Chen Zhoujiang, Liu Weiping, Wang Xin, Liu Yuan, Li Xiaohong
Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, 111 North first Section, second Ring Road, Chengdu 610031, P.R. China.
Institute of Biomaterials and Tissue Engineering, Huaqiao University, 668 Jimei Avenue, Xiamen 361021, P. R. China.
ACS Biomater Sci Eng. 2019 Mar 11;5(3):1343-1353. doi: 10.1021/acsbiomaterials.8b01600. Epub 2019 Feb 12.
Cancer chemotherapy is confronted with insufficient drug penetration in tumors. "Solid tumor priming" is proposed to modulate the abnormal tumor microenvironment but suffers from limited digestion efficiency and underlying tumor metastasis. Losartan (Los) and telmisartan (Tel) are well-known antihypertensive agents and show capabilities in inhibiting collagen synthesis by cancer-associated fibroblasts. Up to now, no attempt has been made to achieve a local and sustained release of Los and Tel in tumors while alleviating the side effects after systemic administration. In the previous study, micelles were loaded into fiber fragments to achieve high drug accumulation in tumors after intratumoral administration. In the current study, Los and Tel are blend electrospun into fibers to retard the collagen synthesis and promote the tissue penetration of micelles released from fiber fragments. The loading of Los and Tel shows no effect on the micelle release, cellular uptake, and cytotoxicities of micelles released from fiber fragments. Because of the hydrophilicity, Los is almost released out after 5 day in pH 6.8 buffers, while hydrophobic Tel is gradually released for 30 days. Thus, fiber fragments with loaded Los and Tel are combined to achieve a sustained remodeling of collagen levels in tumors, and the combination with a ratio of 1/2 showed the most significant and consistent reductions of collagen I levels in tumors, as determined via Western blotting, Masson's trichrome, and immunofluorescence staining. A wide distribution of micelles is observed in the tumor tissues, as well as strong fluorescence in the distal sections of tumors during 14 days. Compared with pristine fiber fragments, the sequential release of Los and Tel induces stronger inhibition of tumor growth, lower expression of hypoxia-inducible factor-α (HIF-α), and fewer tumor metastases to lungs. Thus, this study demonstrates a feasible strategy to enhance the local retention and even distribution of chemotherapeutic agents in tumors in favor of therapeutic efficacy.
癌症化疗面临着药物在肿瘤中渗透不足的问题。“实体瘤预处理”被提出用于调节异常的肿瘤微环境，但存在消化效率有限和潜在肿瘤转移的问题。氯沙坦（Los）和替米沙坦（Tel）是著名的抗高血压药物，具有抑制癌症相关成纤维细胞胶原蛋白合成的能力。到目前为止，尚未尝试在肿瘤中实现Los和Tel的局部和持续释放，同时减轻全身给药后的副作用。在先前的研究中，将胶束装载到纤维片段中，以在瘤内给药后实现肿瘤中的高药物蓄积。在当前研究中，将Los和Tel共混电纺成纤维，以延缓胶原蛋白合成，并促进从纤维片段释放的胶束的组织渗透。Los和Tel的装载对从纤维片段释放的胶束的释放、细胞摄取和细胞毒性没有影响。由于亲水性，Los在pH 6.8缓冲液中5天后几乎完全释放，而疏水性的Tel则在30天内逐渐释放。因此，将装载有Los和Tel的纤维片段组合起来，以实现肿瘤中胶原蛋白水平的持续重塑，通过蛋白质免疫印迹法、Masson三色染色法和免疫荧光染色法测定，1/2比例的组合显示肿瘤中I型胶原蛋白水平的降低最为显著且一致。在肿瘤组织中观察到胶束广泛分布，并且在14天内肿瘤远端切片中荧光较强。与原始纤维片段相比，Los和Tel的顺序释放诱导更强的肿瘤生长抑制、更低的缺氧诱导因子-α（HIF-α）表达以及更少的肺转移。因此，本研究证明了一种可行的策略，可增强化疗药物在肿瘤中的局部滞留和均匀分布，有利于治疗效果。
