Lee Gahyun, Kim Jiwon, Yang Jihyuk, Jang Yerin, Jang Jaehee, Tanaka Masayoshi, Niepa Tagbo H R, Lee Hee-Young, Choi Jonghoon
School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea.
Department of Chemical Science and Engineering, Tokyo Institute of Technology, Yokohama-shi, Kanagawa, 226-8503, Japan.
Int J Nanomedicine. 2025 May 28;20:6875-6889. doi: 10.2147/IJN.S513688. eCollection 2025.
The rapid proliferation of tumor cells increases oxygen demand, while the underdeveloped vasculature limits supply, leading to hypoxia in the tumor microenvironment. This hypoxic condition is a hallmark of solid tumors and contributes to tumor progression, immune suppression, metastasis, and resistance to therapy.
This study aimed to counteract tumor hypoxia and improve therapeutic outcomes by delivering both oxygen and the chemotherapeutic agent doxorubicin directly to tumors.
HON_FA@DOX, a folate-functionalized and perfluorohexane-enhanced liposomal nanosome co-loaded with oxygen and doxorubicin, was developed and characterized based on its physical properties. Its tumor-targeting capability, oxygen delivery efficiency, and therapeutic potential were evaluated under in vitro conditions. Cellular experiments were conducted to assess selective binding, hypoxia modulation, cytotoxicity, and the expression of genes related to apoptosis.
HON_FA@DOX exhibited a doxorubicin encapsulation efficiency of 36.6% and an enhanced oxygen loading capacity of 23.2 mg/L. The nanosomes demonstrated selective binding to FOLR1-expressing tumor cells and sustained release of doxorubicin. This dual-delivery system effectively alleviated hypoxia within the tumor microenvironment and reduced the expression of the hypoxia-related gene HIF-1α by 50%. Furthermore, HON_FA@DOX treatment significantly increased the expression of apoptosis-related genes and mitigated chemotherapy resistance, thereby enhancing the overall anticancer efficacy.
We demonstrated that multifunctional nanosomes delivering both oxygen and doxorubicin effectively alleviated tumor hypoxia and reduced chemotherapy resistance, thereby enhancing anticancer efficacy. This approach presents a promising strategy for addressing tumor hypoxia and may be broadly applicable as an adjunct to conventional cancer therapies.
肿瘤细胞的快速增殖增加了氧气需求，而发育不完善的脉管系统限制了氧气供应，导致肿瘤微环境缺氧。这种缺氧状态是实体瘤的一个标志，促进肿瘤进展、免疫抑制、转移及治疗抵抗。
本研究旨在通过将氧气和化疗药物阿霉素直接递送至肿瘤来对抗肿瘤缺氧并改善治疗效果。
研发了一种叶酸功能化且全氟己烷增强的脂质体纳米粒HON_FA@DOX，其同时负载氧气和阿霉素，并基于其物理性质进行了表征。在体外条件下评估了其肿瘤靶向能力、氧气递送效率及治疗潜力。进行细胞实验以评估选择性结合、缺氧调节、细胞毒性及与凋亡相关基因的表达。
HON_FA@DOX的阿霉素包封率为36.6%，氧气负载能力增强至23.2 mg/L。纳米粒表现出对表达FOLR1的肿瘤细胞的选择性结合及阿霉素的持续释放。这种双递送系统有效缓解了肿瘤微环境中的缺氧，并使缺氧相关基因HIF-1α的表达降低了50%。此外，HON_FA@DOX治疗显著增加了凋亡相关基因的表达并减轻了化疗耐药性，从而增强了整体抗癌疗效。
我们证明了同时递送氧气和阿霉素的多功能纳米粒有效缓解了肿瘤缺氧并降低了化疗耐药性，从而增强了抗癌疗效。该方法为解决肿瘤缺氧提供了一种有前景的策略，可能广泛用作传统癌症治疗的辅助手段。
