Biodegradable Nanoparticles For Drug And Gene Delivery

Cancer has become the leading cause of death worldwide. The past decades has witnessed the development of various anticancer drugs including chemotherapeutics and protein drugs. It should be noted, however, these anticancer drugs usually suffer rapid degradation, short half-life as well as non-specific toxicity in circulation, which may induce serious side effects and reduced therapeutic efficacy. Recently, nanoscale drug delivery systems have emerged as an indispensable platform for modern cancer therapy. These nanoscale drug formulations hold significant advantages, such as protecting drugs from degradation, prolonged circulation time, decreased adverse effects, improved drug availability, passive targeted to the tumor site via EPR effect and enhanced cancer therapy. However, the current nanoscale drug delivery systems often expose slow and deficient drug release at the pathological site, leading to compromised therapeutic effects. To this end, tremendous efforts have been directed to the development of smart bio-responsive nanocarriers that are sufficiently stable under extracellular conditions while release drugs rapidly and efficiently in cancer cells. Based on the p H change in vivo, we can design p H-responsive drug and gene delivery nanoparticles,In chapter 1, a literature overview is presented to give a brief introduction about advantage and disadvantage of nanomedicine, gene nanoparticles classes, polymersomes application.In chapter 2, wedeveloped p H-responsive, reversibly crosslinked, polyetheleneimine(PEI)-based polyplexes coated with hyaluronic acid(HA) for the effective and targeted gene delivery to cancer cells. Low-MW PEI was crosslinked with the ketal-containing linker, and the obtained high-MW analogue afforded potent gene delivery capabilities during transfection while rapidly degraded into low-MW segments upon acid treatment in the endosomes which promoted intracellular DNA release and reduced material toxicity. HA coating of the polyplexes shielded the surface positive charges to enhance their stability under physiological conditionand simultaneously significantly reduce the toxicity. Additionally, HA coating allowed active targeting to cancer cells to potentiate the transfection efficiencies in cancer cells in vitro and in vivo. This study therefore provides an effective approach to overcome the efficiency-toxicity inconsistence of non-viral vectors, which contributes insights into the design strategy of effective and safe vectors for cancer gene therapy.In chapter 3, we developed biodegradable, chimaeric polymersomes based on PEG-PCL which loaded p H-responsive DOX for drug delivery. DLS data demonstrated that the size of drug loaded polymersomes was 100 nm and drug loaded content was 10%. Moreover, we investigated the release of DOX researched 80% in 48 h. Under acid treatment, the polymersomes degraded and the amido bond cleaved. The MTT data also suggested thar drug loaded polymersomes killed more resistant cells than free drugs at lower drug doses. This biodegradable polymersomes provided a new way for drug delivery.In chapter 4, we summarized these work and gave a future plan.