Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma.

While mortality is low for intraocular retinoblastoma patients in the developed world who receive aggressive multimodal therapy, partial or full loss of vision occurs in approximately 50% of patients with advanced bilateral retinoblastoma. Therapies that preserve vision and reduce late effects are needed. Because clinical trials for retinoblastoma are difficult due to the young age of the patient population and relative rarity of the disease, robust preclinical testing of new therapies is critical.

Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor r406 after ocular delivery for retinoblastoma.

Purpose: Retinoblastoma is a childhood cancer of the retina. Clinical trials have shown that local delivery of broad spectrum chemotherapeutic agents is efficacious. Recent studies characterizing the genomic and epigenomic landscape of retinoblastoma identified spleen tyrosine kinase (SYK) as a promising candidate for targeted therapy.

Focal Infection Treatment using Laser-Mediated Heating of Injectable Silk Hydrogels with Gold Nanoparticles.

Medical treatment of subcutaneous bacterial abscesses usually involves systemic high-dose antibiotics and incision-drainage of the wound. Such an approach suffers from two main deficiencies: bacterial resistance to antibiotics and pain associated with multiple incision-drainage-wound packing procedures. Furthermore, the efficacy of high-dose systemic antibiotics is limited because of the inability to penetrate into the abscess.

Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis.

Epigenetic modifications, including changes in DNA methylation, lead to altered gene expression and thus may underlie epileptogenesis via induction of permanent changes in neuronal excitability. Therapies that could inhibit or reverse these changes may be highly effective in halting disease progression. Here we identify an epigenetic function of the brain's endogenous anticonvulsant adenosine, showing that this compound induces hypomethylation of DNA via biochemical interference with the transmethylation pathway.

Self-assembling doxorubicin silk hydrogels for the focal treatment of primary breast cancer.

Standard care for early stage breast cancer includes tumor resection and local radiotherapy to achieve long-term remission. Systemic chemotherapy provides only low locoregional control of the disease; therefore, we describe self-assembling silk hydrogels that can retain and then deliver doxorubicin locally. Self-assembling silk hydrogels show no swelling, are readily loaded with doxorubicin under aqueous conditions and release drug over 4 weeks in amounts that can be fine-tuned by varying the silk content.

Antibiotic-Releasing Silk Biomaterials for Infection Prevention and Treatment.

Effective treatment of infections in avascular and necrotic tissues can be challenging due to limited penetration into the target tissue and systemic toxicities. Controlled release polymer implants have the potential to achieve the high local concentrations needed while also minimizing systemic exposure. Silk biomaterials possess unique characteristics for antibiotic delivery including biocompatibility, tunable biodegradation, stabilizing effects, water-based processing and diverse material formats.

Effect of silk protein processing on drug delivery from silk films.

Sericin removal from the core fibroin protein of silkworm silk is a critical first step in the use of silk for biomaterial-related applications, but degumming can affect silk biomaterial properties, including molecular weight, viscosity, diffusivity and degradation behavior. Increasing the degumming time (10, 30, 60, and 90 min) decreases the average molecular weight of silk protein in solution, silk solution viscosity, and silk film glass-transition temperature, and increases the rate of degradation of a silk film by protease. Model compounds spanning a range of physical-chemical properties generally show an inverse relationship between degumming time and release rate through a varied degumming time silk coating.

Implantable, multifunctional, bioresorbable optics.

Advances in personalized medicine are symbiotic with the development of novel technologies for biomedical devices. We present an approach that combines enhanced imaging of malignancies, therapeutics, and feedback about therapeutics in a single implantable, biocompatible, and resorbable device. This confluence of form and function is accomplished by capitalizing on the unique properties of silk proteins as a mechanically robust, biocompatible, optically clear biomaterial matrix that can house, stabilize, and retain the function of therapeutic components.

A silk hydrogel-based delivery system of bone morphogenetic protein for the treatment of large bone defects.

The use of tissue grafting for the repair of large bone defects has numerous limitations including donor site morbidity and the risk of disease transmission. These limitations have prompted research efforts to investigate the effects of combining biomaterial scaffolds with biochemical cues to augment bone repair. The goal of this study was to use a critically-sized rat femoral segmental defect model to investigate the efficacy of a delivery system consisting of an electrospun polycaprolactone (PCL) nanofiber mesh tube with a silk fibroin hydrogel for local recombinant bone morphogenetic protein 2 (BMP-2) delivery.

Review physical and chemical aspects of stabilization of compounds in silk.

The challenge of stabilization of small molecules and proteins has received considerable interest. The biological activity of small molecules can be lost as a consequence of chemical modifications, while protein activity may be lost due to chemical or structural degradation, such as a change in macromolecular conformation or aggregation. In these cases, stabilization is required to preserve therapeutic and bioactivity efficacy and safety.

Silk fibroin biomaterials for controlled release drug delivery.

Introduction: Given the benefits of polymer drug delivery implants over traditional periodic systemic administration, the development of biomaterial systems with the necessary properties (biocompatibility, degradation, stabilization, controllability) is paramount. Silk fibroin represents a promising, naturally derived polymer for local, controlled, sustained drug release from fully degrading implants and the polymer can be processed into a broad array of material formats.

Areas Covered: This review provides an overview of silk biomaterials for drug delivery, especially those that can function as long-term depots.

Incorporation of proteinase inhibitors into silk-based delivery devices for enhanced control of degradation and drug release.

Controlling the rate of silk degradation is critical to its potential use in biomedical applications, including drug delivery and tissue engineering. The effect of protease concentration on accelerating degradation, and the use of ethylenediamine tetraacetic acid (EDTA) on reducing rates of degradation and on drug release from silk-based drug carriers was studied. Increased rates of proteolysis resulted in increased dye release from silk carriers, while EDTA release from the silk carriers inhibited proteolysis.

Silk fibroin encapsulated powder reservoirs for sustained release of adenosine.

Due to its unique properties, silk fibroin was studied as a biodegradable polymer vehicle for sustained, local delivery of the anticonvulsant adenosine from encapsulated reservoirs. Silk is a biologically derived protein polymer that is biocompatible, mechanically strong and degrades to non-toxic products in vivo. To achieve local, sustained, controlled adenosine release from fully degradable implants, solid adenosine powder reservoirs were coated with silk fibroin.

Antiepileptic effects of silk-polymer based adenosine release in kindled rats.

Pharmacotherapy for epilepsy is limited by high incidence of pharmacoresistance and failure to prevent development and progression of epilepsy. Using the rat hippocampal kindling model, we report on the therapeutic potential of novel silk-based polymers engineered to release the anticonvulsant adenosine. Polymers were designed to release 1000 ng adenosine per day during a time span of ten days.

Silk polymer-based adenosine release: therapeutic potential for epilepsy.

Adenosine augmentation therapies (AAT) make rational use of the brain's own adenosine-based seizure control system and hold promise for the therapy of refractory epilepsy. In an effort to develop an AAT compatible with future clinical application, we developed a novel silk protein-based release system for adenosine. Adenosine releasing brain implants with target release doses of 0, 40, 200, and 1000ng adenosine per day were prepared by embedding adenosine containing microspheres into nanofilm-coated silk fibroin scaffolds.