SBIR Phase I: Controlled Drug Release from and Degradation of PEG-Hydrogels

这个小企业创新研究第一阶段项目旨在开发新型水凝胶药物输送系统。我们已经开发了用于药物缀合至循环大分子的接头，其通过β-消除性裂解以可预测的速率释放天然药物，半衰期跨越数小时至数月，并且不需要酶。然而，循环载体的局限性在于它们通过肾过滤消除，半衰期为7天或更短。为了进一步增加药物递送持续时间，将使用连接物将药物拴系到皮下水凝胶植入物，其中药物释放速率大大超过载体清除率。如果成功，药物可以在很长一段时间内输送。然而，一个障碍是生物降解是可植入载体的要求，并且具有可调的超长降解速率的合适的水凝胶不可用。为了克服这一点，β-消除连接体也将被掺入水凝胶链中，这将允许可调的凝胶降解。因此，药物将使用具有所需裂解速率（例如t1/2 ~1个月）的连接体和具有慢得多的裂解（例如t1/2 ~6个月）的连接体结合到聚合物中;药物将被释放，载体随后生物降解成无害的片段。大多数药物递送植入物将药物包封在具有比药物更小的孔径的聚合物中;聚合物网络中的键的自发水解裂解增加孔径并伴随释放药物。该技术与竞争性技术的不同之处在于，药物通过以精确控制的速率释放游离药物的可裂解接头共价连接到聚合物上;此外，将具有较长裂解速率的第二组可裂解接头掺入水凝胶中，以在药物释放后引起可控的聚合物降解。与包封系统不同，药物释放和聚合物降解是独立可预测的，易于控制，并且不显示包封系统的药物释放的初始爆发或末端药物倾倒特征。商业上的成功将通过以下方式实现：a）合作伙伴关系，我们将我们的技术用于制药公司的专利药物，B）将技术本身分许可用于利基领域（例如再生医学，骨科植入物，眼科植入物），以及c）内部开发重要非专利药物的长效植入物。

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.