nucleic acid delivery based on multidrug resistence mechanism has become a potential strategy in cancer therapy.First, a tumor-targeted gene carrier PPP was successfully constructed for Bcl-2 si RNA delivery, through the conjugation of PBA to PAMAM dendrimer using NHSPEG5k-Mal. The carrier possessed favorable condensation and protect capacity of si RNA from degradation in RNase and serum. The introduction of PBA could facilitate the cellular uptake of Bcl-2 si RNA in Hep G2 cells and significantly inhibit the expression of Bcl-2 gene at both m RNA and protein level. Consenquantly, PPP could obviously inhibit the cell proliferation by inducing the cell apoptosis and improve the antitumor efficiency of doxorubicin by suppressing the resistance to chemotherapeutics.Furthermore, porous PLGA microparticles were developed for achieving the codelivery of doxorubicin and PEI25K/pc DNA-mi R-519 c in an inhalation route, using ammonium bicarbonate as a porogen. The porous PLGA microparticles could significantly increase the bioavailability of doxorubicin and conduct a sustained release of the cargo due to their suitable properties. The cell proliferation, apoptosis and cycle arrest analysis on A549 cells showed that the synergistic effect between these two components ensured the efficient anti-proliferative effects by increasing the intracellular concentration of doxorubicin and activating multiple apoptosis signaling pathway.In conclusion, the small nucleic acid delivery system based on MDR mechanism could potentially be an effective platform for solving the drug resistance and achieving the combined chemo- and gene therapy in tumor treatment.