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Table 1 Novel strategies and various popular transport models to deliver therapeutic drugs through the BBB

From: Blood–brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders

Novel strategies Route Merits Demerits Drugs/molecules References
Osmotic disruption Paracellular • Transient
• Alters barrier-inducing factors
• Promising delivery for recombinant vectors
• Invasive
• Transient cerebral edema
• Non-specific
• Anticancer drugs
• Cytotoxic drugs
• Adenoviral vectors
[188, 189]
Chemical disruption Paracellular • Transient
• Site-specific drug delivery
Conflicting results in clinical trials • Neuropeptides
• Neurotransmitter
• Antibiotics
• Antineoplastic agents
[168, 190, 191]
Biochemical disruption Non-invasive Selective opening of brain tumor capillaries Breaks down the self-defense mechanism • Intracarotid infusion of leukotriene C4 [192]
Evade active efflux transcellular Involved in multidrug resistance Restricts the drug distribution • Phenothiazines
• Inhibitors of serotonin re-uptake
[193]
Tight junction pathways Paracellular (diffusion) A high capacity pore pathway Require novel high resolution techniques to detect single openings and closings Activation of apical sodium-glucose cotransport (SGLT1) [193]
Nanoparticle delivery Paracellular (diffusion) and Transcellular (transcytosis) • Targeted
• Sustained and/or regulated release
• Expensive
• High toxicity
• Clinical efficacy undemonstrated
Liposomal doxorubicin, temozolomide [194,195,196]
Biodegradable polymer Encircle BBB • Controlled drug delivery • Useful for limited patients   [164]
Pro-drug   • High drug residence time
• Specific membrane transporter
• Low selectivity
• Low retention
• Toxicity
• Fatty acids, glyceride or phospholipids
• Precursor ofGABA,
• Niflumic acid
• Valproate or vigabatrin
 
Biological tissue delivery Invasive • Co-grafted cells release therapeutic proteins • Inefficient transfection
• Non-selective expression
• Deleterious regulation
Intracarotid infusion of leukotrienes, bradykinin [169]
Vasoactive peptides Transient Non-invasive • Poor clinical efficacy RMP-7/ labradimil/Cereport [197, 198]
Cell-mediated endocytosis Transcellular Targeted • Toxic for cell carrier system
• Less therapeutic loading
• TAT
• Penetratin
• polyarginines
[199,200,201]
Focused ultrasound Paracellular and Transcellular (diffusion and convection) • Non-invasive
• Targeted
Costly • Antibodies, doxorubicin
• Carboplatin
[202, 203]
Radiation Paracellular and Transcellular • Increases permeability Radiation-induced (Neuro) inflammation Insulin [204, 205]
Intrathecal and intraventricular delivery Bypass BBB • Encounter minimized protein binding
• Decrease enzymatic activity
• Longer drug shelf-life
• Invasive
• Low parenchymal concentrations
• Prompt CSF turnover
• High clinical incidence of hemorrhage
• Neurotoxicity
Recombinant human heparin-N-sulfatase (rhHNS) [206,207,208]
Olfactory pathway Crosses BBB • Non-invasive
• Simple drug administration
• Discomfort nasal mucosa
• Lower efficiency
Neurotropic factor [209]
Interstitial wafers, microchips and nanospheres Crosses BBB • Sustained and controlled release
• Easily implantable without damage
• Invasive
• Distribution is limited through ECS
  [210, 211]
Convection- Enhanced Delivery (Injections, Catheters and Pumps) Bypass BBB
Through transcellular
• Enhances distribution by bulk flow • Invasive
• backflow of infusate
• catheter misplacement risk
• Expensive
• Low efficiency
• Gadolinium
• Magnetic nanoparticles
[198, 212]
Carrier-mediated Transcellular (transcytosis) Non-invasive Controls the delivery and retention of drugs A highly stereospecific drug is converted to structure similar to that of endogenous nutrient Levodopa
• Melphaling
• Glucose
[213]
Receptor-mediated Transcellular (transcytosis) • Allows planned transport linkers to suit the characterized functional requirement of the therapeutic agent, including peptide-based pharmaceuticals and small molecules incorporated within liposomes
• These transporters can be examined for brain delivery
Saturable process, enzymatic drug release, attachment to a BBB transport vector depicts certain drugs inactive • Transferrin receptor
• Lactoferrin receptor
• Insulin receptor
[214,215,216]
Adsorptive mediated Transcytosis • Uses a cationic biological macromolecule   • Cationized bovine serum albumin (BSA)
• Cationized immunoglobulins/monoclonal antibodies (Mabs)
[215, 217]