Department of Biomaterials Science and Technology, Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500AE, The Netherlands; Cristal Therapeutics, Oxfordlaan 55, Maastricht 6229EV, The Netherlands.
Cristal Therapeutics, Oxfordlaan 55, Maastricht 6229EV, The Netherlands.
Biomaterials. 2015;53:370-8. doi: 10.1016/j.biomaterials.2015.02.085. Epub 2015 Mar 18.
Treatment with chemotherapy such as docetaxel (DTX) is associated with significant toxicity and tumour recurrence. In this study, we developed DTX-entrapped core-cross-linked polymeric micelles (DTX-CCL-PMs, 66 nm size) by covalently conjugating DTX to CCL-PMs via a hydrolysable ester bond. The covalent conjugation allowed for sustained release of DTX under physiological conditions in vitro. In vivo, DTX-CCL-PMs demonstrated superior therapeutic efficacy in mice bearing MDA-MB-231 tumour xenografts as compared to the marketed formulation of DTX (Taxotere(®)). Strikingly, a single intravenous injection of DTX-CCL-PMs enabled complete regression of both small (∼150 mm(3)) and established (∼550 mm(3)) tumours, leading to 100% survival of the animals. These remarkable antitumour effects of DTX-CCL-PMs are attributed to its enhanced tumour accumulation and anti-stromal activity. Furthermore, DTX-CCL-PMs exhibited superior tolerability in healthy rats as compared to Taxotere. These preclinical data strongly support clinical translation of this novel nanomedicinal product for the treatment of cancer.
化疗治疗，如多西紫杉醇（DTX），与显著的毒性和肿瘤复发相关。在本研究中，我们通过将 DTX 通过可水解酯键共价连接到 CCL-PM 上来制备 DTX 包载的核交联聚合物胶束（DTX-CCL-PMs，66nm 大小）。这种共价连接使得 DTX 在体外生理条件下能够持续释放。在体内，与市售 DTX 制剂（Taxotere（®））相比，DTX-CCL-PMs 在携带 MDA-MB-231 肿瘤异种移植的小鼠中表现出更好的治疗效果。引人注目的是，单次静脉注射 DTX-CCL-PMs 能够使小（约 150mm(3)）和已建立的（约 550mm(3)）肿瘤完全消退，导致动物 100%存活。DTX-CCL-PMs 的这些显著的抗肿瘤作用归因于其增强的肿瘤蓄积和抗基质活性。此外，与 Taxotere 相比，DTX-CCL-PMs 在健康大鼠中表现出更好的耐受性。这些临床前数据强烈支持将这种新型纳米药物产品用于癌症治疗的临床转化。
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