Lim Yong Geun, Chang Yeji, Park Seon-Ju, Kim Kyoung-Dong, Park Kyeongsoon
Department of Systems Biotechnology, Chung-Ang University, Anseong, Gyeonggi, 17546, South Korea.
Mater Today Bio. 2025 Aug 23;34:102229. doi: 10.1016/j.mtbio.2025.102229. eCollection 2025 Oct.
Several solid tumors contain large hypoxic regions, diminishing drug responses and resulting in limited therapeutic outcomes. Vinblastine sulfate (VBL) targets the tubulin molecule, causing microtubule depolymerization and inducing mitotic arrest, leading to tumor regression. However, hypoxia causes microtubule depolymerization in tumor cells, reducing the number of intact microtubules for drug binding and diminishing the efficacy of microtubule-targeting agents like VBL. Therefore, to relieve tumor hypoxia and enhance chemotherapeutic responses to hypoxic tumors, we developed multifunctional and endogenous stimuli-responsive VBL/manganese dioxide (VBL/MnO) nanodrugs. The VBL/MnO nanodrugs demonstrated colloidal stability and were readily degraded by endogenous stimuli, including acidic pH, hydrogen peroxide, and glutathione, resulting in the release of VBL and oxygen generation. In addition, oxygen-generating VBL/MnO nanodrugs can alleviate hypoxia in tumor cells with high HO levels after their intracellular uptake, thereby improving therapeutic efficacy better than VBL owing to enhanced drug responses and microtubule depolymerization. Furthermore, the accumulation of VBL/MnO nanodrugs in tumor tissues via passive targeting resulted in the effective reduction of hypoxia regions and hypoxia-inducible factor-1α expression . Owing to their remarkable ability to relieve tumor hypoxia, biocompatible VBL/MnO nanodrugs improve drug responses and tubulin aggregation in tumor tissues, ultimately enhancing tumor apoptosis and regression. These findings suggest that the VBL/MnO nanodrugs are a promising therapeutic strategy for enhancing chemotherapeutic responses to hypoxic tumors by ameliorating tumor hypoxia.
几种实体瘤包含大片缺氧区域，这会降低药物反应并导致治疗效果有限。硫酸长春碱（VBL）作用于微管蛋白分子，导致微管解聚并诱导有丝分裂停滞，从而使肿瘤消退。然而，缺氧会导致肿瘤细胞中的微管解聚，减少用于药物结合的完整微管数量，并降低像VBL这样的微管靶向剂的疗效。因此，为了缓解肿瘤缺氧并增强对缺氧肿瘤的化疗反应，我们开发了多功能且内源性刺激响应的VBL/二氧化锰（VBL/MnO）纳米药物。VBL/MnO纳米药物表现出胶体稳定性，并容易被包括酸性pH、过氧化氢和谷胱甘肽在内的内源性刺激降解，从而导致VBL释放并产生氧气。此外，产生氧气的VBL/MnO纳米药物在细胞内摄取后可缓解高HO水平肿瘤细胞中的缺氧，从而由于增强的药物反应和微管解聚而比VBL更好地提高治疗效果。此外，VBL/MnO纳米药物通过被动靶向在肿瘤组织中的积累导致缺氧区域和缺氧诱导因子-1α表达有效减少。由于其缓解肿瘤缺氧的显著能力，生物相容性VBL/MnO纳米药物改善了肿瘤组织中的药物反应和微管蛋白聚集，最终增强了肿瘤凋亡和消退。这些发现表明，VBL/MnO纳米药物是一种通过改善肿瘤缺氧来增强对缺氧肿瘤化疗反应的有前景的治疗策略。
