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A modular and orthogonally reactive platform for fabrication of polymer–drug conjugates for targeted delivery

Increasing interest in the utilization of polymeric systems in diagnostics and delivery has necessitated fabrication of polymers that can undergo facile functionalization with targeting groups and therapeutic/imaging agents in a modular and orthogonal fashion. Herein we disclose the synthesis of an orthogonally functionalizable polymeric support that is reactive towards thiol- and amine-containing molecules. In particular, polymers bearing a maleimide end group along with activated carbonate side chains were synthesized and functionalized sequentially in an orthogonal manner. This orthogonally reactive scaffold was utilized for the preparation of a polymer–drug conjugate, bearing an anti-cancer drug and a targeting agent. Sequential functionalization of polymers was achieved by functionalization of side chain activated carbonate groups with an amine-containing anticancer drug, doxorubicin. The maleimide group at the chain terminus was functionalized with a folic acid ligand through a thiol-maleimide addition reaction. The fabricated polymer–drug conjugate was evaluated as the depot for prolonged release of cytotoxic drugs with in vitro drug release, cytotoxicity and cellular internalization experiments. The results demonstrate that the plug-and-play nature of the dual orthogonally functionalizable copolymers offers a viable platform for modular fabrication of targeted polymer–drug conjugates to address various types of cancers by conjugation of different targeting moieties and drug molecules.