The Preparation And Application Of Reduction-responsive Polymer Drug Delivery System For Enhancing The Cancer Therapeutic Effect

Chemotherapy is an important means of cancer treatment in modern medicine.However,poor water solubility,blood clearance,non-targeting,weak enrichment effect and drug resistance limited the clinical application of traditional chemotherapy drugs.Recently,various drug delivery materials have provided new ideas for enhancing chemotherapy.According the specificity of the lesion sites,the drug delivery vehicle can be designed different types and solve the individual specific problems of patients.Drug delivery system is convenient to prepare with a clear structure which can load drugs through physical adsorption or chemical bonding,and has good biological safety and high drug loading.Nanotechnology has broad and profound developement prospects in biomedical application,which is capable of improving the pharmacokinetics and pharmacodynamics characteristics of conventional therapeutic drug in the body,enhancing drug stability,reducing the toxic and side effects of drug on normal tissues.Nanotechnology offered an optimized developement direction for nano drug delivery system in cancer therapy application.In view of these,this paper selected the antitumor chemotherapy drugs camptothecin（CPT）and doxorubicin（DOX）as the main guest drug molecules to prepare two kind polymer drug delivery systems with reduction-responsive in the tumor microenvironment,and explore their structures,properties,biological safety and antitumor activity,etc.The main research works and results are as follows:1.By adopting an one-step atom transfer radical polymerization（ATRP）method,a hydrophilic poly（ethylene glycol methacrylate）（POEGMA）,a hydrophobic antitumor drug camptothecin（CPT）and a hydrophobic mitochondrial targeting molecule（2-carboxyethyl）triphenylphosphonium bromide（TPP）were grafted on a natural dextran（DEX）to obtained an amphiphilic mitochondrial-targeted polymer prodrug delivery system（DEX-POEGMA-co-PCPT-co-PTPP,abbreviated as DCT）,which could be activated by reducing agent.The hydrophilic part of the polymer prodrug was able to prolong the circulation time of polymer micelles in the blood,and the hydrophobic part was a CPT monomer containing a disulfide bond（SS）,which was used to achieve the reduction-activated controlled drug release in the tumor cells.Meanwhile,TPP molecule could target mitochondria in tumor cells and disrupt mitochondrial membrane potential which could improve the free CPT molecular in the cytoplasmic matrix to enter mitochondria to further induce tumor cell apoptosis.The amphiphilic polymer prodrug could self-assemble in water to form monomolecular micelles with uniform particle size and good biological safety,high drug loading,improved stability,controlled drug release.Experimental results in vivo and in vitro showed that the polymer prodrug has obvious antitumor activity on mouse breast cancer cells（4T1）,human cervical carcinoma cells（He La）,and human breast cancer cells（MCF-7）.Compared to non-targeted polymer prodrugs and free molecule chemotherapy drugs,mitochondrial-targeted polymer prodrug have higher tumor cell growth inhibitory effects.This work proposed a method for designing polymer prodrugs for mitochondrial targeting and reduction-activated of the tumor microenvironment,which provides a new strategy for targeting organelles to enhance the effect of cancer chemotherapy.2.Further,we designed a nanogel system based on reduction-responsive properties with the combination of chemotherapy and photodynamic therapy（PDT）.First,the crosslinker DBHD containing disulfide bonds was used to link the antitumor drug doxorubicin（DOX）and5-aminolevulinic acid（5-ALA）.Then,NH₂-PEG was added to improve the stability of drugs in the aqueous solution and obtained DSA NG.5-ALA is a precursor of the agent porphyrin（PpIX）.The particle size of DSA NG was 105±15 nm,which had good stability under normal physiological environment.When DSA NG entered tumor cells,the high intracellular GSH could cleave the disulfide bonds and the antitumor drug DOX and 5-ALA were released.DOX could inhibit the replication of nucleic acids as well as 5-ALA could in situ converted into photosensitizer PpIX with near-infrared light absorption by the heme biosynthetic pathway in the mitochondria.Under local660 nm laser irradiation,PpIX could absorb light energy and convert the oxygen（³O₂）into highly cytotoxic single oxygen（¹O₂）,so that realize the synergistic tumor cell apoptosis effect beteween chemotherapy and PDT.Both in vivo and in vitro tests have demonstrated the superiority of the combination of chemotherapy and PDT.This work was conducive to design a simple and efficient combined drug delivery system for cancer treatment and showed great prospects for clinical medical transformation.