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Adv Pharm Bull. Inpress.
doi: 10.34172/apb.2024.033
  Abstract View: 99

Research Article

Discovery of a novel dual targeting peptide for human glioma: from in-silico simulation to acting as targeting ligand

Negar Sedghi Aminabad ORCID logo, Yousef Saeedi, Jamal Adiban, Mahdieh Nemati, Donya Shaterabadi, Farhood Najafi, Reza Rahbarghazi, Mehdi Talebi, Amir Zarebkohan* ORCID logo
*Corresponding Author: Email: zarebkohana@tbzmed.ac.ir

Abstract

Receptor-mediated transcytosis (RMT) is a more specific, highly efficient, and reliable approach to crossing the blood-brain-barrier (BBB) for the entry of therapeutic cargos into the brain parenchyma. Here, we introduced and characterized a human-specific novel leptin-derived peptide, using in silico and in vitro experiments. Using bioinformatic analysis and molecular dynamics (MD) simulation, a 14 amino acid peptide sequence (LDP14) was isolated and its interaction with leptin-receptor (ObR) was analyzed compared to Lep30 (as the most efficient leptin-derived peptide in targeting the brain). MD simulation data revealed a significant stable interaction between ligand binding domains (LBD) of ObR with LDP14 more than that of Lep30. Analyses demonstrated suitable cellular uptake of LDP14 and selectively targeting ability for human capillary endothelial cells (hBCEC-D3) and human U87 glioma cell lines compared to Lep30, in RMT, and energy-dependent manner. Data exhibited that LDP14 was unable to enter the rat C6 glioma cells, indicating the species specificity of this peptide. Likewise, data confirmed that the internalization of LDP14-modified G4 PAMAM dendrimers and their polyplex derivative with pEGFP-N1 plasmid occurs in ObR and species-dependent manner. Finally, our findings illustrated that the entry of LDP14-modified dendrimers in hBCEC-D3 cells not only was not affected by protein corona (PC) formation but also PC per se can enhance uptake rate. Commensurate with these descriptions, LDP14 can be used in the delivery of drugs/genes to the brain tissue with great potential application. Besides, there is no need for manipulations for overcoming the undesirable effects of blood proteins on the fate of therapeutic cargo targeting.
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Submitted: 10 Sep 2023
Revision: 14 Jan 2024
Accepted: 03 Mar 2024
ePublished: 10 Mar 2024
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