Zhong Haiqing, Ying Xufang, Bao Xiaoyan, Wu Linjie, Lu Yiying, Dai Qi, Yang Qiyao, Tan Xin, Xu Donghang, Gao Jianqing, Han Min
College of Pharmaceutical Sciences, Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China.
Polytechnic Institute, Zhejiang University, Hangzhou 310058 China.
Asian J Pharm Sci. 2025 Aug;20(4):101059. doi: 10.1016/j.ajps.2025.101059. Epub 2025 Apr 23.
An increasing number of studies have focused on depleting lactate and modulating the tumor's lactic microenvironment to interfere with tumor progression, particularly in breast cancer. Lactate accumulation in tumors contributes to a highly acidic microenvironment that promotes cancer cell survival and resistance to therapies. However, existing lactate depletion agents, primarily enzymes and macromolecules, fall short of clinical applications due to poor stability and their ability to only perform solitary lactate depletion without interfering with the transport process. Consequently, the development of stable molecules that deplete lactate and interfere with lactate transport is critically needed. Therefore, in this study, chlorin e6 (Ce6)-gadolinium chloride (GdCl)-flavin adenine dinucleotide (FAD)/tamoxifen (TAM) molecular chelates were prepared. The chelates fully interfered with lactate transport, depleted lactate in the tumor microenvironment, mitigated photodynamic therapy resistance, and realized synergistic photodynamic-hormonal therapy. FAD has promising capabilities in regulating lactate levels and mitigating acidic microenvironments. However, a strategy for depleting lactate by chelating the coenzyme FAD to form nanoparticles has not yet been reported. Tamoxifen disrupts tumor development and interferes with lactate transport by binding to estrogen receptor and inhibiting the expression of monocarboxylate transporter. In addition, coupling with Gd increased the solubility of Ce6, thereby improving the photodynamic therapy effectiveness. This innovative strategy improves therapeutic efficacy and offers a promising approach for breast cancer treatment.
越来越多的研究聚焦于消耗乳酸并调节肿瘤的乳酸微环境以干扰肿瘤进展，尤其是在乳腺癌中。肿瘤中的乳酸积累会导致高度酸性的微环境，促进癌细胞存活并增强对治疗的抗性。然而，现有的乳酸消耗剂主要是酶和大分子，由于稳定性差且只能单独消耗乳酸而不干扰运输过程，因此无法应用于临床。因此，迫切需要开发能够消耗乳酸并干扰乳酸运输的稳定分子。因此，在本研究中，制备了二氢卟吩e6（Ce6）-氯化钆（GdCl）-黄素腺嘌呤二核苷酸（FAD）/他莫昔芬（TAM）分子螯合物。这些螯合物完全干扰乳酸运输，消耗肿瘤微环境中的乳酸，减轻光动力疗法抗性，并实现光动力-激素协同治疗。FAD在调节乳酸水平和减轻酸性微环境方面具有良好的能力。然而，通过螯合辅酶FAD形成纳米颗粒来消耗乳酸的策略尚未见报道。他莫昔芬通过与雌激素受体结合并抑制单羧酸转运蛋白的表达来破坏肿瘤发展并干扰乳酸运输。此外，与钆偶联增加了Ce6的溶解度，从而提高了光动力疗法的有效性。这种创新策略提高了治疗效果，为乳腺癌治疗提供了一种有前景的方法。
