Tumor Targeting Of HPMA-Based Nanotherapeutics

Cancer remains a leading cause of death worldwide. Nano drug delivery systems are appealing because they offer many potential benefits such as modifying pharmacokinetics and tissue distribution profiles to increase drug accumulation in tumor and avoiding the side effects of the clinical formulation for improving solubility. Poly (N-(2-hydroxypropyl)methacrylamide) (PHPMA), which has excellent prospects for clinical applications, such as non-immunogenic, non-toxic, and well-functionalized, is an alternative hydrophilic polymer.This study consist of two topics based on the Poly (N-(2-hydroxypropyl)methacrylamide)The first part, a novel amphiphilic block copolymer with acid-responsive release, long circulation and specific passive targeting properties was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The targeting peptide cRGD was quantitatively conjugated to the hydrophilic block or the hydrophobic block. The tumor targeting efficiency and pharmacokinetic characteristics were evaluated by both in vitro and in vivo experiments. In vitro, HPMA copolymers containing cRGD both in the hydrophilic block and the hydrophobic block showed effective targeting to cancer cells. But in terms of animal level, they showed very different pharmacokinetic characteristics. cRGD in the hydrophilic block caused shortened blood circulation time and elevated liver and kidney accumulation. The reason may be related to the altered metabolic rate caused by cRGD in the hydrophilic block.The second part of this thesis is to focus on overcoming multi-drug resistance via nanopreparations. All the nanoparticles were prepared through a nanoprecipitation method using Drug-PLGA conjugates (contain doxorubicin, paclitaxel,7-ethyl-10-hydroxy camptothecin), PDLLA-b-PHPMA and the biocompatible VE-PHPMA (as surfactant). Finally, multiple drug loaded nanoparticles with high loading capacity, superior stability and no need to remove surfactant could be obtained. In vitro cytotoxicity of Dox/PTX, Dox/SN38, PTX/SN38 and Dox/PTX/SN38 with different molar ratios were studied and the drug combination with the optimal ratios to has been found. The nanoparticles co-deliver combined Drug-PLGA conjugates with the optimal ratios showed obviously higher therapeutic effects against drug-resistance tumor in vitro and in vivo. Therefore, these nanoparticles may offer alternative strategies to circumvent drug resistance because they can enable preferential accumulation in tumors, deliver drugs via endocytosis to evade drug transporters, and combine the synergistic effects of multiple drug.