Synthesis of click‐reactive HPMA copolymers using RAFT polymerization for drug delivery applications

Abstract

This study describes a versatile strategy combining reversible addition fragmentation transfer (RAFT) polymerization and click chemistry to synthesize well-defined, reactive copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) for drug delivery applications. A novel azide containing monomer N-(3-azidopropyl)methacrylamide (AzMA) was synthesized and copolymerized with HPMA using RAFT polymerization to provide p(HPMA-co-AzMA) copolymers with high control of molecular weight ($10-54 kDa) and polydispersity ( 1.06). The utility of the side-chain azide functionality by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was demonstrated by efficient conjugation (up to 92%) of phosphocholine, a near infra-red dye, and poly(ethylene glycol) (PEG) with different substitution degrees, either alone or in combination. This study introduces a novel and versatile method to synthesize welldefined click-reactive HPMA copolymers for preparing a panel of bioconjugates with different functionalities needed to systemically evaluate and tune the biological performance of polymer-based drug delivery.In our work, we present a versatile postmodification strategy that utilizes RAFT radical polymerization of HPMA and a Additional Supporting Information may be found in the online version of this article.

Structures and Synthesis of Zwitterionic Polymers

“…The problem of incomplete conversion unbalancing the charge neutrality of polyzwitterions in post-polymerization modifications can in principle be avoided when reacting the precursor polymer with prefabricated zwitterionic reagents ( Figure 11) [193,[411][412][413][414][415][416][417][418]. Still, this implies the judicious choice of the reactive groups used for the modification.…”

“…If one of these functional groups is fixed on the precursor polymer and the other one to the zwitterionic reagent, this coupling strategy holds both the potential for high coupling efficiencies and selectivities as well as (for charge neutrality) harmless residual reactive sites if remaining. So far, the use of zwitterionic alkynes has been preferred, which are coupled to polymeric azides ( Figure 12) [193,[414][415][416][417][418]. Still, the inverse strategy should be equally feasible.…”

A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery

“…First, 3-azidopropyl-1-amine was synthesized based on a previous report [30]. The 3-azidopropyl-1-amine (3 equivalents) was then reacted with fluorescein isothiocyanate (FITC) in dimethyl formamide (DMF) in the presence of trimethylamine (1 equivalent).…”

Polymers and Dyes: Developments and Applications

“…The synthesized polymer is hydrophilic and exhibited size-dependent blood circulation. High molecular-weight polymers (54 kDa) had a very good bioavailability and could still be detected 24 hours after injection [101,102].…”