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.
We are developing a drug-delivery system that holds promise for improving drug efficacy, drug safety, and patient quality of life. Based on a novel hydrogel system that may be self-administered by subcutaneous injection, our system precisely controls the timed release of drugs over a chosen period, allowing for weekly or perhaps monthly administration of drugs that currently must be injected daily or twice-daily. The timed release results in improved control over drug levels in the body, minimizing the differences between peak and trough concentrations between administrations and thus enabling maintenance of efficacious drug levels without initial high concentrations that may result in off-target toxicities. Unique to our system, control over drug levels is coupled with precise control over the lifetime of the hydrogel itself to prevent accumulation of the delivery matrix during repeat administration. Unlike currently available slow-release delivery systems that rely upon drug encapsulation, our hydrogel system does not show an initial burst of drug release. In Phase 1 of this grant, we developed the fundamental technology and demonstrated our ability to control both the rate of drug release and the rate of matrix degradation. We prepared hydrogels that released drug surrogates over a wide range of rates and which subsequently degraded in a controlled fashion. We demonstrated our ability to connect small molecules, peptides, and larger proteins to the hydrogel and showed their subsequent controlled release. We developed an understanding of the relationships between hydrogel composition and physical properties such as drug capacity, resulting in an improved hydrogel that displays better structural regularity and degradation behavior. We further developed physical forms of the hydrogel that allow for subcutaneous injection through extremely small-gauge needles, thus minimizing the discomfort associated with injections.
