Shanghai Key Laboratory of Regulatory Biology , East China Normal University , Shanghai 200241 , P. R. China.
Department of Orthopedic Oncology , Changzheng Hospital , Shanghai 200003 , P. R. China.
ACS Appl Mater Interfaces. 2018 Dec 5;10(48):41003-41011. doi: 10.1021/acsami.8b07527. Epub 2018 Nov 19.
Bortezomib is a boronate proteasome inhibitor widely used as an efficient anticancer drug; however, the clinical use of bortezomib is hampered by its adverse effects such as hematotoxicity and peripheral neuropathy, and low efficacy on solid tumors due to unfavorable pharmacokinetics and poor penetration in the solid tumors. In this study, we developed a tripeptide Arg-Gly-Asp (RGD)-targeted dendrimer conjugated with catechol and poly(ethylene glycol) groups for the targeted delivery of bortezomib to metastatic bone tumors. Bortezomib was loaded on the dendrimer via a boronate-catechol linkage with pH-responsive property, which plays an essential role in the control of bortezomib loading and release. The nontargeted bortezomib nanomedicine showed minimal cytotoxicity at pH 7.4, but significantly increased anticancer activity when cyclic RGD (cRGD) moieties were anchored on the dendrimer surface. The ligand cRGD enabled efficient internalization of the bortezomib complex by breast cancer cells such as MDA-MB-231 cells. The targeted nanomedicine efficiently depressed the progression of metastatic bone tumors and significantly inhibited the tumor-associated osteolysis in a model of bone tumors. This study provided an insight into the development of nanomedicine for metastatic bone tumors.
硼替佐米是一种硼酸盐蛋白酶体抑制剂，广泛用作有效的抗癌药物；然而，硼替佐米的临床应用受到其不良反应（如血液毒性和周围神经病）的限制，并且由于药代动力学不理想和在实体瘤中穿透性差，对实体瘤的疗效较低。在这项研究中，我们开发了一种三肽精氨酸-甘氨酸-天冬氨酸（RGD）靶向树突状聚合物，该聚合物与儿茶酚和聚乙二醇基团缀合，用于将硼替佐米靶向递送至转移性骨肿瘤。硼替佐米通过硼酸酯-儿茶酚键装载在树突状聚合物上，具有 pH 响应性，这对控制硼替佐米的装载和释放起着重要作用。非靶向硼替佐米纳米药物在 pH 7.4 时表现出最小的细胞毒性，但当环状 RGD（cRGD）部分锚定在树突状聚合物表面时，其抗癌活性显著增加。配体 cRGD 使硼替佐米复合物能够被乳腺癌细胞（如 MDA-MB-231 细胞）有效内化。靶向纳米药物有效地抑制了转移性骨肿瘤的进展，并显著抑制了骨肿瘤模型中的肿瘤相关骨溶解。本研究为转移性骨肿瘤的纳米医学发展提供了新的思路。
