Co-administration of Transportan Peptide Enhances the Cellular Entry of Liposomes in the Bystander Manner Both In Vitro and In Vivo.
Co-administration of Transportan Peptide Enhances the Cellular Entry of Liposomes in the Bystander Manner Both In Vitro and In Vivo.
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DOI：
10.1021/acs.molpharmaceut.2c00537
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发表时间：
2022-09
影响因子：
4.9
通讯作者：
Yueling Li;Nianwu Wang;M. Hasan;Hong‐Bo Pang
中科院分区：
文献类型：
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作者：
Yueling Li;Nianwu Wang;M. Hasan;Hong‐Bo Pang
脂质体已被广泛用作药物递送载体。进一步提高其治疗效果的一种方法是提高细胞进入效率。与细胞穿透肽（CPP）和其他类型配体的共价缀合一直是解决这一问题的主流策略。尽管有效，但它需要对脂质体进行额外的化学修饰，这对于临床转化来说是不希望的。我们之前的研究表明，转运蛋白 (TP) 肽是一种两亲性 CPP，能够增加细胞对共同给药但非共价偶联的金属纳米颗粒 (NP) 的摄取。这一过程被称为旁观者摄取，代表了一种无需化学修饰即可增加纳米粒子进入细胞的更简单方法。在这里，我们将我们的努力扩展到脂质体。我们的结果表明，与 TP 肽共同给药可改善体外脂质体在多种细胞系中的内化。在原代细胞、离体肿瘤切片和体内肿瘤组织中也观察到了这种效应。另一方面，这种肽辅助脂质体内化并不适用于阳离子 CPP，而阳离子 CPP 是先前研究中旁观者摄取的主要诱导剂。我们还发现，TP 辅助的旁观者对脂质体的摄取是受体依赖性的，并且其活性对巨胞饮途径的抑制剂更敏感，强调了潜在的细胞进入机制。总的来说，我们的研究提供了一种基于 TP 共同给药的简单策略，以增加脂质体的细胞进入，这可能为 TP 肽在纳米治疗中的应用开辟新途径。
Liposomes have been widely used as a drug delivery vector. One way to further improve its therapeutic efficacy is to increase the cell entry efficiency. Covalent conjugation with cell-penetrating peptides (CPPs) and other types of ligands has been the mainstream strategy to tackle this issue. Although efficient, it requires additional chemical modifications on liposomes, which is undesirable for clinical translation. Our previous study showed that the transportan (TP) peptide, an amphiphilic CPP, was able to increase the cellular uptake of co-administered, but not covalently coupled, metallic nanoparticles (NPs). Termed bystander uptake, this process represents a simpler method to increase the cell entry of NPs without chemical modifications. Here, we extended our efforts to liposomes. Our results showed that co-administration with the TP peptide improved the internalization of liposome into a variety of cell lines in vitro. This effect was also observed in primary cells, ex vivo tumor slices, and in vivo tumor tissues. On the other hand, this peptide-assisted liposome internalization did not apply to cationic CPPs, which were the main inducers for bystander uptake in previous studies. We also found that TP-assisted bystander uptake of liposome is receptor dependent, and its activity is more sensitive to the inhibitors of the macropinocytosis pathway, underlining the potential cell entry mechanism. Overall, our study provides a simple strategy based on TP co-administration to increase the cell entry of liposomes, which may open up new avenues to apply TP peptides in nanotherapeutics.