Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
J Pharm Pharmacol. 2021 Mar 4;73(2):169-177. doi: 10.1093/jpp/rgaa005.
In view of their biodegradability, biocompatibility, encapsulation efficiency and targeted release, as well as low toxicity, liposomes are being widely used in the context of drug delivery. However, the efficiency of such drug delivery systems might face limitations by macrophage-mediated clearance (CL), which reduces circulation half-life (T½). This problem can be resolved through surface functionalization via poly (ethylene glycol) (PEG) in the process of PEGylation. However, the use of PEG might have its own disadvantages. Accordingly, the main purpose of this study was to produce novel stealth nanoliposomes using CD47 mimicry peptide [namely self-peptide (SP)] as an alternative to PEG for minimizing macrophage-mediated CL and enhancing circulation T½.
At first, doxorubicin (Dox)-containing liposomes [i.e.liposomal Dox (LD)] were coated with different concentrations of SP (viz. SP-LD) (0.5%, 1% and 2%). In addition, PEG-functionalized LD (i.e. PLD) was fabricated as a standard control group. Then, various types of liposomal formulae were injected into a population of mice, assigned to six groups (four mice per group) for biodistribution. After sacrificing these animals in prespecified time points (namely 0.5, 6, 12, 24, 48, 72, 96 and 168 h), serum, liver, spleen, heart, kidney and lung samples were collected to estimate the encapsulated drug content in different groups through measuring intrinsic autofluorescence signal of Dox.
The tissue distribution results in the liver, spleen, heart, kidney and lung samples indicated a significant difference between the SP-LD and the PLD groups. Furthermore, the examination of Dox content, 6 h after administration, showed a growth rate of 28% in Dox content in the SP group compared with the PLD one. Subsequently, these values were, respectively, 63% and 75% at 24 and 48 h.
The results of tissue distribution and serum kinetic analysis correspondingly revealed that the use of the SP could augment the circulation time of Dox in comparison with PEG, and it could additionally minimize the tissue accumulation of the drug, which is normally the cause of drug-induced toxicity. The use of the SP on nanoliposomes could prolong the circulation of T½ and diminish the tissue accumulation of LD. These findings are relevant for improving therapeutic efficacy and reducing the toxicity of liposomal drugs.
鉴于脂质体具有生物降解性、生物相容性、包封效率和靶向释放以及低毒性等特点，它们被广泛应用于药物传递领域。然而，这种药物传递系统的效率可能会受到巨噬细胞介导的清除（CL）的限制，这会降低循环半衰期（T½）。通过聚乙二醇（PEG）的表面功能化（即 PEG 化）可以解决这个问题。然而，PEG 的使用可能有其自身的缺点。因此，本研究的主要目的是使用 CD47 模拟肽[即自肽（SP）]作为 PEG 的替代品，生产新型隐形纳米脂质体，以最小化巨噬细胞介导的 CL 并延长循环 T½。
首先，用不同浓度的 SP（即 SP-LD）（0.5%、1%和 2%）包被载多柔比星（Dox）的脂质体[即脂质体 Dox（LD）]。此外，还制备了 PEG 功能化的 LD（即 PLD）作为标准对照组。然后，将各种脂质体配方注入一组小鼠体内，分为六组（每组四只小鼠）进行分布研究。在预定的时间点（即 0.5、6、12、24、48、72、96 和 168 h）处死这些动物后，收集血清、肝、脾、心、肾和肺样本，通过测量 Dox 的固有自发荧光信号来估计不同组中包裹药物的含量。
肝、脾、心、肾和肺组织分布结果表明，SP-LD 组与 PLD 组之间存在显著差异。此外，给药后 6 h 时 Dox 含量的检查显示，SP 组的 Dox 含量增长率为 28%，而 PLD 组为 75%。随后，这两个值分别在 24 和 48 h 时增加到 63%和 75%。
组织分布和血清动力学分析的结果相应地表明，与 PEG 相比，使用 SP 可以延长 Dox 的循环时间，并且可以减少药物的组织积累，这通常是药物引起毒性的原因。SP 在纳米脂质体上的使用可以延长 T½的循环时间，减少 LD 的组织积累。这些发现对于提高治疗效果和降低脂质体药物的毒性具有重要意义。
