Establishment And Evaluation Of Matrix Metalloproteinase Responsive Nano Drug Delivery System

Ideal targeting cancer therapy requires the balance between "great therapeutic effect" and "low toxicity". Targeted drug delivery systems are one of advanced research hotspots in cancer treatment field. To achieve the desired effect, it is necessary to develop systems which are controllable and programmable delivery drugs in the tumor tissues. Combining of an increased understanding of tumor microenvironment and latest development of surface engineering technology, we designed the tumor microenvironment responsive drug delivery systems to enhance antitumor effect and limit toxic side effect. The main content of this dissertation are described in two parts as below:1. To achieve a drug delivery system combining the programmable long circulation and targeting ability, surface engineering nanoparticles (NPs), having a sandwich structure consisting of a long circulating outmost layer, a targeting middle layer and a hydrophobic innermost core were constructed by mixing a matrix metalloproteinase MMP2 and MMP9-sensitive copolymers (mPEG-Pep-PCL) and folate receptor targeted copolymers (FA-PEG-PCL). Their physiochemical traits including morphology, particle size, drug loading content, and in vitro release profiles were studied. In vitro studies validated that the inhibition efficiency of tumor cells was effectively correlated with NP concentrations. Furthermore, The PEG layer would detach from the NPs due to the up-regulated extracellular MMP2 and MMP9 in tumors, resulting in the exposure of folate to enhance the cellular internalization via folate receptor mediated endocytosis, which accelerated the release rate of CPT in vivo. The antitumor efficacy, tumor targeting ability and bio-distribution of the NPs were examined in a B16 melanoma cells xenograft mouse model. These NPs showed improved tumor target ability and enhanced aggregation of camptothecin (CPT) in tumor site and prominent suppression of tumor growth.2. We have developed MMPs-responsive and enhanced activation of Fas-FasL pathway nanoparticles. The smart NPs with a sandwich structure, consisted of a MMP-cleavable PEG outer layer, anti-Fas antibody middle layer and a CPT loaded inner core, were fabricated. These NPs could selectively accumulate at the tumor site with high level of MMPs. By the leave of PEG layer, these NPs exposed the FasL and mimic the function of cytotoxic lymphocyte (CTL) to activate or strengthen the Fas-FasL induced apoptosis pathway, thus enhancing the anti-tumor ability. These NPs combined of the function of anti-Fas antibody and CPT, achieved a sustained immune responses and high tumor inhibition of the tumor growth in the B16 xenograft tumor animal model. Finally, pathological analysis (H&E staining, TUNEL staining) revealed the high in-vivo inhibition of tumor mainly come from the enhanced apoptosis of the tumor cells, confirming the synergetic effect of anti-Fas antibody and CPT. Collectively, these NPs showed great promise as a candidate for the combination treatment of immune therapy and chemotherapy.