Dataset Information

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

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.

SUBMITTER: Sedghi Aminabad N

PROVIDER: S-EPMC11347739 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

Discovery of a Novel Dual Targeting Peptide for Human Glioma: From <i>In Silico</i> Simulation to Acting as Targeting Ligand.

Sedghi Aminabad Negar N Saeedi Yousef Y Adiban Jamal J Nemati Mahdieh M Shaterabadi Donya D Najafi Farhood F Rahbarghazi Reza R Talebi Mehdi M Zarebkohan Amir A

Advanced pharmaceutical bulletin 20240310 2

<h4>Purpose</h4>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.<h4>Methods</h4>Here, we introduced and characterized a human/mouse-specific novel leptin-derived peptide using <i>in silico</i>, <i>in vitro</i> and <i>in vivo</i> experiments.<h4>Results</h4>Based on the bioinformatics analysis and molecular dynamics (MD) simulation, a 14 amino a ...[more]

PMID: 39206396

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Project description:BackgroundCarbonic anhydrase IX (CA IX) is a hypoxia-regulated transmembrane protein over-expressed in various types of human cancer. Recently, a new peptide with affinity for human carbonic anhydrase IX (CaIX-P1) was identified using the phage display technology. Aim of the present study is to characterize the binding site in the sequence of CaIX-P1, in order to optimize the binding and metabolic properties and use it for targeting purposes.Methodology/principal findingsVarious fragments of CaIX-P1 were synthesized on solid support using Fmoc chemistry. Alanine scanning was performed for identification of the amino acids crucial for target binding. Derivatives with increased binding affinity were radiolabeled and in vitro studies were carried out on the CA IX positive human renal cell carcinoma cell line SKRC 52 and the CA IX negative human pancreatic carcinoma cell line BxPC3. Metabolic stability was investigated in cell culture medium and human serum. Organ distribution and planar scintigraphy studies were performed in Balb/c nu/nu mice carrying subcutaneously transplanted SKRC 52 tumors. The results of our studies clearly identified amino acids that are important for target binding. Among various fragments and derivatives the ligand CaIX-P1-4-10 (NHVPLSPy) was found to possess increased binding potential in SKRC 52 cells, whereas no binding capacity for BxPC3 cells was observed. Binding of radiolabeled CaIX-P1-4-10 on CA IX positive cells could be inhibited by both the unlabeled and the native CaIX-P1 peptide but not by control peptides. Stability experiments indicated the degradation site in the sequence of CaIX-P1-4-10. Biodistribution studies showed a higher in vivo accumulation in the tumor than in most healthy tissues.ConclusionsOur data reveal modifications in the sequence of the CA IX affine ligand CaIX-P1 that might be favorable for improvement of target affinity and metabolic stability, which are necessary prior to the use of the ligand in clinical approaches.