Tumor Microenvironment Responsive Polymeric Nanomedicines for Cancer Therapy
Supervisor:wang yan mei
Cancer incidence and mortality are rapidly growing worldwide and are responsible for the majority of global deaths.Traditional anti-cancer compounds lack of tumor specificity,resulting in high systemic toxicity.Therefore,targeted delivery is of utmost importance in order to overcome current limitations in cancer therapy.Loading of drugs into properly designed nanocarriers can extend blood circulation,allowing them to accumulate preferably at the tumor site by passive or active targeting.Tumor hypoxia,a hallmark of solid tumor,not only limits chemotherapeutic efficacy,but is strictly associated with tumor angiogenesis and metastasis.Hypoxia could be alleviated by directly delivering oxygen to tumor cells,or be utilized to activate bioreductive anti-cancer prodrug for tumor targeted therapy.But due to the heterogeneity of intratumoral hypoxic conditions,it’s impossible to eradicate tumor cells by monotherapy.Synergistic photodynamic-chemotherapy could achieve superadditive effects(namely"1+1>2")by co-delivering photosensitizer and bioreductive anti-cancer prodrug encapsulated in properly designed stimuli-responsive nanocarriers.We systemically studied three types of tumor microenvironment responsive polymeric nanomedicines for cancer therapy.(1)We developed a block copolymer with perfluorocarbon side chains to increase oxygen capacity,and another block copolymer with TAT peptide being masked via an acidity-sensitive bond.The two copolymers are amphiphilic and can self-assemble into micelles to facilitate the loading of photosensitizer.After accumulating at the tumor site,the membrane penetrating functionality of TAT peptide could be restored due to the cleavage of the acidity-sensitive bond to facilitate tumor uptake.Oxygen consumed during photodynamic can be immediately supplemented by the oxygen-loaded nanoparticles to enhance therapeutic efficacy.(2)We developed a reactive oxygen species(ROS)sensitive nanocarrrier for synergistic photodynamic-chemotherapy by co-encapsulating a photosensitizer and a hypoxia-activated prodrug.In order to bypass macrophage uptake and to improve tumor penetration,the nanomedicine was further modified with red blood cells membrane and tumor-penetrating peptides.Upon laser irradiation,ROS produced by photosensitizer could induce degradation of the ROS-sensitive nanocarrrier and release the activated anti-cancer agent.The synergistic tumor targeted PDT and hypoxia-activated chemotherapy significantly suppressed tumor growth by 85.07%with negligible side effects.(3)We conjugated hyaluronic acid with 2-nitroimidazole,which could be converted to hydrophilic 2-aminoimidazoles under hypoxic environment Photosensitizers and bioreductive prodrugs were loaded into the polymeric nanovesicle.Upon light irradiation,the production of ROS by the loaded photosensitizers aggravated the local hypoxic environment,which further induced the reduction of hydrophobic 2-nitroimidazole into hydrophilic 2-aminoimidazoles,thereby causing the dissociation of the nanoparticles.Furthermore,the bioreductive prodrugs can be activated in the hypoxic environment to release toxic oxidizing radicals for enhanced anti-cancer efficacy.