构建并评价一种新型的多孔离子响应型靶向药物传递系统用于重组人干扰素 α-2b 的递药研究。

Construction and in vivoin vitro evaluation of a nanoporous ion-responsive targeted drug delivery system for recombinant human interferon α-2b delivery.

机构信息

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.

出版信息

Int J Nanomedicine. 2019 Jul 16;14:5339-5353. doi: 10.2147/IJN.S209646. eCollection 2019.

DOI:10.2147/IJN.S209646

PMID:31409991

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6645601/

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

The size distribution of the microspheres was 5~~15 μm, and the microspheres contained nanopores 300~~400 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%.

CONCLUSION

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.

摘要

背景

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。

方法

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。

结果

微球的粒径分布为 5~~15 μm，微球中含有 300~~400 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%。