Firouzabadi Bita Mahdavi, Gigliobianco Maria Rosa, Agas Dimitrios, Sabbieti Maria Giovanna, Alimenti Claudio, Devi Lakshmi Sathi, Casadidio Cristina, Martino Piera Di, Censi Roberta
School of Pharmacy, University of Camerino, ChIP Chemistry Interdisciplinary Project Research Centre, Via Madonna delle Carceri, 62032 Camerino, MC, Italy.
Department of Pharmacy, "G. D'Annunzio" Chieti e Pescara University, Via dei Vestini 1, 66100 Chieti, CH, Italy.
Eur J Pharm Biopharm. 2025 Jul 8:114804. doi: 10.1016/j.ejpb.2025.114804.
Stimuli-sensitive hydrogels are utilized in therapeutic applications for their ability to function as controlled drug delivery systems, particularly as delivery platforms for antibodies in cancer treatment. Their adaptive properties, including biocompatibility, high water retention, and tunable mechanical strength, make them well-suited for local and sustained drug release. In this study, redox-sensitive hydrogels based on thiolated hyaluronic acid (HA-SH) were synthetized as tunable platforms for controlled antibody delivery in cancer therapy. HA-SH hydrogels with different degrees of substitution (DS30, DS50 and DS70) exhibited distinct structural and mechanical properties, with HA-SH DS70 forming a denser network and demonstrating greater stability compared to HA-SH DS30 and DS50. Swelling and degradation studies confirmed redox responsiveness of the gels, with DS30 gel degrading faster than DS50 and DS70 gels in reductive environments. Rheological analysis further showed that higher cross-linking density in DS70 gels enhanced viscosity and mechanical strength compared to DS50 and DS30. Immunoglobulin G (IgG), used as a model drug for immunotherapeutic agents, was loaded into DS30 and DS70 hydrogels. The release followed zero-order kinetics at pH 7.4, highlighting the influence of the polysaccharide intrinsic anionic properties. DS30 hydrogels demonstrated sustained release (85 ± 6 % in 9 days), while DS70 exhibited faster release (71 ± 7 % in 5 days). The IgG release kinetics relied on a dual mechanism involving the combination of gel erosion (depending on DS and structural features), as well as IgG poly-charged nature and its ionic interactions with the hyaluronic acid polymeric network, as highlighted by rheological measurements and differential scanning calorimetry (DSC) analysis. Overall, the study highlights the potential of HA-SH hydrogels as customizable and localized immunotherapeutic delivery systems for controlled and precise cancer treatment.
刺激敏感水凝胶因其作为可控药物递送系统的功能而被用于治疗应用，特别是作为癌症治疗中抗体的递送平台。它们的适应性特性，包括生物相容性、高保水性和可调机械强度，使其非常适合局部和持续药物释放。在本研究中，基于硫醇化透明质酸（HA-SH）的氧化还原敏感水凝胶被合成作为癌症治疗中可控抗体递送的可调平台。不同取代度（DS30、DS50和DS70）的HA-SH水凝胶表现出不同的结构和机械性能，与HA-SH DS30和DS50相比，HA-SH DS70形成更致密的网络并表现出更大的稳定性。溶胀和降解研究证实了凝胶的氧化还原响应性，在还原环境中，DS30凝胶比DS50和DS70凝胶降解得更快。流变学分析进一步表明，与DS50和DS30相比，DS70凝胶中更高的交联密度增强了粘度和机械强度。免疫球蛋白G（IgG）用作免疫治疗剂的模型药物，被负载到DS30和DS70水凝胶中。在pH 7.4时，释放遵循零级动力学，突出了多糖固有阴离子特性的影响。DS30水凝胶表现出持续释放（9天内为85±6%），而DS70表现出更快的释放（5天内为71±7%）。IgG释放动力学依赖于双重机制，包括凝胶侵蚀（取决于取代度和结构特征）的组合，以及IgG的多电荷性质及其与透明质酸聚合物网络的离子相互作用，流变学测量和差示扫描量热法（DSC）分析突出了这一点。总体而言，该研究突出了HA-SH水凝胶作为可定制和局部免疫治疗递送系统用于可控和精确癌症治疗的潜力。
