BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS

Abstract

24The increasing incidence of diseases affecting the central nervous system 25 (CNS) demands the urgent development of efficient drugs. While many of 26 these medicines are already available, the Blood Brain Barrier and to a lesser 27 extent, the Blood Spinal Cord Barrier pose physical and biological limitations 28 to their diffusion to reach target tissues. Therefore, efforts are needed not only 29 to address drug development but specially to design suitable vehicles for 30 delivery into the CNS through systemic administration. In the context of the 31 functional and structural versatility of proteins, recent advances in their 32 biological fabrication and a better comprehension of the physiology of the 33 CNS offer a plethora of opportunities for the construction and tailoring of plain 34 nanoconjugates and of more complex nanosized vehicles able to cross these 35 barriers. We revise here how the engineering of functional proteins offer drug 36 delivery tools for specific CNS diseases and more transversally, how proteins 37 can be engineered into smart nanoparticles or 'artificial viruses' to afford 38 therapeutic requirements through alternative administration routes. 39 40 41

Hyperosmotic treatment synergistically boost efficiency of cell-permeable peptides

“…To address this challenge, variety of macromolecule delivery approaches or reagents have been developed. Perhaps cell-penetrating peptide (CPP)-based delivery system is the most common and safe method for the introduction of exogenous macromolecule to transiently manipulate cell behavior without possibility of permanent genomic changes [3]. …”

Managing CNS Tumors: The Nanomedicine Approach

“…Against this background of hindrance to brain tumor delivery, nanomedicine may enhance the distribution of poorly brain-distributed anticancer agents across the brain endothelium, since nanocarriers may well serve to target brain tumors through passive and active targeting or even through external physical stimuli [53]. Passive targeting occurs with the diffusion of nanomedicines through the interendothelial gaps of the highly vascularized leaky BBTB in the case of high-grade brain tumors, a phenomenon known as the enhanced retention and permeation (EPR) effect [54].…”

Morphogens and blood-brain barrier function in health and disease

“…Although great advances have been made in recent years, the field of BBB drug targeting is in its infancy and only very few current treatments make use of BBB drug delivery techniques. 123,124 Because many of the discussed morphogens -such as Wnt/ b-catenin, TGF-b, and the BMPs -are essential for a wide range of biological processes and the angiopoietins are essential for vessel development and integrity throughout the body, we propose that of these morphogens the semaphorins are the best option for treating BBB breakdown in CNS disorders. Recent studies have shown promising results regarding the use of anti-sema4D therapies.…”