Poly(ethylene Glycol) Shell-sheddable TAT-modified Core Cross-linked Nanomicelle Drugs

The ideal nano-drug can make active and intelligent response to the tumor microenvironment,and realize the active targeting,active transmembrane delivery and intracellular site-specific release of anti-tumor drugs,so as to reduce the side effects and overcome the chemotherapy resistance caused by the overexpression of P-glycoprotein.Therefore,the amphiphilic graft copolymers containing TAT,DOPA and thiolytic cleavable PEG were prepared.By using Fe³⁺and DOPA,acid sensitive coordination bonds can be formed,which can drive the self-assembly of graft copolymers and form reversible core cross-linked nanomicelle drugs.The intelligent response behavior of the nanomicelle drugs was studied:enrich in tumor through enhanced permeability and retention effect?tumor redox environment-responsive shedding of PEG?the exposed TAT transports the drug to lysosome?the coordination between DA and Fe³⁺was changed from bis-complexes to mono-complexes under acidic conditions in lysosomes?quickly release enough doses of anti-tumor drugs and"kill"tumor cells.The paper consists of the following four chapters and the summary of the whole paper:In chapter 1,the drug delivery system and polymer nanomicelles are summarized,and the research content and significance of this paper are introduced.In chapter 2,the detailed synthesis process of amphiphilic graft copolymer mPEG-SS-g-P?ae-Asp?-MCA-DA-TAT,as well as the preparation and characterization of related micelles are described.The results show that mPEG-SS-g-P?ae-Asp?-MCA-DA-TAT could be prepared by ring-opening and graft reaction.Fe³⁺can drive the amphiphilic polymer to self-assemble into spherical micelles with an average size of180.1 nm.The CMC of the micelles is lower(1.41×10^-2 mg/mL).The micelles have the potential to withstand dilution to avoid disassembly of nanomicelles during in vivo circulation.The coordination between DA and Fe³⁺is pH-responsive.The PEG shell of nanomicelles can be removed in the redox environment,while the nanomicelles could still exist stably due to the cross-linking of DA with Fe³⁺.In chapter 3,the morphology,drug-loading content?DLC?,drug-loading efficiency?DLE?,plasma stability and in vitro release characteristics of the DOX-loaded cross-linked nanomicelles?DOX-TAT-CCLMs?were studied.DOX-TAT-CCLMs are spherical micelles with an average size of 251.7 nm.The DLC and DLE of DOX-TAT-CCLMs are 10.18±0.24%and 61.16±1.65%respectively.DOX-TAT-CCLMs can exist stably in a simulated plasma environment.DOX-TAT-CCLMs can realize lysosomal pH-triggered drug release.In chapter 4,the preliminary biological evaluation of the DOX-TAT-CCLMs was carried out.The TAT modification considerably enhanced the mean fluorescence intensity of the nanomicelles endocytosed by MCF-7/ADR cells by 8 times,compared with DOX·HCl after 8 h of incubation.The IC₅₀ value of nanomicelles?11.61±0.95?g/mL?was nearly 4 times lower than that of DOX·HCl against MCF-7/ADR cells,implying that the nanomicelles could overcome drug resistance observed in MCF-7/ADR cells.DOX-TAT-CCLMs has a good antitumor effect on 4T1 tumor-bearing mice,and the antitumor rate is 67%.At last,we summarize the whole paper and elucidate the innovation and deficiency of this paper.