Lee Kate Y J, Lee Gee Young, Lane Lucas A, Li Bin, Wang Jianquan, Lu Qian, Wang Yiqing, Nie Shuming
Departments of Biomedical Engineering and Chemistry, Emory University and Georgia Institute of Technology , Atlanta, Georgia 30322, United States.
Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University , Nanjing, Jiangsu Province 210093, China.
Bioconjug Chem. 2017 Jan 18;28(1):244-252. doi: 10.1021/acs.bioconjchem.6b00224. Epub 2016 Jul 5.
The development of sophisticated nanoplatforms for in vivo targeted delivery of therapeutic agents to solid tumors has the potential for not only improving therapeutic efficacy but also minimizing systemic toxicity. However, the currently low delivery efficiency (about 1% of the injected dose) and the limited tumor penetration of nanoparticles remain two major challenges. Here we report a class of functionalized, long-circulating, and ultrasmall gold nanocarriers (5 nm gold core and 20 nm overall hydrodynamic diameter) for improved drug delivery and deep tumor penetration. By using doxorubicin as a model drug, our design also includes a pH-sensitive hydrazone linkage that is stable at neutral or slightly basic pH but is rapidly cleaved in the acidic tumor microenvironments and intracellular organelles. With a circulation halftime of 1.6 days, the small particle size is an important feature not only for efficient extravasation and accumulation via the enhanced permeability and retention (EPR) effect, but also for faster nanoparticle diffusion and improved tumor penetration. In xenograft animal models, the results demonstrate that up to 8% of the injected nanoparticles can be accumulated at the tumor sites, among the highest nanoparticle delivery efficiencies reported in the literature. Also, histopathological and direct visual examinations reveal dark-colored tumors with deep nanoparticle penetration and distribution throughout the tumor mass. In comparison with pure doxorubicin which is known to cause considerable heart, kidney, and lung toxicity, in vivo animal data indicate that this class of functionalized and ultrasmall gold nanoparticles indeed provides better therapeutic efficacies with no apparent toxicity in vital organs.
开发用于将治疗剂体内靶向递送至实体瘤的精密纳米平台，不仅有提高治疗效果的潜力，还能将全身毒性降至最低。然而，目前较低的递送效率（约为注射剂量的1%）和纳米颗粒有限的肿瘤穿透性仍然是两个主要挑战。在此，我们报告一类功能化、长循环且超小的金纳米载体（5纳米金核，整体流体动力学直径20纳米），用于改善药物递送和实现肿瘤深部穿透。以阿霉素作为模型药物，我们的设计还包括一个对pH敏感的腙键，该键在中性或略碱性pH下稳定，但在酸性肿瘤微环境和细胞内细胞器中会迅速裂解。其循环半衰期为1.6天，小粒径不仅是通过增强渗透和滞留（EPR）效应实现高效渗出和积累的重要特征，也是纳米颗粒更快扩散和改善肿瘤穿透性的重要特征。在异种移植动物模型中，结果表明高达8%的注射纳米颗粒可在肿瘤部位积累，这是文献报道中最高的纳米颗粒递送效率之一。此外，组织病理学和直接视觉检查显示肿瘤颜色较深，纳米颗粒在整个肿瘤块中深部穿透和分布。与已知会引起相当程度心脏、肾脏和肺部毒性的纯阿霉素相比，体内动物数据表明这类功能化超小金纳米颗粒确实具有更好的治疗效果，且对重要器官无明显毒性。
