State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Jiangsu Institute of Nuclear Medicine, Molecular Imaging Center, Jiangsu Institute of Nuclear Medicine, 20 Qianrong Rd, Wuxi 214063, China.
J Colloid Interface Sci. 2019 Feb 15;536:135-148. doi: 10.1016/j.jcis.2018.10.039. Epub 2018 Oct 16.
It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells.
人们普遍认为，聚合物纳米药物在提高抗肿瘤疗效、降低副作用和实现更好的长期预后方面具有优势。然而，仍然存在争议，即它们的治疗效率是否与确保位于其疏水核内的疏水药物在肿瘤部位的有效释放密切相关。为了研究这一争议，我们构建了两种聚合物纳米药物（pH 激活的 sLMWH-UOA 和非敏感的 LMWH-UOA），它们以低分子量肝素（LMWH）和熊果酸（UOA）为原料，用于肝癌的化疗和抗血管生成联合治疗。在体外降解研究中，与非敏感的 LMWH-UOA 相比，pH 激活的 sLMWH-UOA 的降解率增加了 33%。此外，共聚焦显微镜捕捉到 sLMWH-UOA 可以在溶酶体的酸性微环境中有效释放药物，而 LMWH-UOA 几乎不能。更重要的是，与 LMWH-UOA 相比，sLMWH-UOA 表现出 pH 依赖性细胞毒性，表明促进药物释放在增强聚合物纳米药物的细胞毒性方面起着关键作用。此外，体内药效学评价表明，尽管非敏感的 LMWH-UOA 得益于增强的肿瘤靶向药物递送能力，在抗肿瘤联合治疗中相对于游离药物联合治疗具有绝对优势，但 sLMWH-UOA 可以通过在肿瘤中获得更好的药物释放来进一步优化联合治疗效果。综上所述，应用肿瘤触发化学键构建聚合物纳米药物为提高肿瘤细胞的治疗效率提供了广阔的前景。
