Navigating the challenges of metallopharmaceutical agents: strategies and predictive modeling for skin cancer therapy

Skin cancer (SC) is the most prevalent malignancy worldwide, with subtypes varying in aggressiveness: basal cell carcinoma tends to be locally invasive, squamous cell carcinoma has a higher metastatic risk, and melanoma remains the deadliest form. Current treatments such as surgery, radiotherapy, and systemic chemotherapy are associated with aesthetic and functional morbidity, recurrence, and/or systemic toxicity. Although targeted therapies and immunotherapies offer clinical benefits, their high cost and limited accessibility underscore the need for innovative, affordable alternatives. Metal-based compounds (metallopharmaceuticals) are promising anticancer agents due to their ability to induce oxidative stress, modulate redox pathways, and interact with DNA. However, clinical translation has been limited by poor aqueous solubility, rapid degradation, and low skin permeability. This review discusses the most recent preclinical findings on gold, silver, platinum, palladium, ruthenium, vanadium, and copper complexes, mainly in topical and systemic treatments of SC. Advances in chemical and physical enhancers, such as hydrogels and microneedles, and in drug delivery systems, including bacterial nanocellulose membranes and nanoparticles, as well as liposomes and micelles, for enhancing skin permeation and protecting the integrity of metal complexes are also discussed. Additionally, we examine the contribution of photodynamic therapy to SC treatment and the use of mathematical and computational modeling to simulate skin drug transport, predict biodistribution, and support rational nanocarrier design. Altogether, these strategies aim to bridge the gap between physicochemical innovation and clinical applicability, paving the way for more selective, stable, and cost-effective SC treatments.

皮肤癌（Skin Cancer, SC）是全球范围内最常见的恶性肿瘤，其不同亚型的侵袭性存在显著差异：基底细胞癌多呈局部浸润性生长，鳞状细胞癌的转移风险更高，而黑色素瘤则是致死性最强的皮肤恶性肿瘤类型。当前临床常用的治疗手段如手术、放疗及全身化疗，往往会带来外观与功能损伤、肿瘤复发，或伴随全身毒性反应。尽管靶向治疗与免疫治疗可带来临床获益，但高昂的成本与有限的可及性，凸显了开发创新且经济可及的替代治疗方案的迫切需求。金属基化合物（metallopharmaceuticals）是极具前景的抗癌制剂，其可通过诱导氧化应激、调控氧化还原通路以及与DNA相互作用发挥抗肿瘤活性。然而，其临床转化却因水溶性差、快速降解以及皮肤渗透性低等问题受到限制。本综述总结了金、银、铂、钯、钌、钒及铜配合物在皮肤癌局部与全身治疗领域的最新临床前研究进展。此外，本综述还探讨了用于提升皮肤渗透性并保护金属配合物结构完整性的化学与物理促渗手段（如水凝胶、微针），以及各类药物递送系统（包括细菌纳米纤维素膜、纳米颗粒、脂质体与胶束）的研究进展。同时，本文还分析了光动力疗法在皮肤癌治疗中的应用价值，以及利用数学与计算建模模拟皮肤药物转运、预测生物分布并指导合理纳米载体设计的相关研究。综上，上述策略旨在弥合物理化学创新与临床应用之间的鸿沟，为开发更具选择性、稳定性且经济高效的皮肤癌治疗方案铺平道路。