Exploiting the rubbery-state transition of PLGC nanoparticles for enhanced intracellular paclitaxel delivery and anti-tumor efficacy.

The therapeutic efficacy of polymeric nanocarriers is often restricted by rigid, glassy matrices that hinder drug diffusion and poorly controlled surface interactions that limit cellular uptake. This study exploits the temperature-induced, rubbery-state transition of poly(lactide-co-glycolide-co-caprolactone) (PLGC) nanoparticles to enhance the intracellular delivery and anti-tumor efficacy of paclitaxel (PTX). A statistical PLGC terpolymer with a glass transition temperature (Tg) of 35.1 °C was synthesized to facilitate a transition towards a compliant, rubbery state under physiological conditions. To optimize the nano-bio interface, nanoparticles were formulated with a corona of Poloxamer 188 (P188) or Poloxamer 407 (P407). While both surfactants conferred exceptional colloidal stability, the P407-stabilized nanocarriers achieved a remarkable 9-fold higher intracellular accumulation (Mean Fluorescence Intensity; MFI = 45.8 ± 1.2) compared to P188 (MFI = 5.3 ± 0.7), prompting its selection for PTX encapsulation. This enhancement correlates with P407's lower hydrophilic-lipophilic balance (HLB) and longer poly(propylene oxide) (PPO) block, which are hypothesized to support stronger membrane interactions and bypass efflux mechanisms. Mathematical kinetic modeling confirmed that the sustained, pH-responsive PTX efflux at 37 °C is synergistically governed by diffusion and non-Fickian macromolecular chain relaxation of the rubbery PLGC core, overcoming the restricted Fickian diffusion observed in its glassy state at 25 °C. Consequently, PTX-loaded nanoparticles demonstrated robust in vitro anti-tumor efficacy, evidenced by a significantly lower IC50 (52.39 ± 11.11 nM) compared to free PTX (72.81 ± 19.19 nM) after 48 h of exposure, alongside severe cytotoxic morphological changes. Ultimately, integrating a rubbery-state polymer matrix with an optimal surface coating provides a high-performance platform for maximizing the intracellular delivery of hydrophobic chemotherapeutics.