Fabrication And Nanostructural Tuning Of A Novel GSH-Responsive Triblock Polyprodrug Amphiphiles

The research on tumor microenvironments-responsive amphiphilic copolymers have been increasingly regarded as an important area in drug delivery system, and is recieving growing attention.This dissertation mainly has focused on the fabrication of stimuli-responsive polymeric vehicles and their applications as drug delivery system, especially reduction-responsive polymers. The first chapter give a brief introduction concerning the design and preparation of functionalized and responsive polymeric materials for the construction of smart drug delivery system has been a great challenge. And then we introduce through self-assembly, the control of the shape,volume,dimensions, and the integrations of advanced functions can be realised. In the second chapter, we termed the triblock copoloymer as polyprodrug amphiphiles, and through hierarchical assembly, can afford multiple morphologies. The third chapter demonstrated the effect of shape on biological interactions and co-delivery strategy, which may achieve the synergistic effect for cancer therapies.The main content and conclusions of this dissertation are summarized below:(1) Camptothecin (CPT) prodrug monomer with a disulfide linkage, CPTM, was synthesized from methacryloyl chloride,2,2’-dithiodiethanol and triphosgene via fuctionalizing the20-hydroxy of camptothecin. We employed reversible addition-fragmentation transfer (RAFT) technique to polymerize CPTM prodrug monomer using PEG-based macroRAFT agent, affording PCPTM-b-PEG-b-PCPTM triblock copolymers with CPT moieties in the hydrophobic block. Through macromolecular self-assembly, three typical nanostructures, including nanospheres, gear like disks, large compound micelles and staggered lamellae, can be fabricated.(2) The self-asssembly parameters influenced on the formation of nanocarriers were investigated to understand their controllable assembly rule. Studies have revealed that staggered lamellae and large compound vesicles show quite fast cellular uptake, may follow unique internalization pathways. Reductive milieu-triggered release kinetics of CPT, and shape-modulated in vitro cytotoxicity were also explored. It is believed that the morphology can significantly impact in transport, targeting, internalization, degradation and other areas of drug delivery system. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological functions open up new horizons. And these finding will provide the novel basis on the design of next-generation drug delivery systems.In terms of potential applications of polymeric assemblies from polyprodrug amphiphiles in clinical therapies, we explored the following design. Studies have shown that the use of single anti-cancer drug may have limitations due of multi-drug resistance by cancer cell. Herein, we developed a novel polyprodrug amphiphiles triblock copolymer to encapsulate another drug as the co-delivery strategy for chemotherapy. Through the combined use of two or more drugs, such as the DOX(nuclear enzymes DNA topoisomerase II inhibitors) and CPT(nuclear enzymes DNA topoisomerase Ⅱ inhibitors), is extensively used in synergetic therapy. When exposed to biological thiols such as GSH, the disulfide bond linkage could be cleaved, and then an intramolecular cyclization, released the active CPT. At the same time, nanostructure began to dissociate, the process is associated with core hydrophobicity-to-hydrophilicity transition leads to immediate doxorubicin release, that is, the release is synchronized camptothecin permeabilization process. Further in vivo/vitro cell uptake and cytotoxicity experiments found that the CPT conjugated nanocarriers could effectively encapsulate DOX and subsequent realse it in cell, And showed a higher cytotoxicity than copolymer, free CPT, and free DOX in all the doses tested in HepG-2cells. This finding is in agreement with the above results showing that polyprodrug amphiphiles triblock copolymer formed nanocapsules served as a carrier to deliver DOX leading to enhanced antitumor activity and synergistic anticancer effects.