School of Chemistry and Chemical Engineering, Nanjing University, Jiangsu 210023, China.
Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, P. R. China.
J Mater Chem B. 2020 May 27;8(20):4475-4488. doi: 10.1039/d0tb00724b.
Effective treatment of brain metastases is hindered by the blood-brain barrier (BBB) and the rapid development of resistance to drug therapy. Moreover, the clinical application of general formulations is hampered by biological barriers and biological elimination. To tackle this challenge, we report a feasible approach for the assembly of polymer-covalent organic framework (COF) nanocomposites into 150 nm thin platelets as a drug delivery vehicle for enhanced retention in brain tumours. Using intravital imaging, we demonstrate that these polymer-COF nanocomposites are able to traverse the BBB in mice and achieve direct tumour accumulation in intracranial orthotopic models of brain metastasis from renal cancer (BMRC). These nanocomposites can target brain tumour cells and respond to tumour microenvironmental characteristics, including acidic and redox conditions. Intracranial tumour acidity triggers the breakdown of the nanoassemblies to polymer-COF nanocomposites due to the presence of borate bonds. Furthermore, in vivo studies on the nanocomposites showed enhanced brain tumour-targeting efficiency and therapeutic effects compared to those of free-drug dosing. Mice treated with drug-loaded polymer-COF nanocomposites also show protection from systemic drug toxicity and improved survival, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to BMRC and other central nervous system (CNS) tumours.
血脑屏障（BBB）和对药物治疗的快速耐药性阻碍了脑转移的有效治疗。此外，一般制剂的临床应用受到生物屏障和生物消除的阻碍。为了应对这一挑战，我们报告了一种将聚合物-共价有机骨架（COF）纳米复合材料组装成 150nm 薄片状作为药物输送载体以增强脑肿瘤滞留的可行方法。通过活体成像，我们证明这些聚合物-COF 纳米复合材料能够在小鼠体内穿透血脑屏障，并在肾癌细胞（BMRC）脑转移的颅内原位模型中实现直接肿瘤积累。这些纳米复合材料能够靶向脑肿瘤细胞，并响应肿瘤微环境特征，包括酸性和氧化还原条件。由于硼酸酯键的存在，颅内肿瘤酸度会触发纳米组装体分解为聚合物-COF 纳米复合材料。此外，体内研究表明，与游离药物给药相比，载药聚合物-COF 纳米复合材料具有增强的脑肿瘤靶向效率和治疗效果。用载药聚合物-COF 纳米复合材料治疗的小鼠还表现出对全身药物毒性的保护和生存能力的提高，这证明了这种纳米级平台具有将新型联合疗法递送至 BMRC 和其他中枢神经系统（CNS）肿瘤的临床前潜力。
