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

SBIR 第一阶段：PEG-水凝胶的受控药物释放和降解

• 批准号: 1248239
• 负责人: Gary Ashley
• 金额: $ 15万
• 依托单位: ProLynx LLC
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1248239&HistoricalAwards=false
• 关键词: SBIR; Phase; Controlled; Drug; Release

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.

这个小型企业创新研究阶段项目旨在开发新型的水凝胶药物递送系统。我们已经开发了用于循环大分子的药物结合的接头，这些大分子通过β-衡量性裂解以可预测的速率释放天然药物，而半衰期跨越了几个月至几个月，并且不需要酶。但是，循环载体的局限性是通过肾脏过滤消除，半衰期为7天或更短。为了进一步增加药物递送持续时间，接头将用于将药物束缚在皮下水凝胶植入物上，在该植入物中，药物释放的速率大大超过了载体清除率。如果成功的话，可以在很长一段时间内提供药物。但是，障碍是生物降解是可植入的载体的要求，并且没有可调，超长降解速率的合适水凝胶。为了克服这一点，还将将β-纤维化连接器纳入水凝胶链中，以允许可调凝胶降解。因此，将使用具有所需裂解速率的接头（例如T1/2〜1个月）将药物束缚在水凝胶上，并将连接器置于聚合物中；该药物将被释放，随后生物降解成无害的碎片。该项目的更广泛的影响/商业潜力是使肽成为治疗剂。大多数药物传递的植入物都将药物封装在孔径小于药物的聚合物中。聚合物网络中键的自发水解切割会增加孔径，并同时释放药物。该技术与竞争技术不同，因为该药物通过可切合的接头将其共价绑在聚合物上，这些连接器以精确控制的速度释放免费药物。此外，将第二组具有较长裂解速率的可切割接头纳入水凝胶中，以引起药物释放后可控的聚合物降解。与封装系统不同，药物释放和聚合物降解是可以独立预测的，易于控制的，并且没有显示封装系统的药物释放或终末药物倾斜特征的初始爆发。 a）合作伙伴关系将实现商业成功，在该伙伴关系中，我们将技术用于制药公司的专有药物，b）将技术本身作为用于利基领域使用的技术本身（例如，再生医学，骨科植入物，眼科植入物），以及c）长效植入植物的内部发展植入植物的内部发展。