Liu Yuan, Wang Hong, Tang Maosheng, Cao Wenxiong, Zhang Zhanlin, Li Xiaohong
Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
Department of Ultrasound, West China hospital, Sichuan university, Chengdu, 610041, PR China.
Acta Biomater. 2020 Jul 1;110:231-241. doi: 10.1016/j.actbio.2020.04.005. Epub 2020 May 4.
The shapes of drug carriers have significant effects on the drug's blood circulation lifetime and tumor accumulation levels. In this study, nonspherical drug carriers of fiber rods are enhanced with hierarchically targeting capabilities to achieve long circulation in blood, on-demand recovery of cell targeting ligands in tumor tissues and dual ligands-mediated cellular uptake. Zwitterionic polymers are conjugated on fiber rods via acid-labile linkers as stealth coronas to reduce the capture by macrophages and shield the targeting ligands. Compared with commonly used poly(ethylene glycol), the zwitterionic grafts show significantly higher inhibition of protein adsorption and lower internalization by macrophages, leading to around 2 folds longer blood circulation and over 2.5 folds higher drug accumulation in tumors than pristine fiber rods. To address the conflicts between blood circulation and cellular uptake, the zwitterionic coronas are efficiently removed in the slightly acidic tumor microenvironment. The exposure of targeting ligands could activate the internalization by tumor cells, resulting in higher cytotoxicity and tumor accumulation than those with stable linkers. Fiber rods are grafted with dual ligands of folate and biotin, and the optimal ligand densities and ratios are determined to maximize the tumor cell uptake. Compared with other treatment, fiber rods with decorated zwitterionic coronas and acid-liable exposure of dual targeting ligands enhance the suppression of tumor growth, prolong animal survival, and cause less lung metastasis. The development of fiber rods with hierarchically targeting capabilities shows great potential in improving the blood circulation, tumor accumulation and cellular uptake, and eventually promoting therapeutic efficacy. STATEMENT OF SIGNIFICANCE: The targeted delivery of chemotherapeutic agents will encounter a series of biological and pathological barriers. In this study, fiber rods were empowered with hierarchically targeting capabilities to resolve the conflict between blood circulation and cellular uptake. This strategy has shown several advantages over the existing methods. Firstly, zwitterionic polymers were used as blood circulation ligands, and concrete evidence was provided via head-to-head comparison with commonly used poly(ethylene glycol) ligands in the macrophage uptake and in vivo tissue distribution. Secondly, the depletion of circulation ligands and on-demand exposure of targeting ligands in tumor tissues showed crucial effects on the uptake by tumor cells. Thirdly, the densities and ratios of the dual targeting ligands were initially determined for a maximal cellular internalization.
药物载体的形状对药物的血液循环寿命和肿瘤蓄积水平有显著影响。在本研究中，纤维棒状的非球形药物载体具有分级靶向能力，可实现血液中的长循环、肿瘤组织中细胞靶向配体的按需恢复以及双配体介导的细胞摄取。两性离子聚合物通过酸不稳定连接子共轭在纤维棒上作为隐形冠层，以减少巨噬细胞的捕获并屏蔽靶向配体。与常用的聚乙二醇相比，两性离子接枝物对蛋白质吸附的抑制作用显著更高，且巨噬细胞的内化作用更低，导致血液循环时间比原始纤维棒长约2倍，肿瘤中的药物蓄积比原始纤维棒高2.5倍以上。为了解决血液循环和细胞摄取之间的矛盾，两性离子冠层在微酸性肿瘤微环境中被有效去除。靶向配体的暴露可激活肿瘤细胞的内化作用，导致细胞毒性和肿瘤蓄积高于具有稳定连接子的情况。纤维棒接枝有叶酸和生物素的双配体，并确定了最佳配体密度和比例以最大化肿瘤细胞摄取。与其他治疗方法相比，具有修饰的两性离子冠层和双靶向配体酸不稳定暴露的纤维棒增强了对肿瘤生长的抑制作用，延长了动物存活时间，并减少了肺转移。具有分级靶向能力的纤维棒的开发在改善血液循环、肿瘤蓄积和细胞摄取并最终提高治疗效果方面显示出巨大潜力。意义声明：化疗药物的靶向递送将遇到一系列生物和病理障碍。在本研究中，纤维棒具有分级靶向能力以解决血液循环和细胞摄取之间的矛盾。该策略相对于现有方法显示出几个优点。首先，两性离子聚合物用作血液循环配体，并通过与常用聚乙二醇配体在巨噬细胞摄取和体内组织分布方面的直接比较提供了具体证据。其次，循环配体的消耗和肿瘤组织中靶向配体的按需暴露对肿瘤细胞的摄取显示出关键作用。第三，初步确定了双靶向配体的密度和比例以实现最大细胞内化。
