High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer
High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer
复制标题
负载紫杉醇的 pH 敏感可裂解脂质体通过消耗乳腺癌中的肿瘤胶原蛋白 I 实现高肿瘤渗透
DOI：
10.1021/acsami.5b01473
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发表时间：
2015
影响因子：
9.5
通讯作者：
Qin He
中科院分区：
文献类型：
--
作者：
Li Zhang;Yang Wang;Yuting Yang;Yayuan Liu;Shaobo Ruan;Qianyu Zhang;Xiaowei Tai;Jiantao Chen;Tai Xia;Yue Qiu;Huile Gao;Qin He
肿瘤中的I型胶原网络可以阻止载于纳米颗粒中的药物的渗透，这将导致抗肿瘤功效受损。在这项研究中，在治疗前注射游离氯沙坦（血管紧张素抑制剂）以降低I型胶原的水平，这可以促进纳米颗粒的渗透。随后注射pH敏感的可裂解脂质体（Cl-Lip）以发挥抗肿瘤作用。Cl-Lip由PEG 5 K-Hydrazone-PE和DSPE-PEG 2K-R8构成。当Cl-Lip通过增强的渗透性和保留（EPR）效应到达肿瘤部位时，在肿瘤的低细胞外pH条件下，PEG 5 K-Hydrazone-PE从Cl-Lip水解，然后暴露R8肽，体外实验表明，脂质体可以通过R8肽的介导内化到肿瘤细胞中。4 T1细胞对Cl-Lip的体外靶向性及紫杉醇负载Cl-Lip（PTX-Cl-Lip）的细胞毒性均具有pH敏感性，体内实验表明Cl-Lip具有良好的肿瘤靶向性。Cl-Lip去除胶原后可渗透至肿瘤深部，肿瘤内蓄积量增加22.0%，肿瘤组织内氧分布增强。抗肿瘤研究表明，游离氯沙坦与PTX-Cl-Lip组合（59.8%）比单独注射PTX-Cl-Lip（37.8%）在4 T1荷瘤小鼠中更有效。所有结果表明，氯沙坦消耗胶原I显着增加PTX-CL-Lip的渗透，游离氯沙坦和PTX-CL-Lip的组合可以导致更好的化学药物的抗肿瘤效果。因此，联合策略可能是更好地治疗具有高水平胶原I的实体瘤的有希望的策略。
The network of collagen I in tumors could prevent the penetration of drugs loaded in nanoparticles, and this would lead to impaired antitumor efficacy. In this study, free losartan (an angiotensin inhibitor) was injected before treatment to reduce the level of collagen I, which could facilitate the penetration of nanoparticles. Then the pH-sensitive cleavable liposomes (Cl-Lip) were injected subsequently to exert the antitumor effect. The Cl-Lip was constituted by PEG5K-Hydrazone-PE and DSPE-PEG2K-R8. When the Cl-Lip reached to the tumor site by the enhanced permeability and retention (EPR) effect, PEG5K-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low extra-cellular pH conditions of tumors, then the R8 peptide was exposed, and finally liposomes could be internalized into tumor cells by the mediation of R8 peptide.In vitroexperiments showed both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive.In vivoexperiments showed the Cl-Lip had a good tumor targeting ability. After depletion of collagen I, Cl-Lip could penetrate into the deep place of tumors, the tumor accumulation of Cl-Lip was further increased by 22.0%, and the oxygen distributed in tumor tissues was also enhanced. The antitumor study indicated free losartan in combination with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip only (37.8%) in 4T1 tumor bearing mice. All results suggested that depletion of collagen I by losartan dramatically increased the penetration of PTX-Cl-Lip and combination of free losartan and PTX-CL-Lip could lead to better antitumor efficacy of chemical drugs. Thus, the combination strategy might be a promising tactic for better treatment of solid tumors with a high level of collagen I.