Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier

Tam, Vivienne; Sosa, Chris; Li, Rui; Yao, Nan; Priestley, Rodney D.

doi:10.1016/j.ijpharm.2016.10.031

Cited by 77 publications

(52 citation statements)

References 100 publications

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“…A possible solution to these limitations lies on tailored delivery of enzymes by means of biodegradable and biocompatible nanomedicines (NMeds). Different NMeds, including polymeric micelles, liposomes, and polymer- and lipid-based nanoparticles (NPs) [ 7 ] have been exploited for enzyme encapsulation as they are able to protect enzymes from undesired immunologic reactions and biodegradation, to ameliorate the biodistribution of the enzyme, to improve the pharmacological response, and to modulate enzyme release at the target site limiting undesirable side-effects [ 8 , 9 ]. In this field, polymeric NPs, particularly those made of polylactide-co-glycolic acid (PLGA), have attracted considerable interest over the last few years as versatile tools for enzymatic delivery [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function

et al. 2020

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Enzymes have gained attention for their role in numerous disease states, calling for research for their efficient delivery. Loading enzymes into polymeric nanoparticles to improve biodistribution, stability, and targeting in vivo has led the field with promising results, but these enzymes still suffer from a degradation effect during the formulation process that leads to lower kinetics and specific activity leading to a loss of therapeutic potential. Stabilizers, such as bovine serum albumin (BSA), can be beneficial, but the knowledge and understanding of their interaction with enzymes are not fully elucidated. To this end, the interaction of BSA with a model enzyme B-Glu, part of the hydrolase class and linked to Gaucher disease, was analyzed. To quantify the natural interaction of beta-glucosidase (B-Glu,) and BSA in solution, isothermal titration calorimetry (ITC) analysis was performed. Afterwards, polymeric nanoparticles encapsulating these complexes were fully characterized, and the encapsulation efficiency, activity of the encapsulated enzyme, and release kinetics of the enzyme were compared. ITC results showed that a natural binding of 1:1 was seen between B-Glu and BSA. Complex concentrations did not affect nanoparticle characteristics which maintained a size between 250 and 350 nm, but increased loading capacity (from 6% to 30%), enzyme activity, and extended-release kinetics (from less than one day to six days) were observed for particles containing higher B-Glu:BSA ratios. These results highlight the importance of understanding enzyme:stabilizer interactions in various nanoparticle systems to improve not only enzyme activity but also biodistribution and release kinetics for improved therapeutic effects. These results will be critical to fully characterize and compare the effect of stabilizers, such as BSA with other, more relevant therapeutic enzymes for central nervous system (CNS) disease treatments.

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Section: Introductionmentioning

confidence: 99%

Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function

et al. 2020

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“…Drugs with the proper molecular design that do not always comply with the structure–activity relationship can be recognized by these influx transporters and show high permeability across the BBB [ 2 , 8 , 9 ]. Over recent decades, a plethora of nanotechnology strategies have been investigated to overcome the limited ability to deliver active molecules from the systemic circulation into the CNS [ 10 , 11 , 12 , 13 , 14 , 15 ]. For this, drug-loaded nanoparticles of a different nature (e.g., lipid, polymeric) and size are surface-decorated with ligands that bind receptors overexpressed in the BBB and cross the BBB by transcytosis [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mixed Amphiphilic Polymeric Nanoparticles of Chitosan, Poly(vinyl alcohol) and Poly(methyl methacrylate) for Intranasal Drug Delivery: A Preliminary In Vivo Study

2020

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Intranasal (i.n.) administration became an alternative strategy to bypass the blood–brain barrier and improve drug bioavailability in the brain. The main goal of this work was to preliminarily study the biodistribution of mixed amphiphilic mucoadhesive nanoparticles made of chitosan-g-poly(methyl methacrylate) and poly(vinyl alcohol)-g-poly(methyl methacrylate) and ionotropically crosslinked with sodium tripolyphosphate in the brain after intravenous (i.v.) and i.n. administration to Hsd:ICR mice. After i.v. administration, the highest nanoparticle accumulation was detected in the liver, among other peripheral organs. After i.n. administration of a 10-times smaller nanoparticle dose, the accumulation of the nanoparticles in off-target organs was much lower than after i.v. injection. In particular, the accumulation of the nanoparticles in the liver was 20 times lower than by i.v. When brains were analyzed separately, intravenously administered nanoparticles accumulated mainly in the “top” brain, reaching a maximum after 1 h. Conversely, in i.n. administration, nanoparticles were detected in the “bottom” brain and the head (maximum reached after 2 h) owing to their retention in the nasal mucosa and could serve as a reservoir from which the drug is released and transported to the brain over time. Overall, results indicate that i.n. nanoparticles reach similar brain bioavailability, though with a 10-fold smaller dose, and accumulate in off-target organs to a more limited extent and only after redistribution through the systemic circulation. At the same time, both administration routes seem to lead to differential accumulation in brain regions, and thus, they could be beneficial in the treatment of different medical conditions.

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“…The high level of expression of efflux transporters (such as P-glycoprotein) in the BBB further prevents many molecules from reaching the brain. Drugs that can diffuse through the BBB must be of small molecular size (less than 500 Da), highly lipophilic, and not ionized at physiological pH [ 19 ]. This is not the case for the more specific CK2 inhibitors such as DMAT, TBB, and CX4945 which are relatively hydrophilic.…”

Section: Inhibitorsmentioning

confidence: 99%

CK2—An Emerging Target for Neurological and Psychiatric Disorders

et al. 2017

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Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders.

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Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier

Cited by 77 publications

References 100 publications

Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function

Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function

Mixed Amphiphilic Polymeric Nanoparticles of Chitosan, Poly(vinyl alcohol) and Poly(methyl methacrylate) for Intranasal Drug Delivery: A Preliminary In Vivo Study

CK2—An Emerging Target for Neurological and Psychiatric Disorders

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