pH-Triggered Swelling and Disassembly of Tertiary Amine-Containing Block Copolymer Self-Assemblies: Role of Molecular Weight in Nanocarrier Design

pH-responsive polymers constitute an important nanocarrier system for tumor-targeted drug delivery as they enable drug release either through nanoparticle swelling or by complete disintegration in response to the acidic environment of cancer cells and tissues. Within this class, tertiary amine-containing polymers bearing 2-(diethylamino) ethyl methacrylate (DEAEMA) or 2-(azepan-1-yl) ethyl methacrylate (AEMA) units are widely used due to their physiologically relevant pKa values and strong potential for size-tunable drug delivery. Despite their popularity, inconsistent behaviors have been reported, with some systems exhibiting predominant swelling at tumor extracellular pH levels (6.5–6.8), while others undergo spontaneous disassembly. The mechanistic origins of these contrasting responses remain unclear, posing a critical challenge for the rational design of reproducible, pH-responsive nanocarriers. To address this gap, we synthesized a series of [poly(ethylene glycol) monoethyl ether]5k-b-poly[(2-(azepan-1-yl)ethyl acrylate)x] (PEG5k-b-PAEA) and [poly(ethylene glycol) monoethyl ether]5k-b-poly[(2-(diethylamino)ethyl methacrylate)y] (PEG5k-b-PDEAEMA) of varying molecular weights via RAFT polymerization and postpolymerization modification. Systematic evaluation of their transmittance and hydrodynamic diameter revealed that self-assembled nanostructures from higher molecular-weight polymers undergo rapid structural reorganization and efficient disassembly at acidic pH, whereas lower molecular-weight analogs exhibit only limited swelling or partial disassembly. These results implied a molecular weight threshold that governs pH-responsiveness and provides fundamental design strategies for the manufacturing of size-tunable, tumor-targeted polymeric drug delivery systems. Additionally, the polymers showed thermoresponsiveness modulated by pH and molecular weight, highlighting their dual stimuli-responsive capability.