Anastasia Groshev

Artificial Neural Network in Drug Delivery and Pharmaceutical Research

Artificial neural networks (ANNs) technology models the pattern recognition capabilities of the neural networks of the brain. Similarly to a single neuron in the brain, artificial neuron unit receives inputs from many external sources, processes them, and makes decisions. Interestingly, ANN simulates the biological nervous system and draws on analogues of adaptive biological neurons. ANNs do not require rigidly structured experimental designs and can map functions using historical or incomplete data, which makes them a powerful tool for simulation of various non-linear systems.ANNs have many applications in various fields, including engineering, psychology, medicinal chemistry and pharmaceutical research. Because of their capacity for making predictions, pattern recognition, and modeling, ANNs have been very useful in many aspects of pharmaceutical research including modeling of the brain neural network, analytical data analysis, drug modeling, protein structure and function, dosage optimization and manufacturing, pharmacokinetics and pharmacodynamics modeling, and in vitro in vivo correlations. This review discusses the applications of ANNs in drug delivery and pharmacological research.

Brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles for brain cancers.

Abstract Objectives: To prepare and characterize in vitro a novel brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles (NPs) for the treatment of brain cancer. Methods: Doxorubicin-loaded NPs were prepared by the nanoprecipitation method using PLGA-COOH (dl-lactide-co-glycolide). The NPs were coated with a glutathione-PEG conjugate (PEG-GSH) in order to target delivery to the brain. The NPs were characterized via in vitro studies to determine particle size, drug release, cellular uptake, immunofluorescence study, cytotoxic assay, and in vitro blood–brain barrier (BBB) assay. Results: The NPs showed a particle size suitable for BBB permeation (particle size around 200 nm). The in vitro release profile of the NPs exhibited no initial burst release and showed sustained drug release for up to 96 h. The immunofluorescence study showed the glutathione coating does not interfere with the drug release. Furthermore, in vitro BBB Transwell™ study showed significantly higher permeation of the doxorubicin-loaded NPs compared with the free doxorubicin solution through the coculture of rat brain endothelial (RBE4) and C6 astrocytoma cells (p < 0.05). Conclusions: We conclude that the initial in vitro characterization of the NPs demonstrates potential in delivering doxorubicin to cancer cells with possible future application in targeting brain cancers in vivo.

Preparation and characterization of methylene blue nanoparticles for Alzheimer's disease and other tauopathies.

Methylene blue (MB) has been shown to slow down the progression of the Alzheimers disease (AD) and other tauopathies; however distribution of MB into the brain is limited due its high hydrophilicity. In this study, we aimed to prepare novel hydrophobic glutathione coated PLGA nanoparticles to improve bioavailability of MB in the brain. Glutathione coated poly-(lactide-co-glycolide) (PLGA-b-PEG) nanoparticles (NPs) were prepared and tested in two different cell culture models of AD expressing microtubule associated protein tau (tau). The NPs showed a particle size averaging 136.5±4.4nm, which is suitable for the blood brain barrier (BBB) permeation. The in vitro release profile of the NPs exhibited no initial burst release and showed sustained drug release for up to 144 hours. Interestingly, treatment of newly formulated MB-NPs showed a potent reduction in both endogenous and over expressed tau protein levels in human neuroblastoma SHSY-5Y cells expressing endogenous tau and transfected HeLa cells over-expressing tau protein, respectively. Furthermore, in vitro BBB Transwell™ study showed significantly higher permeation of MB-NP compared to the MB solution through the co culture of rat brain endothelial 4 (RBE4) and C6 astrocytoma cells (p<0.05). The proposed MB loaded nanoparticles could provide a more effective treatment option for AD and many other related disorders.

Nanoparticulate Transscleral Ocular Drug Delivery

Ocular drug delivery is one of the most challenging areas of drug delivery due to the unique mostly avascular nature of the major eye structures and presence of two blood barriers. Effectiveness of a more conventional systemic delivery falls short due to low drug levels in the eye tissue. Periocular approaches require penetration of fibrous sclera and present their own limitations. Utilization of nanotechnology presents new avenue of drug system development with potential to penetrate protective barriers and sustain ample tissue saturation. More specifically, transscleral delivery permits a range of applications in targeted delivery, gene, stem cell, protein and peptides, oligonucleotide, and ribozyme therapies. The exciting range of current applications is expounded in this review.

Preparation and Characterization of Microemulsion of Cilostazol for Enhancement of Oral Bioavailability

Cilostazol is a promising drug for antiplatelet combination therapy that is very important for treatment for various cardiovascular disorders. However, oral delivery of this drug is greatly impeded by the poor solubility in aqueous solutions. The aim of this study was to develop microemulsion (ME) delivery system capable of improving the drug bioavailability. In this study, Capmul MCM C8 (glycerol monocaprylate) based MEs containing Tween 20(polysorbate 20) and/or Labrafil M 1944(poly oxyglycerides) as surfactant(S) and Transcutol P(diethyl glycol monoethyl ether) as cosurfactant(CoS) were studied as potential delivery systems of cilostazol. A number of such systems were prepared containing different S:CoS ratios(1:1, 2:1 and 3:1) based on phase diagrams. Loading of cilostazol was selected as per solubilization capacity and was characterized for pH, viscosity, conductivity, particle size, zeta potential and % transmittance. The MEs systems were further investigated for chemical stability, diffusion and bioavailability. Cilostazol displayed high solubility in microemulsions with particle size up to 70 nm. It was also stable at ambient temperature up to 6 months without significant change in particle size, zeta potential, and % transmittance. Dilution up to 100 fold with aqueous medium observed a visible cloudiness having a particle size up to 104 nm. The in vitro release, and ex vivo intraduodenal diffusion, and in vivo study indicated the capacity of developed ME to improve the bioavailability (1.43 fold) via oral route administration when compared with commercially available tablets (Pletoz-50).

Clinical outcomes from maximum-safe resection of primary and metastatic brain tumors using awake craniotomy

OBJECTIVE To retrospectively analyze outcomes in patients undergoing awake craniotomies for tumor resection at our institution in terms of extent of resection, functional preservation and length of hospital stay. PATIENTS AND METHODS All cases of adults undergoing awake-craniotomy from September 2012-February 2015 were retrospectively reviewed based on an IRB approved protocol. Information regarding patient age, sex, cancer type, procedure type, location, hospital stay, extent of resection, and postoperative complications was extracted. RESULTS 76 patient charts were analyzed. Resected cancer types included metastasis to the brain (41%), glioblastoma (34%), WHO grade III anaplastic astrocytoma (18%), WHO grade II glioma (4%), WHO grade I glioma (1%), and meningioma (1%). Over a half of procedures were performed in the frontal lobes, followed by temporal, and occipital locations. The most common indication was for motor cortex and primary somatosensory area lesions followed by speech. Extent of resection was gross total for 59% patients, near-gross total for 34%, and subtotal for 7%. Average hospital stay for the cohort was 1.7days with 75% of patients staying at the hospital for only 24h or less post surgery. In the postoperative period, 67% of patients experienced improvement in neurological status, 21% of patients experienced no change, 7% experienced transient neurological deficits, which resolved within two months post op, 1% experienced transient speech deficit, and 3% experienced permanent weakness. CONCLUSIONS In a consecutive series of 76 patients undergoing maximum-safe resection for primary and metastatic brain tumors, awake-craniotomy was associated with a short hospital stay and low postoperative complications rate.

Artificial Neural Networks in Pharmaceutical Research, Drug Delivery and Pharmacy Curriculum

The purpose of this work was to review the applications of ANN, Artificial Neural Networks, in the pharmaceutical research, drug delivery systems, and pharmacy curriculum. With the advent of the computers and their applications in biosciences, significant changes are under way in the research processes and it is crucial for the research laboratories and pharmacy schools to be aware of the benefits of bioinformatics methods such as ANNs. Literature survey was conducted to assess the scope of applications of ANNs in the pharmaceutical research and the ability of ANNs to provide new areas of professional opportunities to the Pharmacy students. Our literature survey results indicated that ANNs can be very useful in many aspects of pharmaceutical research including pharmacokinetics and pharmacodynamics modeling, optimization of dosage and drug delivery systems. ANNs can be taught as a part of the PharmD (Doctor of Pharmacy) curriculum to equip the students for quick and effective formulation design and optimization of pharmaceutical doses. In this work, we have successfully summarized the applications of ANNs in pharmaceutical research and found that ANNs play an increasingly important role in pharmaceutical research and education.