Nanopartículas híbridas termossensíveis baseadas em proteína-polímero como um potencial sistema carreador de agentes terapêuticos contra o câncer

Abstract

In recent years, hybrid materials combining proteins and polymers have attracted significant interest in the biomedical field, particularly in the development of controlled drug delivery systems. The conjugation of these two classes of materials enables the integration of biocompatibility, stability, and functionality into a single system. Among natural proteins, silk fibroin (SF) stands out as a promising biocompatible material, while poly(N-vinylcaprolactam) (PNVCL) offers a thermoresponsive behavior suitable for therapeutic applications. In this context, the SF–PNVCL hybrid system emerges as an innovative strategy for the development of nanocarriers capable of responding to specific stimuli, such as temperature increases, thereby optimizing the release of therapeutic agents. In this work, novel thermoresponsive hybrid systems based on silk fibroin (SF) and PNVCL were developed, aiming to produce nanoparticles capable of promoting controlled release of therapeutic agents, using curcumin as a model drug. The hybrid systems were synthesized using a grafting-from strategy via reversible addition-fragmentation chain-transfer (RAFT) polymerization, through the functionalization of fibroin with chain transfer agents (CTA1 and CTA2). A second synthetic route was established by activating CTA2 with pentafluorophenol (PFP). The systems were characterized by Fouriertransform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and powder X-ray diffraction (PXRD). The nanoparticles were further evaluated by dynamic light scattering (DLS), zeta potential measurements, and transmission electron microscopy (TEM). The results revealed that the hybrid systems exhibited nanoparticulate morphology (~200 nm), good colloidal stability, and a thermoresponsive phase transition near 40 °C. Additionally, the nanoparticles demonstrated curcumin encapsulation efficiency of approximately 40%, with enhanced release at elevated temperatures. The release kinetics showed a better fit to the Weibull and Gompertz models (R² > 0.99), indicating a controlled and thermoresponsive release process. In vitro cytotoxicity assays, evaluated by flow cytometry, revealed low toxicity in normal cells (MRC-5) and high selectivity toward the 4T1 cancer cell line, with up to 49.5% cell inhibition. Based on these findings, SF– PNVCL hybrid systems represent a promising platform for the development of smart carriers for targeted therapeutic applications.