Anjali Hirani

Brain-targeted delivery of docetaxel by glutathione-coated nanoparticles for brain cancer.

Gliomas are some of the most aggressive types of cancers but the blood–brain barrier acts as an obstacle to therapeutic intervention in brain-related diseases. The blood–brain barrier blocks the permeation of potentially toxic compounds into neural tissue through the interactions of brain endothelial cells with glial cells (astrocytes and pericytes) which induce the formation of tight junctions in endothelial cells lining the blood capillaries. In the present study, we characterize a glutathione-coated docetaxel-loaded PEG-PLGA nanoparticle, show its in vitro drug release data along with cytotoxicity data in C6 and RG2 cells, and investigate its trans-blood–brain barrier permeation through the establishment of a Transwell cellular co-culture. We show that the docetaxel-loaded nanoparticle’s size enables its trans-blood–brain barrier permeation; the nanoparticle exhibits a steady, sustained release of docetaxel; the drug is able to induce cell death in glioma models; and the glutathione-coated nanoparticle is able to permeate through the Transwell in vitro blood–brain barrier model.

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.

Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration

Abstract Age-related macular degeneration (AMD) is one of the leading causes of blindness in the US affecting millions yearly. It is characterized by intraocular neovascularization, inflammation and retinal damage which can be ameliorated through intraocular injections of glucocorticoids. However, the complications that arise from repetitive injections as well as the difficulty posed by targeting the posterior segment of the eye make this interesting territory for the development of novel drug delivery systems (DDS). In the present study, we described the development of a DDS composed of triamcinolone acetonide-encapsulated PEGylated PLGA nanoparticles (NP) incorporated into PLGA–PEG–PLGA thermoreversible gel and its use against VEGF expression characteristic of AMD. We found that the NP with mean size of 208 ± 1.0 nm showed uniform size distribution and exhibited sustained release of the drug. We also demonstrated that the polymer can be injected as a solution and transition to a gel phase based on the biological temperature of the eye. Additionally, the proposed DDS was non-cytotoxic to ARPE-19 cells and significantly reduced VEGF expression by 43.5 ± 3.9% as compared to a 1.53 ± 11.1% reduction with triamcinolone. These results suggest the proposed DDS will contribute to the development of novel therapeutic strategies for AMD.

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.

Blood-Brain Barrier Permeation of Glutathione-Coated Nanoparticle

Brain-related diseases are some of the most aggressive, but are also some of the hardest to treat. One of the main obstacles in attempting to treat brain-related diseases is surmounting the blood-brain barrier, a physiological barrier that separates neural tissue from the blood through the interactions of glial cells and endothelial cells. The present study describes the establishment of an in vitro blood-brain barrier model through the co-culture of rat brain endothelial (RBE4) and astrocytic (C6) cells on Transwell™ permeable support inserts. Coating organic, drug-encapsulating nanoparticles with glutathione helps the nanoparticles cross the in vitro blood-brain barrier model better than identical concentrations of uncoated nanoparticles and the free drug solution. This provides the basis for conjugating nanoparticles or other drug vectors with glutathione in clinical settings to enhance the trans-blood-brain barrier permeation of brain-targeted therapies. The implementation of this method in therapies has the potential to influence therapies of brain-related disorders by specifically targeting neural tissue with therapeutic compounds.

Nano-Biomaterials For Ophthalmic Drug Delivery

The capabilities of nanotechnology are leading to widespread use of nanomaterials in biotechnology and medicine. Nanomaterials exist in various sizes, compositions, and morphology. Due to their large numbers, classifi cation systems should be implemented for proper evaluation of the nanomaterials for effi cacy and prevention of toxicity. Many nanomaterials are being studied for potential therapeutic applications in ocular disease. Conventional treatments still possess side effects and limitations and the use of nano-biomaterials for ophthalmic drug delivery can allow for design and administration of delivery systems with targeted and sustained release capabilities. Additionally, off-target activities and toxicity can be reduced.

Nanoplatforms for Delivery of siRNA to the Eye.

Drug delivery to the eye is challenging for formulation scientists due to physiological barriers that separate the eye from the rest of the body. A variety of ocular disorders demand the development of optimal drug delivery systems for the administration of drugs and therapeutic agents that can overcome barriers that restrict drug bioavailability. SiRNA inhibits the expression of target genes and has immense potential as a biological tool for the therapeutic inhibition of disease causing genes; however, delivery of siRNA to ocular tissue is a challenge. Recent literature suggests that nanoplatforms show great promise in enhancing ophthalmic drug delivery. A drug delivery system involving nanoparticles and siRNA could surpass problems faced in ocular delivery with improved biodistribution and lower toxicity. This review covers recent research in the area of nanocarrier siRNA drug delivery for various ocular disorders.

Aflibercept Nanoformulation Inhibits VEGF Expression in Ocular In Vitro Model: A Preliminary Report

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the United States, affecting approximately 11 million patients. AMD is caused primarily by an upregulation of vascular endothelial growth factor (VEGF). In recent years, aflibercept injections have been used to combat VEGF. However, this treatment requires frequent intravitreal injections, leading to low patient compliance and several adverse side effects including scarring, increased intraocular pressure, and retinal detachment. Polymeric nanoparticles have demonstrated the ability to deliver a sustained release of drug, thereby reducing the necessary injection frequency. Aflibercept (AFL) was encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) via double emulsion diffusion. Scanning electron microscopy showed the NPs were spherical and dynamic light scattering demonstrated that they were uniformly distributed (PDI < 1). The encapsulation efficiency and drug loading were 75.76% and 7.76% respectively. In vitro release studies showed a sustained release of drug; 75% of drug was released by the NPs in seven days compared to the full payload released in 24 h by the AFL solution. Future ocular in vivo studies are needed to confirm the biological effects of the NPs. Preliminary studies of the proposed aflibercept NPs demonstrated high encapsulation efficiency, a sustained drug release profile, and ideal physical characteristics for AMD treatment. This drug delivery system is an excellent candidate for further characterization using an ocular neovascularization in vivo model.