This Small Business Innovation Research Phase I project seeks to develop novel hydrogel drug-delivery systems. We have developed linkers for drug conjugation to circulating macromolecules that release the native drug by beta-eliminative cleavage at predictable rates with half-lives spanning hours to months, and do not require enzymes. However, a limitation of circulating carriers is that they are eliminated by renal filtration with half-lives of 7 days or less. To further increase drug delivery duration, the linkers will be used to tether drugs to subcutaneous hydrogel implants, where the rate of drug release greatly exceeds the carrier clearance. If successful, drugs could be delivered over very long periods of time. However, a barrier is that bio-degradation is a requirement of implantable carriers, and suitable hydrogels with tunable, ultra-long degradation rates are not available. To surmount this, beta-eliminative linkers will be also incorporated into hydrogel chains that will allow tunable gel degradation. Thus, a drug will be tethered to the hydrogel using a linker with a desired cleavage rate (e.g. t1/2 ~1 month), and a linker with much slower cleavage (e.g. t1/2 ~6 months) incorporated into the polymer; the drug would be released and the carrier subsequently bio-degraded into innocuous fragments. The broader impact/commercial potential of this project is to enable peptides as therapeutic agents. Most drug-delivery implants encapsulate drugs in a polymer having a smaller pore size than the drug; spontaneous hydrolytic cleavage of bonds in the polymer network increases the pore size and concomitantly releases drug. This technology differs from competitive technologies in that the drug is covalently tethered to the polymer by cleavable linkers that release the free drug at precisely controlled rates; further, a second set of cleavable linkers with longer cleavage rates are incorporated into the hydrogel to cause controllable polymer degradation subsequent to drug release. Unlike encapsulating systems, drug release and polymer degradation are independently predictable, simple to control, and do not show the initial bursts of drug release or terminal drug-dumping characteristic of encapsulating systems. Commercial success will be achieved by a) partnerships where we use our technology for proprietary drugs of pharmaceutical companies, b) sub-licensing the technology per se for use in niche areas (e.g. regenerative medicine, orthopedic implants, ophthalmology implants), and c) internal development of long-acting implants of important off-patent drugs
