Author:
Yazdian-Robati Rezvan,Amiri Ehsan,Kamali Hossein,Khosravi Aysun,Taghdisi Seyed Mohammad,Jaafari Mahmoud Reza,Mashreghi Mohammad,Moosavian Seyedeh Alia
Abstract
AbstractAlthough liposomes have improved patient safety and the pharmacokinetic profile of free drugs, their therapeutic efficacy has only shown marginal improvement. The incorporation of active-targeted ligands to enhance cellular uptake has shown promise in preclinical studies. However, no active-targeted liposomes have successfully translated into clinical use thus far. This study aimed to evaluate the targeting ability and antitumor efficiency of A6, a specific short peptide (KPSSPPEE) when incorporated into PEGylated liposomal doxorubicin (PLD). The results revealed significantly enhanced cellular uptake. The cytotoxicity of the formulations was determined by 3 h and 6 h incubation of formulations with cells, followed by 48 h incubation to evaluate the targeted ability of the formulations and the results indicated the higher cytotoxicity of A6-PLD (IC50 of 7.52 µg/mL after 6 h incubation) in the CD44 overexpressing C26 cell line compared to non-targeted PLD (IC50 of 15.02 µg/mL after 6 h incubation). However, CD44-negative NIH-3T3 cells exhibited similar uptake and in vitro cytotoxicity for both A6-PLD (IC50 of 38.05 µg/mL) and PLD (IC50 of 34.87 µg/mL). In animal studies, A6-PLD demonstrated significantly higher tumor localization of doxorubicin (Dox) (~ 8 and 15 µg Dox/g tumor for 24 and 48 after injection) compared to PLD (~ 6 and 8 µg Dox/g tumor for 24 and 48 after injection), resulting in effective inhibition of tumor growth. The median survival time (MST) for Dextrose 5% was 10, PLD was 14 and A6-PLD was 22 days. In conclusion, A6-PLD, a simple and effective targeted liposome formulation, exhibits high potential for clinical translation. Its improved targetability and antitumor efficacy make it a promising candidate for future clinical applications.
Funder
National Institute for Medical Research Development
Publisher
Springer Science and Business Media LLC
Subject
Physical and Theoretical Chemistry,Pharmaceutical Science,Oncology,Biomedical Engineering
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