Page 8 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

1. Introduction capillary endothelial cells, surrounded by a basal lamina,
astrocytic perivascular end-feet, pericytes, and neurons.
2
The large family of neurodegenerative diseases includes The presence of tight junctions (TJs) between adjacent
Alzheimer’s disease (AD), Parkinson’s disease (PD), endothelial cells reinforces the selective permeability of
amyotrophic lateral sclerosis (ALS), and HD. Over the BBB, preventing paracellular diffusion of molecules
33 million people worldwide are affected by these (Figure 1). The primary function of BBB is to physically
conditions and, with the rapid aging of the population; and metabolically control the transport of endogenous
they have become a major public health problem and a and exogenous molecules, thereby maintaining brain
1
heavy socio-economic burden. In developed countries, homeostasis and function while protecting the brain
the population over 65 has grown considerably over the microenvironment from systemic neurotoxic substances
past 50 years, coinciding with a rise in the incidence of and pathogens (e.g., bacteria, viruses, etc.). The transport
3
neurodegenerative diseases. These diseases are now among of molecules at the level of brain and blood vessel cells is
the leading causes of mortality. Their management is governed by two main pathways: One passive and the other
often challenging and complex for caregivers and imposes
substantial costs on healthcare systems. These diseases are active. The passive pathway is the paracellular pathway,
characterized by a loss of neurons, leading to deficits in which allows water-soluble molecules to pass through
memory, cognition, and motor behavior. TJs. The active pathways are the transcellular pathways,
which depend on the physicochemical properties of
At present, most treatments are either palliative or the transported molecules and include the transcellular
ineffective, offering no curative solutions. They mainly lipophilic pathway (e.g., lipid-soluble molecules),
alleviate the clinical symptoms of these diseases but rarely transport proteins for specific molecules (e.g., glucose,
target the underlying pathophysiological mechanisms. Some amino acids, etc.), receptor-mediated transcytosis
patients do not respond to pharmacological treatments, (e.g., insulin, transferrin, etc.), and adsorptive transcytosis
while others develop drug resistance. In addition, several of (e.g., albumin and other plasma proteins). These pathways
these diseases lack any form of treatment altogether. are responsible for transporting the nutrients and gases
In this context, the scientific and medical community required to control brain homeostasis and functions. 2
has made significant efforts to design and validate Because of its vital physiological roles, the BBB poses a
pharmacological treatments that target the brain regions significant challenge to treating brain diseases by severely
affected by these diseases. However, many systemically limiting or completely blocking the intracerebral (i.c.)
administered therapeutics show limited or no accumulation bioavailability of therapeutics. Indeed, this BBB excludes
in the brain parenchyma and often cause off-target effects nearly 100% of large neurotherapeutics (e.g. monoclonal
due to non-specific accumulation in healthy tissues. One antibodies, recombinant proteins, nucleic acids) and over
of the main barriers to the delivery of therapeutics from 98% of small molecules (<400 Da), largely due to their
4
the vascular compartment to the brain parenchyma is the physicochemical properties. This barrier explains the
blood–brain barrier (BBB). limited efficacy of many therapies for brain disorders.
5
The BBB is one of the most selective and semi-permeable In addition, the presence of active efflux transporters
endothelial barriers. It consists of a monolayer of brain (e.g., ATP-binding cassette transporters) at the BBB

Figure 1. Schematic diagram of the blood–brain barrier and tight junctions. Adapted from “Brain vascular system”. Retrieved from https://app.biorender.
com/biorender-templates.

Volume 11 Issue 2 (2025) 2 doi: 10.36922/jctr.24.00061