High Throughput Screening of Valganciclovir in Acidic Microenvironments of Polyester Thin Films

Abstract

Ganciclovir and valganciclor are antiviral agents used for the treatment of cytomegalovirus retinitis. The conventional method for administering ganciclovir in cytomegalovirus retinitis patients is repeated intravitreal injections. In order to obviate the possible detrimental effects of repeated intraocular injections, to improve compliance and to eliminate systemic side-effects, we investigated the tuning of the ganciclovir pro-drug valganciclovir and the release from thin films of poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or mixtures of both, as a step towards prototyping periocular valganciclovir implants. To investigate the drug release, we established and evaluated a high throughput fluorescence-based quantification screening assay for the detection of valganciclovir. Our protocol allows quantifying as little as 20 ng of valganciclovir in 96-well polypropylene plates and a 50× faster analysis compared to traditional HPLC measurements. This improvement can hence be extrapolated to other polyester matrix thin film formulations using a high-throughput approach. The acidic microenvironment within the polyester matrix was found to protect valganciclovir from degradation with resultant increases in the half-life of the drug in the periocular implant to 100 days. Linear release profiles were obtained using the pure polyester polymers for 10 days and 60 days formulations; however, gross phase separations of PCL and acid-terminated PLGA prevented tuning within these timeframes due to the phase separation of the polymer, valganciclovir, or both.

Non-aqueous, tissue compliant carbene-crosslinking bioadhesives

“…Thin film carbene adhesives grafted diazirine precursor directly to polyester surfaces and resulted in proof-of-concept wet adhesion to swine aortas and a tunable shear adhesion strength. [26] The polyester film employed has the advantage of photo or time adjustable drug delivery and adjustable mechanical properties [27][28][29][30][31][32][33] but they do not conform to irregular tissue surfaces. To overcome this limitation, a liquid formulation based on dendrimers was developed that could be spread on tissue surfaces, yet photo-crosslink into a strong bonding interfacial adhesive.…”

On-Demand Bioadhesive Dendrimers with Reduced Cytotoxicity

“…However, the degree of infiltration of giant cells was reduced to none for PAMAM-g-diazirine possibly due to the germicidal ability of –NH 2 groups [ 35 , 39 ]. These results indicate that the tissue adhesive warrants further investigation towards vascular patches, drug depots, and hydrogel biosensor implants [ 17 , 18 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

“…The in-situ crosslinking processes and swelling behavior of fibrin glue were found to be challenging for the hydrated tissue environment [ 7 ]. Tissue adhesives need to be able to bond both natural materials and synthetic films for applications involving implantable biosensors and drug depots [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Formation of covalent bonds between thin film or hydrogel adhesive formulations and soft tissue substrates is a promising strategy to achieve a reliable adhesion strength [ 3 , 15 , 16 , 19 ].…”

Thrombogenic Responses from Electrocured Tissue Adhesives

“…From a clinical perspective, they allow the incorporation of modern therapies, including drug delivery, hemostasis, and sealants. Others seek to expand the technology towards immobilizing various biomaterials, drug delivery depots, and medical implants [4][5][6][7][8][9][10][11][12][13][14]. Surgical adhesives commercialized or in development use varying methods to immobilize natural or synthetic materials through chemical bonding or molecular interlocking mechanism [15][16][17][18][19][20].…”