Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization‐Induced Self‐Assembly in Aqueous Media

Abstract

Hydrolytically degradable block copolymer nanoparticles are prepared via reverse sequence polymerization‐induced self‐assembly (PISA) in aqueous media. This efficient one‐pot protocol involves the reversible addition‐fragmentation chain transfer (RAFT) polymerization of N,N’‐dimethylacrylamide (DMAC) using a monofunctional or bifunctional trithiocarbonate‐capped poly(ε‐caprolactone) (PCL) precursor. DMAC monomer is employed as a co‐solvent to solubilize the hydrophobic PCL chains. At an intermediate DMAC conversion of 20‐60%, the homogeneous reaction mixture is diluted with water to 10‐25% w/w solids. The growing amphiphilic block copolymer chains undergo nucleation to form sterically‐stabilized PCL‐core nanoparticles with PDMAC coronas. 1H NMR studies confirm >99% DMAC conversion while gel permeation chromatography (GPC) studies indicate well‐controlled RAFT polymerizations (Mw/Mn ≤ 1.30). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) indicate spheres of 20‐120 nm diameter. As expected, hydrolytic degradation occurs within days at 37 ºC in either acidic or alkaline solution. Degradation is also observed in phosphate‐buffered saline (PBS) (pH 7.4) at 37 ºC. However, no degradation can be detected over a three‐month period when these nanoparticles are stored at 20 ºC in deionized water (pH 6.7). Finally, PDMAC30‐PCL16‐PDMAC30 nanoparticles are briefly evaluated as a dispersant for an agrochemical formulation based on a broad‐spectrum fungicide (azoxystrobin).

Synthesis of Poly(propylene oxide)–Poly(N,N′-dimethylacrylamide) Diblock Copolymer Nanoparticles via Reverse Sequence Polymerization-Induced Self-Assembly in Aqueous Solution

“…Recently, we reported the synthesis of hydrolytically degradable poly­(ε-caprolactone)–poly­( N,N ′ - dimethylacrylamide) nanoparticles via reverse sequence PISA in aqueous media . This represents an interesting alternative approach to the PISA synthesis of hydrolytically degradable nanoparticles via statistical copolymerization of a vinyl monomer with various cyclic monomers developed by other research groups. ,, Herein, we expand on this new strategy using poly­(propylene oxide) (PPO) as a weakly hydrophobic precursor for reverse sequence PISA, as detailed in Scheme .…”

“…Ultimately, both routes lead to the formation of much smaller sterically-stabilized diblock copolymer nanoparticles. Furthermore, we recently reported the efficient synthesis of PCL-core nanoparticles by reverse sequence PISA synthesis . In this case, various PCL precursors were dissolved as a concentrated aqueous solution using an alternative hydrophilic monomer, N,N ′-dimethylacrylamide (DMAC), as a cosolvent.…”

“…Subsequently, RAFT polymerization followed by in situ dilution with water led to the formation of well-defined sterically-stabilized spherical nanoparticles that underwent hydrolytic degradation under relatively mild conditions. 47 Herein we report a new reverse sequence aqueous PISA formulation. In this case, we use the water-miscible monomer DMAC as a cosolvent for a weakly hydrophobic trithiocarbonate-capped poly(propylene oxide) (PPO-TTC) precursor in concentrated aqueous solution.…”

Recent progress in polymerization‐induced self‐assembly: From the perspective of driving forces

“…Besides the search for new monomer/solvent pairs, several new strategies for PISA were proposed to avoid the strict selection rule of monomer/solvent pairs for PISA. [115,146,147] For example, Zhao et al reported the polymerizationinduced interfacial self-assembly of the hydrophobic methyl methacrylate (MMA) in a toluene/water emulsion using a hydrophilic while oleophobic macro-CTA. [115] The interfacial chain extension of the macro-CTA yielded amphiphilic BCPs that self-assembled into microcapsules at the oil/water interface.…”

Polymerization‐induced self‐assembly for drug delivery: A critical appraisal

“…Strategies to circumvent premature monomer degradation during ROPISA rely on adjusting the pH and reaction temperature, 157 or resort to NP transfer from polar aprotic solvents to water post‐PISA 231 . Alternatively, reverse sequence PISA, a novel approach to PISA recently established by the Armes group, 235,236 could be an interesting work‐around to incorporate hydrolysis‐sensitive groups in the core 237 . Biodegradability may also be incorporated in the hydrophilic block, for example by chain‐extending poly(sarcosine), 234 or in a terpolymer between the hydrophilic and the hydrophobic block, circumventing the need for ROPISA 189 …”