Stimuli-responsive dextran nanocarriers for biomedical applications

Abstract

The field of nanomedicine stands on the brink of a revolution and could offer groundbreaking solutions to some of the most persistent challenges in healthcare. Recent forecasts predict that the global market for nanomedicines will reach an astonishing $350 billion by 2030, reflecting the immense potential of this technology. One of the most promising applications is the fight against cancer, a disease that still affects millions worldwide, with around 20 million new cases annually. Conventional chemotherapy, while often effective against tumors, faces a critical limitation: its inability to distinguish between healthy cells and cancer cells. This fundamental challenge—creating sufficient therapeutic impact while sparing healthy tissue—has remained unresolved despite decades of intensive research, further underscoring the urgent need for more advanced treatment methods. Nanomedicine enables targeted cancer therapies by developing smart nanocarriers (NCs) that deliver drugs precisely to tumors without harming healthy tissue. Particularly, stimulus-responsive NC systems represent a major therapeutic breakthrough, addressing the crucial challenge of balancing treatment effectiveness with patient safety—a hurdle that has long hindered oncological treatments. Until now, however, the focus has primarily been on self-assembling polymeric nanoparticles and liposomal formulations, both of which have limitations. While the former are mainly used for hydrophobic drugs, the latter suffer from inherent stability issues. This doctoral research advances nanomedicine by developing innovative dextran-based nanocarriers, designed for stimulus-responsive delivery of diverse payloads with high encapsulation efficiency and colloidal stability. The study tackles critical challenges in controlled drug release by engineering smart nanocarriers that respond to specific pathological conditions, particularly the redox imbalance in tumor tissues. Leveraging the biocompatibility and versatility of dextran, this work lays the foundation for a new precision medicine platform capable of responding to disease microenvironments. Since the overproduction of reactive oxygen species (ROS) and glutathione (GSH) is characteristic of the tumor microenvironment, this research involves NCs based on dextran conjugates with unique responsiveness to ROS, GSH, and their combination, ensuring targeted release in the tumor area. The latter—related to dualresponsive NCs—marks a significant advancement due to its synergistic effect on the drug release profile of nanoparticles. The system’s responsiveness was further expanded by incorporating light-sensitive components, enabling external control over drug release for combined chemo-photodynamic therapy. A key achievement of this work is demonstrating exceptional encapsulation versatility, successfully loading both small-molecule drugs (doxorubicin, cisplatin) and large biomolecules (VEGF) with remarkably high efficiency. Systematic optimization of the nanocarrier architecture—particularly the shell density—allowed precise control over release kinetics tailored to different therapeutic needs. This adaptability was extended to wound-healing materials through the innovative integration of hydrophilic NCs into hydrophobic polymer fibers, addressing a known formulation challenge in biomedical materials. This study also contributes to overcoming translational barriers in nanomedicine by extensively optimizing formulation processes. The developed protocols using mini-emulsion techniques ensure reproducible production of stable NCs with uniform properties, while novel conjugation strategies enhance synthetic efficiency. These advancements were complemented by thorough in vitro evaluations, demonstrating excellent biocompatibility and cellular uptake in relevant cell lines. Looking ahead, this research opens promising avenues for clinical translation and further development. The modular design of the dextran-NC platform allows expansion into diverse therapeutic domains, including potential applications in gene delivery and immunotherapy, extending beyond initial uses. The same core technology could enable RNA therapies or treatments for inflammatory diseases by responding to specific immune signals. Within the rapidly growing field of nanomedicine, this work provides a robust foundation for developing next-generation, patient-specific therapies that dynamically adapt to disease conditions, offering improved treatment outcomes for a wide range of medical applications.