Design, Synthesis and Characterization of Novel Co-Polymers Decorated with Peptides for the Selective Nanoparticle Transport across the Cerebral Endothelium

Abstract

The development of new strategies for enhancing drug delivery to the brain represents a major challenge in treating cerebral diseases. In this paper, we report on the synthesis and structural characterization of a biocompatible nanoparticle (NP) made up of poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) co-polymer (namely PELGA) functionalized with the membranotropic peptide gH625 (gH) and the iron-mimicking peptide CRTIGPSVC (CRT) for transport across the blood-brain barrier (BBB). gH possesses a high translocation potency of the cell membrane. Conversely, CRT selectively recognizes the brain endothelium, which interacts with transferrin (Tf) and its receptor (TfR) through a non-canonical ligand-directed mechanism. We hypothesize that the delivery across the BBB of PELGA NPs should be efficiently enhanced by the NP functionalization with both gH and CRT. Synthesis of peptides and their conjugation to the PLGA as well as NP physical-chemical characterization are performed. Moreover, NP uptake, co-localization, adhesion under dynamic conditions, and permeation across in vitro BBB model are evaluated as a function of gH/CRT functionalization ratio. Results establish that the cooperative effect of CRT and gH may change the intra-cellular distribution of NPs and strengthen NP delivery across the BBB at the functionalization ratio 33% gH–66% CRT.

PLGA Nanoparticle-Based Formulations to Cross the Blood–Brain Barrier for Drug Delivery: From R&D to cGMP

“…Tandem systems that utilized multiple modifications have been reported. Guarnieri et al [57] demonstrated the cooperative effects of glycoprotein H 625, a CMT modification with iron-mimicking protein CRT and RMT modification, in enhancing PLGA NP permeation of BBB. Liu et al [58] developed a PLGA NP drug delivery system modified with angiopep-2 (RMT) and 1, 2-Dioleoyl-3-trimethylammonium-propane (AMT), for gefitinib and Golgi phosphoprotein 3 for the treatment of glioblastoma.…”

Assisting PNA Transport Through Cystic Fibrosis Human Airway Epithelia With Biodegradable Hybrid Lipid-Polymer Nanoparticles

“…PNA*-hNPs were prepared by an emulsion/solvent diffusion technique as previously reported 27 . Brie y, 100 µL of a water solution of PNA* (50 nmol/mL) were added to 1 mL of methylene chloride containing PLGA 502H (10 mg; 1% w/v) 29 under vortex mixing (2400 rpm, Heidolph, Germany) and DPPC (0.5 mg/mL), achieving a water-in-oil emulsion (w/o). Just after mixing, the w/o emulsion was added to 12.5 mL of ethanol 96% (v/v) under moderate magnetic stirring, leading to the immediate formation of hNPs.…”

A Decade of Organs-on-a-Chip Emulating Human Physiology at the Microscale: A Critical Status Report on Progress in Toxicology and Pharmacology

“…The emergence of transparent membrane materials such as PTFE have improved these limitations [ 169 ]. Falanga et al employed transparent PET membranes for studying the effect of particle decoration with the membranotropic peptide gH625 and the iron-mimicking peptide CRTIGPSVC on the transport of nanoparticles across a murine BBB, based on b.End3 brain endothelial cells [ 170 ]. Brown et al have adapted and improved the traditional sandwich design and generated a human neurovascular unit (NVU) model that allowed paracrine signaling of the co-cultured cells in a more physiological setup, by seeding brain microvascular endothelial cells on the bottom side of the membrane and introducing human pericytes, astrocytes, and neurons in a collagen hydrogel above [ 171 ].…”