Construction And Evaluation Of Tumor Microenvironment Dual Sensitive Nanoparticle Drug Delivery System

Cancer has become the most serious threaten for human health. At present, clinical treatment methods mainly include surgical operation, radiotherapy, chemotherapy and biotherapy. However, chemotherapy remains the primary treatment for cancer among these treatment measures. As we all know, many chemotherapeutic agents have great limitations in their clinical use, such as low selectivity, short circulation time in vivo and severe side effects. Conversely, nano-scaled drug delivery systems which possess distinct advantages have emerged as a promising platform for cancer therapy.Compared with the conventional chemotherapeutic agents, polymeric drug delivery systems for cancer therapy have the following advantages:(1) improving drug solubility; (2) altering the pharmacokinetics and tissue distribution; (3) prolonging the circulation time through avoiding rapid clearance by the reticuloendothelial system; (4) enhancing the drug accumulation in the tumor tissue via the Enhanced Permeability and Retention (EPR) effect; (5) reducing the side effects.Stimuli-responsive drug-delivery systems have attracted great attention for controlled drug release. The tumor tissues and cells have a low pH value and high concentration of glutathione. According to these features, we designed a nanoparticle drug delivery system which is sensitive to the two kinds of tumor microenvironment at the same time.3,3'-Dithiodipropionic acid modified paclitaxel (DTPA-PTX) and 2,3-dimethylmaleic anhydride (DMMA) are conjugated to the amino groups of poly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-PLL). The surface charge of the obtained mPEG-b-(PLL-co-(PLL-DMMA)-co-(PLL-DTPA-PTX)) nanoparticles (DAPDC) can change from negative at blood pH to positive at tumor extracellular pH, implying that the DAPDC will have a prolonged blood circulation time through avoiding rapid clearance by the reticuloendothelial system and an enhanced cell uptake at the tumor site. Compared with the control group, the in vitro studies show that the DAPDC exhibit effective cellular uptake, rapid intracellular drug release and significantly enhanced cytotoxicity against MCF-7 tumor cells, owing to the tumor-relevant pH and reductive conditions. These indicate that the charge-conversional DAPDC provide an excellent platform for potential tumor therapy.