The Preparation Of Stimuli-responsive Polymer-drug Conjugates Based On Functional Poly(lactide)s

Chemotherapy is an important therapeutic method in the comprehensive treatment of cancer. However, most of the chemotherapeutics, such as cisplatin ? vincristine(VCR) and doxorubicin(DOX), often suffer from their inherent limitations, e.g., poor water solubility, severe toxic and side effects, and low therapeutic index. On the contrary, polymeric nanomedicines usually possess prolonged blood circulation and reduced non-specific uptake owing to their surface modifications, enhanced tumor accumulation via the Enhanced Permeability and Retention(EPR) effect, and decreased inherent toxicity. According to the drug-incorporation mechanisms,polymer nanoparticle carriers can be divided into two categories including polymer-drug conjugates by covalent conjugation, polymer vesicles by physical package. Compared to other types of nanomedicines, polymer-drug conjugates typically possess excellent stability against environmental changes and can overcome the shortcomings of other types of nanomedicines. However, such linkages might be too stable even in the tumor cells to release anti-tumor drugs effectively. The insufficient drug release may impair the overall anticancer efficiency of these polymer-drug conjugates and hamper their final applications into human bodies,permeability and retention(EPR) effect. Besides, The conventional polymeric nanomedicines based on biocompatible water-soluble polymers usually cannot readily be excreted from the body due to their nondegradability.Based on the characteristics of the tumor microenvironment, In this study,pH-sensitive, water-soluble norbornene-functional polylactide-based prodrugs(PLA-g-mOEG/PTX) were successfully designed and synthesized. First, we have successfully constructed a new class of polymer carrier with norbornene-functional polylactide-based backbones carrying mOEG-based grafts and hydrazide groups,made through ring-opening polymerization(ROP) of norbornene-functional lactide monomer using organocatalyst, followed by a highly efficient 1,3-dipolar cycloaddition click reaction without copper catalyst, photoinitiated thiol-ene click reaction. Then, functionalized paclitaxels(LEV-PTX) were grafted to pendant hydrazide functionalized polymer carrier(PLA-g-mOEG/hyd) via an acid-labile hydrazone bond to achieve efficient and specific intracellular release of PTX.Furthermore, redox-responsive polymeric prodrugs, P(LA-g-mOEG)-b-P(LA-SS-PTX),were successfully synthesized by combination of ROP, click, ester, and condensation reactions. The polymeric prodrugs were synthesized via the following steps:(i)P(LA-g-mOEG)-b-PLA amphiphilic brush block copolymers were synthesized via sequential ring-opening polymerizations; then,(ii) the hydroxyl functionalized block copolymers were prepared via a thiol-ene click reaction;(iii)P(LA-g-mOEG)-b-P(LA-SS-COOH) was synthesized by an esterification reaction;(iv) PTX was directly conjugated to the side groups of P(LA-g-mOEG)-b-P(LA-SS-COOH) through another esterification reaction.Drug release demonstrate that the prodrugs, while stable at physiological environment, effectively release PTX under tumor microenvironment. As illustrated by cytotoxicity study, while the corresponding polymer carrier was nontoxic, the polymeric prodrug exhibited higher therapeutic efficacy toward MCF-7 and A549 cancer cells. The norbornene-functional polylactide-based polymeric prodrug has appeared as a novel anticancer nanomedicine for cancer therapy.