College of Pharmacy, Jiangsu University, Zhenjiang 212013, People's Republic of China.
Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing 210023, People's Republic of China.
Int J Nanomedicine. 2019 Jul 16;14:5339-5353. doi: 10.2147/IJN.S209646. eCollection 2019.
Like most protein macromolecular drugs, the half-life of rhIFNɑ-2b is short, with a low drug utilization rate, and the preparation and release conditions significantly affect its stability.
A nanoporous ion-responsive targeted drug delivery system (PIRTDDS) was designed to improve drug availability of rhIFNα-2b and target it to the lung passively with sustained release. Chitosan rhIFNα-2b carboxymethyl nanoporous microspheres (CS-rhIFNα-2b-CCPM) were prepared by the column method. Here, an electrostatic self-assembly technique was undertaken to improve and sustain rhIFNα-2b release rate.
The size distribution of the microspheres was 515 μm, and the microspheres contained nanopores 300400 nm in diameter. The in vitro release results showed that rhIFNα-2b and CCPM were mainly bound by ionic bonds. After self-assembling, the release mechanism was transformed into being membrane diffusion. The accumulative release amount for 24 hrs was 83.89%. Results from circular dichrogram and SDS-PAGE electrophoresis showed that there was no significant change in the secondary structure and purity of rhIFNα-2b. Results from inhibition rate experiments for A549 cell proliferation showed that the antitumor activity of CS-rhIFNα-2b-CCPM for 24 hrs retained 91.98% of the stock solution, which proved that the drug-loaded nanoporous microspheres maintained good drug activity. In vivo pharmacokinetic experimental results showed that the drugs in CS-rhIFNα-2b-CCPM can still be detected in vivo after 24 hrs, equivalent to the stock solution at 6 hrs, which indicated that CS-rhIFNα-2b-CCPM had a certain sustained-release effect in vivo. The results of in vivo tissue distribution showed that CS-rhIFNα-2b-CCPM was mainly concentrated in the lungs of mice (1.85 times the stock solution). The pharmacodynamics results showed that CS-rhIFNα-2b-CCPM had an obvious antitumor effect, and the tumor inhibition efficiency was 29.2%.
The results suggested a novel sustained-release formulation with higher drug availability and better lung targeting from CS-rhIFNα-2b-CCPM compared to the reference (the stock solution of rhIFNα-2b), and, thus, should be further studied.
与大多数蛋白质大分子药物一样，rhIFNɑ-2b 的半衰期较短，药物利用率低，且制剂和释放条件显著影响其稳定性。
设计了一种纳米多孔离子响应靶向药物传递系统（PIRTDDS），以提高 rhIFNα-2b 的药物利用度，并通过被动肺靶向实现持续释放。采用柱法制备壳聚糖 rhIFNα-2b 羧甲基纳米多孔微球（CS-rhIFNα-2b-CCPM）。采用静电自组装技术提高和维持 rhIFNα-2b 的释放速率。
微球的粒径分布为 515 μm，微球中含有 300400 nm 直径的纳米孔。体外释放结果表明，rhIFNα-2b 和 CCPM 主要通过离子键结合。自组装后，释放机制转变为膜扩散。24 小时累积释放量为 83.89%。圆二色谱和 SDS-PAGE 电泳结果表明，rhIFNα-2b 的二级结构和纯度无明显变化。A549 细胞增殖抑制率实验结果表明，CS-rhIFNα-2b-CCPM 对 24 小时的抗肿瘤活性保留了原液的 91.98%，证明载药纳米多孔微球保持了良好的药物活性。体内药代动力学实验结果表明，24 小时后 CS-rhIFNα-2b-CCPM 中的药物仍能在体内检测到，相当于 6 小时时的原液，表明 CS-rhIFNα-2b-CCPM 在体内具有一定的缓释效果。体内组织分布结果表明，CS-rhIFNα-2b-CCPM 主要集中在小鼠肺部（是原液的 1.85 倍）。药效学结果表明，CS-rhIFNα-2b-CCPM 具有明显的抗肿瘤作用，肿瘤抑制效率为 29.2%。
与对照（rhIFNα-2b 原液）相比，CS-rhIFNα-2b-CCPM 具有更高的药物利用度和更好的肺部靶向性，为一种新型的缓释制剂，应进一步研究。
