Photoresponsive Drug Delivery From Anthracrene-Modified Hydrogels

Abstract

<p> Photoresponsive polymers can act as controllable drug delivery systems that may revolutionize ophthalmic drug delivery for disease treatment in the posterior segment of the eye. Localized, controlled drug delivery devices have significant therapeutic advantages for treating diseases of back of the eye by increasing patient compliance and maintaining therapeutic levels of drug in the tissue. Sustained-release delivery systems that respond to light/laser stimuli are under development to control the rate of delivery resulting in a tuneable treatment profile ideal for retinal diseases. The use of light as a crosslinking mechanism has the potential to create unique materials with controllable swelling, degradation and diffusion properties. </p> <p> This thesis investigates the synthesis and development of universal, graftable PEG-anthracene molecules and their applications in photosensitive alginate and hyaluronate (HA) "photogels". Anthracene undergoes reversible dimerization with wavelengths above 300 nm and de-dimerization/dissociation below 300 nm; due to its well-understood chemistry and symmetry, it was used as a starting point and proof-ofconcept for the synthesis of reversible dimerizing crosslinkers that may be generically grafted to different polymers to cause crosslinking/decrosslinking. After synthesis, watersoluble PEG-anthracene macromolecules were grafting via carbodiimide chemistry to the carboxyl groups along the polymer backbone of alginate and HA at various densities to create viscous liquids or gels with good handling properties. </p> <p> Light irradiation can be used to control the swelling and effective crosslinking density of the photogels which in tum can control drug delivery from photocrosslinked hydro gels as illustrated through the decrease or increase in the delivery of a variety of low molecular weight (<1000 Da) and high molecular weight (>10,000 Da) model drug compounds from both alginate and HA photogels with various light treatments. Novel loading mechanisms were developed through the loading of compounds into uncrosslinked gels followed by crosslinking 365 nm exposures to "lock" in the model drug compounds. Diffusion coefficients effectively compared the different systems showing increase exposures of 365 nm resulted in greater decrease in release of compounds demonstrating the ability to fine-tune release rates. Different formulations and control gels demonstrate a variety of different release profiles. The photogels were valuable long-term controlled release systems (>80 days) that also demonstrate high cytocompatibility when grown with ophthalmic cell lines. </p> <p> Novel photoresponsive biomaterials for smart delivery of therapeutics which use light-controlled crosslinking and decrosslinking mechanisms have been developed. The PEG-anthracene graftable photocrosslinkers show the ability to introduce photocontrolled crosslinking into hydrogel systems. While anthracene as the photodimerizer and alginate and HA as the bulk materials are used as a proof-of-concept in this work, this grafting system can be further manipulated to include new photosensitive dimerizers and other applicable polymers. The ability to use light stimuli to control release rates in a continual fashion, rather than having delivery that is strictly on or off, is a valuable finding that may lead to the development of drug delivery systems that can be catered towards individuals and the progression of their disease. </p>