National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074, Wuhan City, P. R. China.
Nanoscale. 2017 May 11;9(18):5859-5871. doi: 10.1039/c7nr01097d.
To realize the sustained release and long-term intratumoural retention of water-soluble cisplatin, thermo/pH-sensitive cisplatin-directed coordination-crosslinking nanogels (Pt-PNA) were developed via the coordination bonds of Pt-carboxyl groups. As the coordination ratio (CR) of the Pt-carboxyl bonds increased from 5% to 35%, the sizes of the Pt-PNA nanogels decreased from 999 nm to 167 nm, and their zeta potentials increased from -35 mV to -13 mV. Only through a simple mixing of cisplatin and PNAs, the entrapment efficiencies (EEs) of the Pt-PNA nanogels reached near 100% (>90%), and the drug-loading amounts (DLs) of cisplatin could achieve up to 25.5 ± 0.1%. For water-soluble cisplatin, Pt-PNA nanogels exhibited a sustained release for as long as 5 days. The thermo/pH-sensitive sol-gel phase-transition behaviour of the Pt-PNA nanogels were investigated via inverting-vial and rheological methods. Platinum elemental analysis indicated that the Pt-PNA nanogels showed a much stronger ability of cisplatin retention in tumours than free cisplatin. The platinum content in a tumour treated by the Pt-PNA nanogels was far higher than that by free cisplatin: 200.7 ± 63.6 μg vs. 82.7 ± 26.8 μg at the 1st day, or 118.9 ± 35.2 μg vs. 18.5 ± 9.4 μg at the 14th day. The evaluation of the in vivo antitumour efficacy indicated that only after a single dose of Pt-PNA nanogels, the tumour volume continuously decreased to 0.73 ± 0.07 times that of the original tumour volume (OTV) for 14 days; however, it rapidly increased by 3.37 ± 0.82, 8.01 ± 0.53 and 9.25 ± 1.85 times that of the OTV with the same dose of free cisplatin, PNA, and NS, respectively. Some preliminary evaluations of the biocompatibility indicated that the toxic side effects of cisplatin could be greatly improved via cisplatin-directed coordination-crosslinking with PNA. As a result, Pt-PNA nanogels could likely become a promising versatile strategy for improving antitumour efficacy and reducing the toxicity and size effects of platinum-based drugs, and they could also be developed as promising nanomedicines for regional chemotherapy.
为了实现水溶性顺铂的持续释放和长期在肿瘤内滞留，通过 Pt-羧基之间的配位键，开发了温敏/pH 响应的顺铂导向配位交联纳米凝胶（Pt-PNA）。随着 Pt-羧基键的配位比（CR）从 5%增加到 35%，Pt-PNA 纳米凝胶的粒径从 999nm 减小到 167nm，其 zeta 电位从-35mV 增加到-13mV。仅通过简单地将顺铂和 PNAs 混合，Pt-PNA 纳米凝胶的包封效率（EE）即可接近 100%（＞90%），并且顺铂的载药量（DL）可达到 25.5±0.1%。对于水溶性顺铂，Pt-PNA 纳米凝胶可实现长达 5 天的持续释放。通过翻转小瓶和流变学方法研究了 Pt-PNA 纳米凝胶的温敏/pH 敏感溶胶-凝胶相转变行为。铂元素分析表明，与游离顺铂相比，Pt-PNA 纳米凝胶在肿瘤中具有更强的保留顺铂的能力。用 Pt-PNA 纳米凝胶处理的肿瘤中的铂含量远高于游离顺铂：第 1 天为 200.7±63.6μg 比 82.7±26.8μg，或第 14 天为 118.9±35.2μg 比 18.5±9.4μg。体内抗肿瘤疗效评价表明，仅用 Pt-PNA 纳米凝胶单次给药，肿瘤体积在 14 天内连续减小至原始肿瘤体积（OTV）的 0.73±0.07 倍；然而，用相同剂量的游离顺铂、PNA 和 NS 处理时，肿瘤体积分别迅速增加 3.37±0.82、8.01±0.53 和 9.25±1.85 倍。对生物相容性的一些初步评价表明，通过 PNA 对顺铂进行顺铂导向配位交联，可大大改善顺铂的毒副作用。因此，Pt-PNA 纳米凝胶可能成为一种有前途的通用策略，可提高抗肿瘤疗效，并降低基于铂类药物的毒性和尺寸效应，并且还可作为用于区域化疗的有前途的纳米药物。
