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Adv Pharm Bull. 2024;14(2): 453-468.
doi: 10.34172/apb.2024.033
PMID: 39206396
PMCID: PMC11347739
  Abstract View: 446
  PDF Download: 199

Research Article

Discovery of a Novel Dual Targeting Peptide for Human Glioma: From In Silico Simulation to Acting as Targeting Ligand

Negar Sedghi Aminabad 1,2 ORCID logo, Yousef Saeedi 3, Jamal Adiban 4, Mahdieh Nemati 1,2, Donya Shaterabadi 1,2, Farhood Najafi 5, Reza Rahbarghazi 6,7, Mehdi Talebi 7,8, Amir Zarebkohan 1,9* ORCID logo

1 Department of Medical Nanotechnology, Advanced Faculty of Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Department of Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
4 Ministry of Health and Medical Education, Tehran, Iran.
5 Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran.
6 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
7 Department of Applied Cell Sciences, Advanced Faculty of Medical Sciences, Tabriz University of Medical, Tabriz, Iran.
8 Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
9 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
*Corresponding Author: Amir Zarebkohan, Email: zarebkohana@tbzmed.ac.ir

Abstract

Purpose: Receptor-mediated transcytosis (RMT) is a more specific, highly efficient, and reliable approach to crossing the blood-brain-barrier (BBB) and releasing the therapeutic cargos into the brain parenchyma.

Methods: Here, we introduced and characterized a human/mouse-specific novel leptin-derived peptide using in silico, in vitro and in vivo experiments.

Results: Based on the bioinformatics analysis and molecular dynamics (MD) simulation, a 14 amino acid peptide sequence (LDP 14) was introduced and its interaction with leptin-receptor (ObR) was analyzed in comparison with an well known leptin-derived peptide, Lep 30. MD simulation data revealed a significant stable interaction between ligand binding domains (LBD) of ObR with LDP 14. Analyses demonstrated suitable cellular uptake of LDP 14 alone and its derivatives (LDP 14-modified G4 PAMAM dendrimer and LDP 14-modified G4 PAMAM/pEGFP-N1 plasmid complexes) via ObR, energy and species dependent manner (preferred uptake by human/mouse cell lines compared to rat cell line). Importantly, our findings illustrated that the entry of LDP 14-modified dendrimers in hBCEC-D3 cells not only is not affected by protein corona (PC) formation, as the main reason for diminishing the cellular uptake, but also PC per se can enhance uptake rate. Finally, fluorescein labeled LDP 14-modified G4 PAMAM dendrimers efficiently accumulated in the mice brain with lower biodistribution in other organs, in our in vivo study.

Conclusion: LDP 14 introduced as a novel and highly efficient ligand, which can be used for drugs/genes delivery to brain tissue in different central nervous system (CNS) disorders.

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Submitted: 10 Sep 2023
Revision: 14 Jan 2024
Accepted: 03 Mar 2024
ePublished: 10 Mar 2024
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