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Frances Lasowski, Heather Sheardown; Clever Clots: Using Fibrin Gels for the Controlled Delivery of Roscovitine and Atropine to Improve Vision in Children. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3218.
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Retinoblastoma is the most common ocular cancer in children. Recent work with animal models suggests that cyclin dependent kinase inhibitors, such as roscovitine, could work as chemo-preventative agents to prevent the development of tumors. Additionally, atropine has been suggested for use with children to retard the development of myopia. Since these therapeutics are required for use in young, developing children, it is desirable to create a transscleral delivery vehicle to reduce side effects by localizing drug delivery while ensuring patient compliance and minimizing invasiveness.
The proposed material for these applications is a fibrin gel, as these gels are used clinically and have shown positive release kinetics with chemotherapeutic agents for retinoblastoma. Gels comprised of varying amounts of fibrinogen, thrombin and calcium chloride were examined. Various concentrations of therapeutics were loaded to the fibrinogen before thrombin addition and clot formation. Clot formation time was assessed through absorbance readings at 500 nm. Fibrin gel entrapment was assessed by mechanically disrupting the clot 1 hour after formation. Liquid expressed from the clot was obtained by centrifugation and represented "free" drug, which was compared to the total amount of drug loaded. Release studies were performed into 1mL of buffer and measured using absorbance specific for the particular drug. Scleral perfusion studies were performed using porcine sclera at four degrees Celsius in a diffusion chamber, with samples being replaced after measurement by absorbance.
Scleral perfusion studies show that about 16% of the available drug passes through the sclera in the first 30 hours, and this increases to 20% at 7 days, which is when the sclera begins to degrade. About 5% of the drug remains in the sclera at day 7. Preliminary results show that the addition of therapeutics to fibrinogen increases the time to form a clot of the same density, supported by measurements showing gels containing therapeutics are larger than those without. Entrapment studies show that approximately 90% of atropine, is "free", suggesting it is not interacting with the fibrinogen and will be quickly released. Only about 70% of roscovitine is "free", suggesting some interaction with the fibrinogen and a slower release.
These results show that transscleral delivery via fibrin gels is possible for the delivery of these therapeutics. Roscovitine’s increased interactions are beneficial, as the amount of drug required for its therapeutic effects are less than those required for atropine.
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