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

这个小型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连接到循环大分子的连接物，这些大分子通过可预测的半衰期为几个小时到几个月的β-消除裂解释放天然药物，并且不需要酶。然而，循环载体的一个限制是它们被肾滤过消除，半衰期为7天或更短。为了进一步延长给药时间，连接物将被用来将药物拴在皮下水凝胶植入物上，在皮下水凝胶植入物中，药物释放速度大大超过载体清除。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植入性载体的要求，并且没有合适的水凝胶具有可调的超长降解率。为了克服这一点，消除β连接的连接物也将被加入到水凝胶链中，从而允许可调的凝胶降解。因此，药物将使用具有所需切割速率(例如T1/2~1个月)的连接体和具有更慢切割速度(例如T1/2~6个月)的连接体结合到水凝胶上；药物将被释放，载体随后被生物降解成无害的碎片。该项目的更广泛的影响/商业潜力是使多肽能够作为治疗剂。大多数药物输送植入物将药物包裹在比药物具有更小孔径的聚合物中；聚合物网络中键的自发水解性断裂增加了孔大小，并伴随着释放药物。这项技术与竞争技术的不同之处在于，药物通过可切割接头以共价方式连接到聚合物上，这些接头以精确控制的速度释放游离药物；此外，具有更长切割速率的第二组可切割接头被加入到水凝胶中，以在药物释放后导致可控的聚合物降解。与包囊系统不同的是，药物释放和聚合物降解是独立可预测的，易于控制，并且不表现出包囊系统的药物释放的初始突发或最终的药物倾倒特征。商业上的成功将通过a)合作伙伴关系实现，其中我们将我们的技术用于制药公司的专利药物，b)将技术本身再授权用于利基领域(例如再生医学、整形外科植入物、眼科植入物)，以及c)内部开发重要的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.