Aqueous RAFT Synthesis of pH-Responsive Triblock Copolymer mPEO-PAPMA-PDPAEMA and Formation of Shell Cross-Linked Micelles

Herein we report the synthesis and characterization of polymeric cross-linking agents and novel shell cross-linked (SCL) micelles utilizing reversible addition-fragmentation chain transfer (RAFT) polymerization. A series of pH-responsive ABC triblock copolymers consisting of alpha-methoxypoly(ethylene oxide)-b-poly[N-(3-aminopropyl)methacrylamide]-b-poly[2-(diisopropylamino)ethyl methacrylate] (mPEO-PAPMA-PDPAEMA) have been synthesized via RAFT polymerization in aqueous media at 70 degrees C employing a PEO-based macro-chain transfer agent (macro-CTA). These triblock copolymers molecularly dissolve in aqueous solution at low pH (<5.0) due to protonation of primary amine residues on the PAPMA block and tertiary amine residues on the PDPAEMA block. Above pH 6.0, the polymers self-assemble into micelles consisting of PDPAEMA cores, PAPMA shells, and mPEO coronas. Hydrodynamic dimensions of the triblock copolymer micelles depend on both triblock copolymer composition and solution pH. Narrowly dispersed poly(N-isopropylacrylamide) was synthesized utilizing the difunctional CTA, 2-(1-carboxy-1-methylethylsulfanylthiocarbonylsulfanyl)-2-methyl-propionic acid (CMP). The chain ends of the PNIPAM were converted from carboxylic acids to N-hydroxysuccinimidyl esters (NHS) through dicyclohexylcarbodiimide (DCC) coupling, yielding an amine-reactive polymeric cross-linking agent, NHS-PNIPAM-NHS. SCL micelles were attained via reaction of PAPMA (shell) amine functionality with NHS-functionalized PNIPAM. These SCL micelles swell when the solution pH is lowered below the pK(a), of the PDPAEMA block. The polymeric cross-linking agent NHS-PNIPAM-NHS synthesized in this work has inherent temperature-responsive segments and a cleavable trithiocarbonate unit which have future potential in mediating drug delivery from SCL micelles.