pH-Responsive Carrier-Free Nanodrug for Efficient Delivery and Synergistic Therapy

The development of nanocarrier systems is often constrained by limited low drug-loading capacity, insufficient control over drug release profiles, and inadequate tumor-targeting efficiency. To address this challenge, we engineered pH-responsive carrier-free nanodrug delivery systems based on dynamic boronic ester linkages. This approach aims to enhance the drug-loading efficiency, enable controlled drug release, and facilitate the codelivery of two therapeutic agents to achieve synergistic therapeutic effects. Modified crizotinib (CZT-diol) was synthesized by introducing a diol group to impart amphiphilicity to the molecule. BTZ/CZT-diol nanoparticles (BC NPs) were fabricated through self-assembly, utilizing CZT-diol as the carrier and bortezomib (BTZ) as the model drug. The physicochemical properties of BC NPs were characterized, and drug-loading efficiency and release kinetics were analyzed using high-performance liquid chromatography. Cytotoxicity, cellular uptake, and 3D tumor spheroid experiments were performed using HeLa cells to evaluate the therapeutic potential of NPs. The BTZ loading efficiency of BC NPs reached 97.79% at a BTZ-to-CZT-diol molar ratio of 1:15. The critical micelle concentration of NPs was determined as 0.013 mg/mL. Under weakly acidic conditions, BTZ release approached 80%, while CZT-diol exhibited a maximum release rate of 97% within 45 h. In vitro cytotoxicity studies demonstrated that BC NPs with various BTZ-to-CZT-diol molar ratios showed strong cytotoxicity against HeLa cells, with CI values below 0.5 (IC65 - IC20). Furthermore, 3D tumor spheroid assays revealed that BC NPs achieved sustained inhibition of tumor spheroid growth, outperforming the free drug group. This innovative strategy eliminates the use of traditional carrier materials while enabling controlled and efficient drug delivery, resulting in significantly enhanced therapeutic outcomes. © 2025 American Chemical Society.