Multiscale Characterization of Thermoresponsive Poly( N -vinylcaprolactam) Across Hydration States for Drug Delivery

Abstract Poly(N-vinylcaprolactam) (PNVCL) is a thermoresponsive polymer of particular interest for stimuli-responsive drug delivery due to its physiologically relevant lower critical solution temperature (LCST). However, temperature-induced conformational changes vary significantly with polymer concentration, making the polymer’s hydration state a crucial design parameter. In this study, we investigated the thermoresponsive properties of PNVCL at hydration states representative of various drug delivery applications, extending current knowledge on dissolved PNVCL to hydration states also relevant for cutaneous application. PNVCL with low molecular weight (<5000 g/mol) and low dispersity (1.2–1.8) was synthesized via free radical polymerization, and the molecular weight was characterized using a multimethod approach. UV–vis spectrophotometry, Raman spectroscopy, and small- and wide-angle X-ray scattering (SAXS/WAXS) were employed to probe conformational changes at multiple length scales. We found distinct structural transitions around the LCST for all hydration states, consistent with a coil-to-globule transition. The LCST exhibited a significant dependence on hydration state, with transitions occurring at 27 °C for powder PNVCL and at 48 °C for highly diluted PNVCL (10 mg/mL in water). These findings highlight the importance of accounting for concentration-dependent shifts in LCST when designing PNVCL-based drug delivery systems, particularly for applications involving changes in local polymer concentration upon administration.