Polydoxorubicin Prodrugs Triggered By Tumor Microenvironment To Degrade: Design And In Vitro Evaluation

Cancer is a serious threat to people’s health,but micromolecular chemotherapeutic drugs have many limitations.Traditional nanodrug delivery systems also have the problems of low drug content and high drug leakage.Based on the microenvironment difference between the tumor cells and the normal physiology,a nanodrug self-delivery system linked by dynamic covalent bonds can be designed.Although drug leaks have decreased to some extent,it is still unavoidable in this system.And drug content is relatively low because drugs are usually bonded to the side or tail of the nanocarrier.To solve these problems,it is necessary to develop a nanodrug self-delivery system which has a low drug leakage as possible and maintains a high drug content also the drugs can be released at a specific site.Therefore,this thesis will focus on the research of polydoxorubicin prodrug nanodrug self-delivery system with drugs as repeating units constructed by dynamic covalent bonds.Mainly carried out the following work:Through the reaction of doxorubicin(DOX)and N-(tert-butoxycarbonyl)acrylic acid hydrazide(Boc-AH)or 1-(tert-butyl)2-(4-nitrophenyl)hydrazine-1,2-dicarboxylate(Boc-NH),the acid-triggered decomposition polyprodrugs which showed long-acting drug delivery and ultra-low leakage were synthesized.They had an ultra-high drug content because the repeating unit of the polyprodrugs were derivatives of DOX and the inter-DOX fragment were small.Polyprodrugs nanoparticles were stable in neutral medium,and degraded into DOX and its derivatives by breaking the hydrazone bond in an acidic medium.In addition,due to the low solubility of the released DOX derivatives,polyprodrugs could release the drug slowly in an acidic medium and present a release behavior with controlled solubility.They showed stronger anti-tumor efficacy than DOX in in vitro cell experiments.And by changing the structure of the two polyprodrug units,the solubility of the released drug was changed to control the drug release rate.Based on the high-concentration of glutathione in the tumor cells microenvironment,an p H/GSH dual-responsive polyprodrug nanodrug self-delivery system with ultra-low drug leakage was prepared,and the polyprodrug was endowed with tumor selectivity.The polyprodrug nanoparticles had high drug content,and degraded into DOX and its derivatives under simulated tumor cell microenvironment conditions.Polyprodrug nanoparticles showed drug release behavior with controlled solubility due to the lower solubility of DOX derivatives than DOX,and the polyprodrug nanoparticles showed extremely low drug leakage in normal physiological media.Compared with DOX,an enhanced anti-tumor efficacy was achieved by polyprodrug nanoparticles in in vitro cell experiments.The decomposition products of polyprodrug nanoparticles synthesized in the previous works were all DOX derivatives,and the physiological activity of DOX derivatives would be affected.In order to release the anti-tumor drug DOX and maintain its physiological activity,a specific chemical structure was used to synthesize a p H/GSH dual-responsive polyprodrug with high drug content and ultra-low drug leakage.Under the conditions of simulating tumor cell microenvironment,the dynamic covalent bond was broken and then an intramolecular nucleophilic reaction carried out.In addition,the nanodrug self-delivery system has ultra-low drug leakage in normal physiological media.In in vitro cell experiments,polyprodrug nanoparticles showed stronger anti-tumor efficacy than DOX.These polyprodrug nanodrug self-delivery systems had high drug content,low drug leakage and slowed drug release behavior with controlled solubility.They decomposed at the tumor microenvironment and showed enhanced anti-tumor efficacy,making them have potential applications in tumor treatments in the future.