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

[...]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. In terms of anatomical microstructure, the juxtaposition of multiple cell types such as luminal brain capillary endothelial cells (BCECs) with pericytes, astrocytes, and microglia cells at the abluminal surface makes the BBB a selective cell barrier between the blood and CNS.5 7 It has been indicated that compounds with a molecular weight of less than 500 Da and hydrophobic factors can cross the BBB interface.8,9 From a physiological aspect, the interactive BBB cell layer is crucial for the function and normal activity of neurons. The selection of ligands is based on specific physicochemical and biological properties such as bio compatibility, lack of immunogenicity, specificity, easy and low-cost synthesis steps, suitable size, and shape.14 Up to now, several biological ligands derived from hormones, transcriptional factors, and animal venoms including angiopep-2,1517 melittin,18 chlorotoxin (Chx),1921 candoxin-derived peptide (CDX),22,23 transferrin (Tf),24 26 insulin-like growth factor (IGF),27 leptin receptor (ObR),28,29 etc. have been used for different delivery purposes. D8 and Angiopep-2 are two fascinating examples that are in clinical trials for delivery purposes.30,31 Leptin, a 167 amino acid peptide sequence, is an adipose tissue-derived hormone with an average molecular weight of 16kD and several biological properties.32 This hormone can modulate the activity of immune cells, the autonomic nervous system, the metabolism rate, and the endocrine system.33 Emerging data have revealed the impact of leptin on BBB function.34 Crystallographic analysis of leptin has exhibited a long-chain helical structure with the potential to cross the BBB interface following attachment to EC receptors.35 Based on several molecular investigations, ObR is expressed in the luminal surface of BBB, blood-CSF barrier, and choroid plexus to uptake leptin and regulate food ingestion and metabolism.36 Upon the activation of ObR, leptin enters the brain parenchyma via the activation of transcytosis.37 In terms of intracellular domains, six types of ObR have been indicated with different effects on BBB.