Combinatorial approaches in post-polymerization modification for rational development of therapeutic delivery systems.

The combinatorial polymer library approach has been proven to be effective for the optimization of therapeutic delivery systems. The library of polymers with chemical diversity has been synthesized by (i) polymerization of functionalized monomers or (ii) post-polymerization modification of reactive polymers. Most scientists have followed the first approach so far, and the second method has emerged as a versatile approach for combinatorial biomaterials discovery. This review focuses on the second approach, especially discussing the post-modifications that employ reactive polymers as templates for combinatorial synthesis of a library of functional polymers with distinct structural diversity or a combination of different functionalities. In this way, the functional polymers have a consistent chain length and distribution, which allows for systematic optimization of therapeutic delivery polymers for the efficient delivery of genes, small-molecule drugs, and protein therapeutics. In this review, the modification of representative reactive polymers for the delivery of different therapeutic payloads are summarized. The recent advances in rational design and optimization of therapeutic delivery systems based on reactive polymers are highlighted. This review ends with a summary of the current achievements and the prospect on future directions in applying the approach of post-polymerization modification of polymers to accelerate the development of therapeutic delivery systems. STATEMENT OF SIGNIFICANCE: A strategy to rationally design and systematically optimize polymers for the efficient delivery of specific therapeutics is highly needed. The combinatorial polymer library approach could be an effective way to this end. The post-polymerization modification of reactive polymer precursors is applicable for the combinatorial synthesis of a library of functional polymers with distinct structural diversity across a consistent degree of polymerization. This allows for parallel comparison and systematic evaluation/optimization of functional polymers for efficient therapeutic delivery. This review summarizes the key elements of this combinatorial polymer synthesis approach realized by post-polymerization modification of reactive polymer precursors towards the development and identification of optimal polymers for the efficient delivery of therapeutic agents.