Design And Application Of Tumor Microenvironment-Responsive Drug Delivery Systems

Drug delivery systems (DDSs) have received tremendous attention for cancer therapy, due to their ability to protect the encapsulated drugs from degradation, and to enhance the bioavailability of drugs by intravenous administration. To achieve efficient antitumor effect, it needs high dosage of drug, which results in toxic and side effect to normal tissues. Therefore, successful drug delivery for cancer treatment requires the balance between efficacy and safety, which often limits in a very narrow therapeutic window. To make treatments with conventional drugs more effectively and safety, it is necessary to develop DDSs that can control the release of drug at the appropriate site, e.g. in tumor cells. An increased understanding of tumor microenvironment and their critical role in tumor development and progression provide new opportunities to design "stimuli-responsive" or "smart" DDSs for more efficiently cancer therapy. In this dissertation, we focused on the development of "tumor microenvironment-responsive" DDSs to enhance antitumor effect, and to limit toxic and side effect. The main content of this dissertation aredescribed in two parts as below:1. We have developed a siRNA delivery system that can release cargo in the tumor intracellular redox environment. The redox-responsive drug delivery system was prepared by filming-rehydration method using amphiphilic Janus dendrimer containing disulfide linkages. The morphology of the SSJD was confirmed as spherical unilamellar layer vesicle. It could effectively complex siRNA at physiological conditions, and within the presence of reductive force (eg.10mM DTT) it completely released encapsulated siRNA in2hours, which suggests the possibility of efficient release of siRNA in a reductive milieu of cytosol. We further demonstrated that this delivery system could enhance GFP reporter gene knockdown in MDA-MB-231GFP cells.2. We have developed a tumor-acidity-responsive and intracellular redox environment responsive core-shell-corona polyion complex (PIC) nanoparticle. It was prepared by electrostatic interactions between positively charged and Pt(IV) contained (?)NP/Pt with negatively charged tumor acidity-responsive PEGylated diblock copolymer PPC-DA. Our result shows that the PEGylated delivery system could prolong circulation of platinum drugs in blood. The area under the curve in blood was 9.2-fold greater than that of (?)P/Pt. The platinum accumulation in tumor tissue was also greatly improved. While, at the tumor site, the lower extracellular pH led to the release of positively charged nanoparticles (?)P/Pt and enhanced the cellular uptake of platinum drugs by cisplatin-resistance A549cells. Then the cisplatin was released from (?)P/Pt into cytoplasm under reductive force, resulting successfully inhibition of cisplatin-resistant tumor in the xenograft murine model. This design provides a novel strategy to the treatment of cisplatin resistant tumor.