Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2022 Nov 7;19(11):4123-4134. doi: 10.1021/acs.molpharmaceut.2c00537. Epub 2022 Sep 7.
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.
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偶联一直是解决这个问题的主流策略。虽然有效，但它需要对脂质体进行额外的化学修饰，这对于临床转化是不可取的。我们之前的研究表明，转导肽（TP），一种两亲性 CPP，能够增加共给药但不共价偶联的金属纳米颗粒（NPs）的细胞摄取。这种过程称为旁观者摄取，它代表了一种在不进行化学修饰的情况下增加 NPs 细胞进入的更简单方法。在这里，我们将努力扩展到脂质体。我们的结果表明，与 TP 肽共同给药可改善脂质体在体外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，这种肽辅助的脂质体内化不适用于阳离子 CPP，它们是之前研究中旁观者摄取的主要诱导剂。我们还发现，TP 辅助的脂质体旁观者摄取依赖于受体，其活性对巨胞饮途径抑制剂更敏感，这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来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。
