Getting into the Brain: Are We in Yet or Just Knocking at the Door?

Nanomedicine, a promising addition to the spectrum of biomedicine, has viewed countless breakthroughs in the implementations of "site-specific" drug delivery. The promises of nanomedicines revolve around their unique physicochemical properties that permit the transport of therapeutics to the desired site of action, improve the pharmacokinetic endpoint, maximize the pharmacological influence of treatment, and overcome the limitation of remedies that otherwise would impede the therapeutic effectiveness. One of most insurmountable challenge possessed by conventional drug-delivery in getting therapeutics across the central-nervous-system is to conquer the harsh passage of the blood-brain barrier (BBB). Many published studies revealed BBB to be a complex, dynamic interface that acclimatizes to the needs of the central nervous system (CNS). These physical and biochemical barriers pose a significant challenge to the effective management of brain-related disorders such as neurodegenerative diseases. This challenge is widely accepted and defeated with the advent of a new class of brain-targeted nanomedicines. This review is an effort to overview the key research trends in nanotechnology over the past decade concerning the BBB as a regulatory interface and factors affecting CNS drug delivery. The review further summarized the specific diversity of various nanomedicinal approaches, the critical and elementary structural component of their design, the surface engineering of vehicles carrying drug at the nanoscale, selected current clinical successes, and future prospects along with hidden perils.

Multilocus variable number tandem repeat analysis (MLVA)-typing of Brucella abortus isolates of India reveals limited genetic diversity.

Multilocus variable number tandem repeat analysis (MLVA) technique has wide applications in studying phylogenies and short-term epidemiology of pathogens. The technique has been extensively used worldwide in molecular epidemiology of Brucella genus. Only one study on this aspect is reported from India despite its economic and public health significance in country. The present study isolated B. abortus from domesticated bovines of Jammu region of Jammu and Kashmir state, India, and applied MLVA for 16 loci (MLVA-16). MLVA results were compared with the results of a previous study and with MLVA data of Indian isolates present in http://microbesgenotyping.i2bc.paris-saclay.fr/database. In the study, 136 samples from bovines (cattle and buffaloes) of 47 farms of Jammu region were processed for isolation. Eleven isolates of B. abortus biovar 1 from 6 farms were obtained. In MLVA-16 analysis, although the isolates were classified in a single cluster, 5 genotypes were obtained with a specific genotype being prevalent on each farm. The study identifies that MLVA-16 is capable to differentiate B. abortus strains in an area having high genetic similarity among isolates. On comparing the results with previous study and database, the isolates were found to have high genetic similarity indicating that the genetic diversity of B. abortus in India is very limited. It probably indicates that India is contaminated recently with B. abortus. To test this hypothesis, analysis of whole genome sequencing data of diverse collection of Indian B. abortus strains is required.

Comparison of Species and Cell-Type Differences in Fraction Unbound of Liver Tissues, Hepatocytes, and Cell Lines.

Fraction unbound (fu) of liver tissue, hepatocytes, and other cell types is an essential parameter used to estimate unbound liver drug concentration and intracellular free drug concentration. fu,liver and fu,cell are frequently measured in multiple species and cell types in drug discovery and development for various applications. A comparison study of 12 matrices for fu,liver and fu,cell of hepatocytes in five different species (mouse, rat, dog, monkey, and human), as well as fu,cell of Huh7 and human embryonic kidney 293 cell lines, was conducted for 22 structurally diverse compounds with the equilibrium dialysis method. Using an average bioequivalence approach, our results show that the average difference in binding to liver tissue, hepatocytes, or different cell types was within 2-fold of that of the rat fu,liver Therefore, we recommend using rat fu,liver as a surrogate for liver binding in other species and cell types in drug discovery. This strategy offers the potential to simplify binding studies and reduce cost, thereby enabling a more effective and practical determination of fu for liver tissues, hepatocytes, and other cell types. In addition, fu under hepatocyte stability incubation conditions should not be confused with fu,cell, as one is a diluted fu and the other is an undiluted fu Cell density also plays a critical role in the accurate measurement of fu,cell.

Development and characterization of a long-acting nanoformulated abacavir prodrug.

AIM: A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability. METHODS: Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice. RESULTS: MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks. CONCLUSION: MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen.

Bench-to-bedside translation of magnetic nanoparticles.

Magnetic nanoparticles (MNPs) are a new and promising addition to the spectrum of biomedicines. Their promise revolves around the broad versatility and biocompatibility of the MNPs and their unique physicochemical properties. Guided by applied external magnetic fields, MNPs represent a cutting-edge tool designed to improve diagnosis and therapy of a broad range of inflammatory, infectious, genetic and degenerative diseases. Magnetic hyperthermia, targeted drug and gene delivery, cell tracking, protein bioseparation and tissue engineering are but a few applications being developed for MNPs. MNPs toxicities linked to shape, size and surface chemistry are real and must be addressed before clinical use is realized. This article presents both the promise and perils of this new nanotechnology, with an eye towards opportunity in translational medical science.

Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues.

Magnetic nanoparticles (MNPs) accumulate at disease sites with the aid of magnetic fields; biodegradable MNPs can be designed to facilitate drug delivery, influence disease diagnostics, facilitate tissue regeneration and permit protein purification. Because of their limited toxicity, MNPs are widely used in theranostics, simultaneously facilitating diagnostics and therapeutics. To realize therapeutic end points, iron oxide nanoparticle cores (5-30 nm) are encapsulated in a biocompatible polymer shell with drug cargos. Although limited, the toxic potential of MNPs parallels magnetite composition, along with shape, size and surface chemistry. Clearance is hastened by the reticuloendothelial system. To surmount translational barriers, the crystal structure, particle surface and magnetic properties of MNPs need to be optimized. With this in mind, we provide a comprehensive evaluation of advancements in MNP synthesis, functionalization and design, with an eye towards bench-to-bedside translation.