The Construction Of Bio-responsive Polymeric Nanocarriers And Their Applications In Drug Delivery And Antitumor Therapy

Cancer has become one of the most important threats to global human health.Traditional cancer therapy generally depended on a single therapeutic treatment including chemotherapy,radiation therapy,photothermal therapy（PTT）,photodynamic therapy（PDT）and immunotherapy.However,it usually required high dosages or multiple injections,which remains many limitations including low therapy effect and severe side effects.Chemotherapy,as a major clinical therapy mean,has been widely applied in cancer treatment.Nevertheless,most anticancer drugs confront some limitations,especially such as the nonspecific distribution,poor antitumor efficacy and severe toxicity.In comparison with chemotherapy or PDT alone,combining chemo-photodynamic therapy has emerged as a promising cancer treatment,which use PDT to overcome the multidrug resistance of chemotherapeutic agents.The dual advantages of chemo-photodynamic therapy by nanocarriers effectively improve the bioavailability of drugs for reducing toxicity and increasing efficiency.Polymer-based nanotherapeutics show stable or switchable chemical structures and excellent biocompatibility.Meanwhile,nanogels perform biocompatibility,high loading capacity,superior structural stability.Therefore,they have become research hotspots in nanocarrier drug delivery systems.In this paper,the construction of amphiphilic polymer prodrugs and nanogles were taken as the starting point,several new types of bio-responsive nanoprodrugs were designed and constructed for improving drug treatment effects.The specific content of these nanoprodrugs are shown as follows:（1）In this study,a hydrophobic anticancer drug doxorubicin（DOX）was connected to the dextran-based polymer DEX-P（OEGMA-b-MGMA）backbone by using a pH-responsive hydrazone bond to obtain a class of amphiphilic polymer prodrugs DEX-P（OEGMA）-b-P（MGMA-DOX）（DOM@DOX）.Compared to normal tissues,unique conditions in the tumor microenvironment,such as a lower pH,can induce accurate release of drug into specific lesions.This strategy provides an efficient approach to overcome the issues of unexpected drug leakage and poor circulation stability,thereby reducing the side effects and enhancing the effect of cancer treatment.In this study,we design a class of acid activatable supramolecular nano-prodrug（DOM@DOX）with bottlebrush architecture,which connects with a hydrophilic OEGMA chain by atom transfer radical polymerization（ATRP）and further conjugates with an anticancer drug doxorubicin（DOX）via an acidity-responsive hydrazine bond.Furthermore,DOM@DOX prodrug have a high drug loading up to 48 wt%for DOX,and the prodrug can maintain a stable nano-sized spherical shape in aqueous solution by a self-assembly strategy.In an acidic environment inside tumor cells,the hydrazine bond of the prodrug breaks,leading to the release of DOX from parental micelles.Attributed to the small size of the carrier,the prodrug exhibits good intratumoral permeability,good circulation stability and significant tumor suppression efficiency in the tumor-bearing mouse models,which should benefit for the development of new generation nanomedicine for enhanced chemotherapy.（2）To improve the therapeutic efficiency of chemotherapy,a class of reactive oxygen species（ROS）responsived amphiphilic DEX-b-P（CPTMA-co-OEGMA）（DCPT）prodrug was obtained.The DCPT polyprodrug show unimolecular micelles,ROS-activatable decomposition and controlled release.In this system,the camptothecin（CPT）was selected as a chemotherapy drug and poly（ethylene glycol）methyl ether methacrylate（OEGMA）played a role of hydrophilic block to enhance the water solubility of DCPT micelles.In the high ROS levels of the tumor microenvironment,micelles disassembled and simultaneously the CPT would be released from the DCPT micelles.The resulting DCPT polyprodrug was intravenously injected into the mouse for evaluating the anti-tumor effectiveness.Firstly,the DCPT could be efficiently accumulated in the tumor site with enhanced permeability and retention（EPR）effect.Secondly,the DCPT micelles with high stability would facilitate the endocytosis efficiency.Then,the DCPT micelles would be exposed to a high ROS level in mitochondria,and the active CPT molecule would be released due to the cleavage of carbonate bond,resulted in mitochondria impairment and cell apoptosis.The4T1-tumor growth would be greatly inhibited by these two DCPT polyprodrugs,with outstanding in vivo biosafety.The rational design of polyprodrug nanomedicine may be served as a promising strategy for the development of tumor microenvironment-responsive ANMs,thus improving chemotherapy efficacy.（3）Photodynamic therapy（PDT）,with appealing advantages of the minimal invasiveness and nonsystemic toxicity,is regarded as a kind of novel therapeutic approach synergy with chemotherapy in the treatment of malignant cancers.However,most current clinically using single photosensitizer（PS）or chemotherapeutic agent present huge challenge in the nonselective toxicity,physiological instability and low therapy efficacy.Herein,we designed a reduction-responsive nanogels（NGs）delivery system based on disulfide bond to crosslink purpurin 18（P18）and chemotherapy agent HCPT for achieveing photodynamic/chemotherapy.Specifically,DBHD@P18@HCPT nanogels（denoted as DPH NGs）was prepared by chemically cross-linking method,with high drug loading and an optimao nanogels size（～60 nm）results for well permeability.Due to a high GSH level in tumor environment,the nanogels happened decomposition and selectively release these cargos in diseased regions.P18 not only would produce cytotoxic reactive oxygen species（ROS）to kill cancer cells upon laser irradiation at 660 nm,but also could be used as a powerful NIR fluorescence imaging agents.Meanwhile,DBHD@P18-Mn@HCPT nanogels was formed between P18 and Mn²⁺ions to endow it with magnetic resonance（MR）imaging ability.Therefore,our prepared DPH NGs showed excellent chemotherapy effect and phototoxicity under the laser irradiation of 660 nm both in vitro and in vivo.Additionally,DPH NGs delivery system possesses MRI/NIRF dual-modal imaging ability,which benefit for precise disease diagnosis,real-time monitoring of treatment progress.