Brain Barrier for Effective Delivery of Neura

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Receptor Targeted Polymeric Nanostructures Capable of Navigating Across the Blood-Brain Barrier for Effective Delivery of Neural Therapeutics Taru Dube, Sonika Chibh, Jibanananda Mishra, and Jiban Jyoti Panda ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00207 • Publication Date (Web): 03 Aug 2017 Downloaded from http://pubs.acs.org on August 4, 2017

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ACS Chemical Neuroscience

Receptor Targeted Polymeric Nanostructures Capable of Navigating Across the BloodBrain Barrier for Effective Delivery of Neural Therapeutics Taru Dube1#, Sonika Chibh1#, Jibanananda Mishra2* and Jiban Jyoti Panda1* 1

Institute of Nano Sciences and Technology, Mohali, Punjab – 160062, India

2

School of Bioengineering and Biosciences, Lovely Professional University, Phagwara,

Punjab – 144411, India #

Both authors have contributed equally

*

Corresponding author

Taru Dube M. Pharm. (Pharmaceutics) PhD Scholar, INST, Mohali Sonika Chibh M. Tech. (Biotechnology) PhD Scholar, INST, Mohali Dr. Jibanananda Mishra* M. Phil, Ph.D Associate Professor, LPU, Punjab Tel: +91 8146679626 Email ID:[email protected] Dr. Jiban Jyoti Panda* Ph.D Scientist, INST, Mohali Tel: +91-172 - 2210075; Fax: +91-172-221107 Email ID: [email protected]

1 ACS Paragon Plus Environment


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Abstract The window of neurological maladies encompasses 600 known neurological disorders. In the last few years, an inordinate upsurge in the incidences of neuronal ailments with increased mortality rate has been witnessed globally. Despite noteworthy research in the discovery and development of neural therapeutics, brain drug delivery still encounters limited success due to meager perviousness of most of the drug molecules through the blood-brain barrier (BBB), a tight layer of endothelial cells that selectively impedes routing of the molecules across itself. In this review, we have tried to present a comprehensive idea on the recent developments in nanoparticle based BBB delivery systems, with a focus on the advancements in receptor targeted polymeric nanoparticles pertaining to BBB delivery. We have also attempted to bridge the gap between conventional brain delivery strategies and nanoparticle based BBB delivery for in-depth understanding. Various strategies are being explored for simplifying delivery of molecules across the BBB, however they have their own limitations such as invasiveness, need for hospitalization and surgery. Introduction of nanotechnology can impressively benefit the brain drug delivery. Though, many nanoparticles are being explored, but there are still several issues that need to be analyzed scrupulously before a real and efficient BBB traversing nanoformulation is realized. Keywords:

Blood-brain

barrier,

Nanotechnology,

Neuronal

diseases,

Polymeric

nanoparticles, Receptors


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1. Introduction We have witnessed an upsurge in the percentage of neural diseases in the last few years, and the burden is projected to climb 31.7% by 2020.1 This would pose a sizeable burden on the medical/healthcare needs pertaining to these diseases. In the last few decades, a dramatic rise in the development of novel neural therapeutics is being observed. However, no significant success has been achieved in the management of brain disorders like glioblastoma, Alzheimer’s, Parkinson’s disease etc. The utmost challenge in the therapy of different neural disorders lies in the incompetence of most of the drugs or therapeutics to cross the bloodbrain barrier (BBB). Brain is protected and isolated from rest of the body by a highly organized and extremely selectively permeable membrane system, BBB. A variety of strategies are being explored for ferrying molecules across the BBB. All these techniques have their own merits and demerits to deal with. Nanotechnology like any other field has shown up significant progress in successfully delivering drugs/therapeutics to the difficult parts/areas of the body, and many nanoparticulate systems are being explored for their proficiency to cross the BBB and deliver neural therapeutics. However, still there are many issues that need to be analyzed thoroughly before a real and effective BBB traversing nanoformulation is being realized. In this review, we have tried to present a comprehensive idea on the current developments in the field of nanoparticle based BBB delivery systems, with a focus on the advancement in the field of receptor targeted polymeric nanoparticles pertaining to BBB delivery. We have also tried to bridge the gap between conventional brain delivery strategies and nanoparticle based BBB delivery for better understanding. 2. The blood-brain barrier



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Blood-brain barrier is formed by the tight junctions of endothelial cells which lines the brain capillaries (Figure 1). The tight junctions restrict passage of molecules across the capillary endothelium of the brain. Though, endothelial cell tight junctions constitute most part of the BBB; however it is also formed by other cell types such as astrocytic end feets, pericytes etc. Astrocytes provide biochemical support to the BBB endothelial cells. In fact, BBB is a dynamic barrier which is formed by different enzymes like cholinesterases, γaminobutyric acid transaminases, aminopeptidase, and endopeptidases; all are involved in the metabolization of neurotransmitters. There are also various other toxin metabolizing enzymes, all of which constitute the enzymatic BBB. In addition, efflux transporters like Pglycoprotein (P-gp) are also present in the BBB that efflux drugs from the endothelial cells to the blood and thus restrict the entry of many molecules across the BBB.2,3 Interestingly, BBB is not a barrier in realism and unlike other barriers, it is dynamic in nature allowing certain molecules to pass through to maintain nutrient supply to the brain as well as restricting other noxious substances getting into the brain. Only molecules like amino acids, sugars, and others which are important for proper functioning of the brain are allowed to cross through the BBB. These molecules cross the BBB by means of specific transporters. The hurdle created by the BBB is by rule and not just a chance, as it prohibits the entry of harmful compounds, toxins into the brain. Brain has to pay the price for this clean neuronal microenvironment by the inability of many neuropharmaceuticals/nootropics to cross the BBB. Practically, 100% of large molecular drugs like the proteins, drugable ribonucleic acid (RNA) molecules, and other gene therapy candidates could not traverse the BBB. It is yet another misconception that all small molecular drugs could cross the BBB. It has been observed that even 98% of the small molecular drugs cannot cross the BBB.4 The BBB present a transendothelial resistance of


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around 1500-2000 Ωcm2 compared to just 3-30 Ωcm2 in other body tissues, which makes it further difficult for molecules to toss in through the BBB.3,5

Figure 1. Schematic illustration showing the blood-brain barrier; which is formed by the tight junctions of endothelial cells which lines the brain capillaries and their further association with the perivascular astrocytes and pericytes. These together create the biggest hurdle in the delivery of therapeutic molecules for neurological diseases. 3. Mechanism of entry of molecules across the BBB Tight junctions prevailing in the BBB limit paracellular transport and only permit transcellular transport to certain degree. Molecules are generally transported through the BBB majorly via two mechanisms (Figure 2): 5 ACS Paragon Plus Environment


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a) Lipid-mediated free transmembrane diffusion, or b) Catalyzed transport. 3.1 Transmembrane diffusion Transmembrane diffusion is the primary mechanism for delivery across the BBB.6 While mostly hydrophobic molecules are capable of being traversed through the BBB; hydrophilic and large molecules like antibodies (150 kDa for Immunoglobulin G) are not.4 A small molecule can permeate the BBB by lipid-mediated transport if (a) it is lipid soluble, and (b) its molecular weight is

Brain Barrier for Effective Delivery of Neura

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