Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells
Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells
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DOI：
10.2147/ijn.s170274
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发表时间：
2018-01-01
影响因子：
8
通讯作者：
ten Hagen, Timo L. M.
中科院分区：
文献类型：
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作者：
Amin, Mohamadreza;Bagheri, Mahsa;ten Hagen, Timo L. M.
前言：聚乙二醇化脂质体作为化疗药物的载体被广泛使用和研究。虽然包封药物的药代动力学被显著改变，导致有利的循环时间、改善的肿瘤积累和更好的可管理或减少的副作用，但治疗效果令人失望。主要的缺点是不能到达肿瘤细胞，有限的穿透深度，和受损的摄取肿瘤cell.Materials和方法：在这里，我们研究的含义HIV-1的转录反式激活因子（达特）衍生的肽插入聚乙二醇化脂质体阿霉素（PLD），并遵循在体外和体内的命运。PLD安装有25-400达特肽每脂质体没有PLD stability.Results的影响：虽然达特肽促进载体的活性内吞作用，我们观察到，这些肽并没有促进内体逃逸或增强细胞内的阿霉素的可用性。有趣的是，掺入达特肽并没有改变药代动力学或生物分布，我们发现这是由于血清蛋白对TAT修饰的脂质体的调理作用失调。达特肽修饰的PLD上的蛋白质冠（PC）屏蔽活性部分并有效地减少含达特肽的纳米颗粒的清除。然而，肿瘤内活性受到存在的达特肽的数量的影响。在达特肽密度为100时观察到最佳抗肿瘤功效，而较低的量显示出与未修饰的PLD相当的结果。在200达特肽，制剂似乎是最有效的，这可能是从增强与肿瘤细胞的相互作用后直接extravasation.Conclusion：我们得出结论，通过优化TAT修饰的PLD，发生PC平衡药物代谢动力学和肿瘤渗透通过干扰与亲和力。
Introduction: PEGylated liposomes are widely used and studied as carriers for chemotherapeutics. While pharmacokinetics of the encapsulated drug is drastically altered resulting in favorable circulation time, improved tumor accumulation, and better manageable or reduced side effects, therapeutic efficacy has been disappointing. Major drawbacks are a failure to reach the tumor cell, limited penetration depth, and impaired uptake by tumor cells.Materials and methods: Here, we study the implication of HIV-1 transactivator of transcription (TAT)-derived peptides inserted on PEGylated liposomal doxorubicin (PLD) and followed in vitro and in vivo fate. PLDs were installed with 25-400 TAT peptides per liposome without an effect on PLD stability.Results: While TAT peptides facilitate active endocytosis of the carriers, we observed that these peptides did not promote endosomal escape or enhanced intracellular availability of doxorubicin. Interestingly, incorporation of TAT peptides did not change pharmacokinetics or biodistribution, which we found to result from a dysopsonization of the TAT-modified liposomes by serum proteins. A protein corona (PC) on TAT peptide-modified PLDs shields the active moieties and effectively reduces clearance of the TAT peptide containing nanoparticles. However, intratumoral activity was influenced by the number of TAT peptides present. The best antitumor efficacy was observed with a TAT peptide density of 100, while lower amounts showed results comparable to unmodified PLDs. At 200 TAT peptides, the preparation appeared to be least effective, which likely results from augmented interaction with tumor cells directly upon extravasation.Conclusion: We conclude that by optimizing TAT-modified PLDs, the occurring PC balances pharmacokinetics and tumor penetration through interference with avidity.