Current Advances in Delivery of Biotherapeutics Across the Blood-Brain Barrier

Abstract

Significant efforts through genomic approaches have been dedicated toward the identification of novel protein-protein interactions as promising therapeutic targets for indications such as Alzheimer's disease, Parkinson's disease and neuropsychiatric disorders. Additionally, the number of biotherapeutic agents entering the Pharmaceutical sector continues to increase and according to EvaluatePharma's "World Preview 2014" report, "the compounded annual growth rate of biologics is expected to be 8.5 percent from 2008-2014, eight to 10 times greater than the growth rate of small molecules". However, there are limited examples of success in developing biotherapeutic modalities for central nervous system (CNS) diseases in the drug development pipeline. A primary reason for the lack of application of biotherapeutics to neuroscience targets, is that the blood-brain barrier (BBB) isolates and protects CNS structures creating a unique biochemically and immunologically privileged environment, therefore passage of macromolecules across this barrier has additional challenges. An understanding of the anatomical and physiological properties of this barrier with respect to penetration of biotherapeutics is presented in this review document. In this summary, recent advances in biotherapeutic delivery mechanisms across the BBB including transcranial brain drug delivery, focused ultrasound technology, nasal delivery, absorptive endocytosis, and receptor mediated endocytosis are evaluated using an industrial perspective. With acknowledgement that each approach has advantages and disadvantages, this review discusses the opportunities and challenges that are encountered during application of these methods across a variety of therapeutic areas such as, pain, obesity, neuroscience, and oncology. Utilizing an industrial perspective, including consideration of cost of goods and commercial feasibility for these approaches, this review highlights technology features which would enable industry investments toward novel BBB delivery technologies for biologics. Through continued development and improvement of such technology, new therapeutic options to treat and potentially cure central nervous system diseases could eventually evolve.

Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections

“…Various strategies are being investigated to avoid the need for direct intracranial drug delivery. Noninvasive strategies include drug manipulation, carrier-mediated drug delivery, receptor/vector-mediated delivery, and intranasal drug delivery (131,144), and some of these approaches may prove useful in gene therapy efforts. Nanotechnology applications include the delivery of drugs and other small molecules, such as genes and oligonucleotides, across the barrier (182).…”

Nasal-nanotechnology: revolution for efficient therapeutics delivery

“…The olfactory section to be found in the upper distant divisions of the nasal channels intimates the prospective for certain drug molecules to circumvent the blood brain barrier and penetrate into the brain (Bahadur & Pathak, 2012b). Even though the clinical potential of this drug administration route still remains controversial, there is substantial curiosity in investigating nasal route for the treatment of many intra-cerebral diseases such as Parkinson's and Alzheimer's (Merkus et al, 2003;Illum, 2004;Merkus & van den Berg, 2007;Malerba et al, 2011;Rajadhyaksha et al, 2011). Peptides and proteins are capable to penetrate into brain passing through the olfactory bulb and trigeminal pathways subsequent to nasal delivery, as an outcome escaping the blood brain barrier (Veronesi et al, 2011;Caban et al, 2012).…”

HIF-1 at the Blood-Brain Barrier: A Mediator of Permeability?

“…Such a strategy using combination therapies could have high benefit under particular scenarios. Indeed selective opening of the endothelium tight junctions to facilitate drug delivery to the brain is also an area of intense research since delivery of therapeutics to the CNS remains highly challenging [99,100]. Of course the feasibility of such an approach, although very attractive, remains to be properly researched to ensure exploitation of the benefits of BBB modulation, while minimizing the potential damage.…”