PLGA-PEG-ANG-2 Nanoparticles for Blood-Brain Barrier Crossing: Proof-of-Concept Study.

Gina P Hoyos-Ceballos,Betty L López-Osorio,Federica Da Ros,Flavio Forni,Giovanni Tosi,Barbara Ruozi,Antonietta Vilella,Jason T Duskey,Ilaria Ottonelli,Eleonora Daini,Maria Angela Vandelli,Michele Zoli

doi:10.3390/pharmaceutics12010072

Gina P Hoyos-Ceballos, Betty L López-Osorio + Show 10 more

Open Access

https://doi.org/10.3390/pharmaceutics12010072

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Abstract

The treatment of diseases that affect the central nervous system (CNS) represents a great research challenge due to the restriction imposed by the blood–brain barrier (BBB) to allow the passage of drugs into the brain. However, the use of modified nanomedicines engineered with different ligands that can be recognized by receptors expressed in the BBB offers a favorable alternative for this purpose. In this work, a BBB-penetrating peptide, angiopep-2 (Ang–2), was conjugated to poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles through pre- and post-formulation strategies. Then, their ability to cross the BBB was qualitatively assessed on an animal model. Proof-of-concept studies with fluorescent and confocal microscopy studies highlighted that the brain-targeted PLGA nanoparticles were able to cross the BBB and accumulated in neuronal cells, thus showing a promising brain drug delivery system.

Highlights

Discovering new methods to treat diseases is becoming increasingly complicated because of the numerous natural biological barriers in our bodies such as opsonization by proteins in the blood, first-pass clearance organs, and the immune response [1,2]
We focused on creating and characterizing targeted Ang–2 poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs); the surface was engineered by conjugating Ang–2 directly to the polymer, and nanoformulation was gained, or with post-formulation anchorage to NP through the conjugation of the thiol-containing cysteine added to the Ang–2 and a maleimide containing PLGA
The 1H-NMR spectra of PLGA-Mal, Ang–2, and the PLGA modified with Ang–2 (PLGA-Ang–2)

Summary

Introduction

Discovering new methods to treat diseases is becoming increasingly complicated because of the numerous natural biological barriers in our bodies such as opsonization by proteins in the blood, first-pass clearance organs, and the immune response [1,2]. A very promising targeting ligand for the delivery of nanomedicines into the brain is Angiopep-2 (Ang–2), a 19 amino acid peptide (TFFYGGSRGKRNNFKTEEY-OH) which binds the low-density lipoprotein receptor-related protein 1 (LRP1), which is widely expressed throughout the central nervous system (CNS) (by endothelial cells on the basolateral surface, neuroblasts, microglia, astrocytes, and neurons) [9,10,11,12] This ligand has been highly sought after in its use to deliver nanomedicines to the brain because of its ability to activate transcytosis across the BBB, as well as its upregulation in human glioma cells [13,14,15]. Ang–2 has been conjugated to numerous nanocarrier types in order to improve BBB crossing, including liposomes, tandem micelles, PEG-PCL, solid lipid nanoparticles, dendrigraft poly-l lysine, and poly-amidoamine dendrimers to deliver various active compounds (Coumarin, docetaxel, siRNA, etc.) [16,17,18,19]

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