Department of Chemistry, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
J Control Release. 2022 Oct;350:688-697. doi: 10.1016/j.jconrel.2022.06.068. Epub 2022 Sep 7.
Targeted drug delivery, often referred to as "smart" drug delivery, is a process whereby a therapeutic drug is delivered to specific parts of the body in a manner that increases its concentration at the desired sites relative to others. This approach is poised to revolutionize medicine as exemplified by the recent FDA approval of Cytalux (FDA approves pioneering drug for ovarian cancer surgery - Purdue University News) which is a folate-receptor targeted intraoperative near infrared (NIR) imaging agent that was developed in our laboratories. Fracture-associated morbidities and mortality affect a significant portion of world population. United states, Canada and Europe alone spent $48 billion in treating osteoporosis related fractures although this number doesn't count the economic burden due to loss in productivity. It is estimated that by 2050 ca 21 million hip fractures would occur globally which will be leading cause of premature death and disability. Despite the need for improvement in the treatment for fracture repair, methods for treating fractures have changed little in recent decades. Systemic delivery of fracture-homing bone anabolics holds great promise as a therapeutic strategy in this regard. Here we report the design of a fracture-targeted peptide comprised of a payload that binds and activates the parathyroid hormone receptor (PTHR1) and is linked to a targeting ligand comprised of 20 D-glutamic acids (D-Glu) that directs accumulation of the payload specifically at fracture sites. This targeted delivery results in reduction of fracture healing times to <1/2 while creating repaired bones that are >2-fold stronger than saline-treated controls in mice. Moreover, this hydroxyapatite-targeted peptide can be administered without detectable toxicity to healthy tissues or modification of healthy bones in dogs. Additionally, since similar results are obtained upon treatment of osteoporotic and diabetic fractures in mice, and pain resolution is simultaneously accelerated by this approach, we conclude that this fracture-targeted anabolic peptide displays significant potential to revolutionize the treatment of bone fractures.
靶向药物输送，通常被称为“智能”药物输送，是一种将治疗药物递送到身体特定部位的方法，这种方法可以增加药物在所需部位的浓度，相对于其他部位而言。这种方法有望彻底改变医学，最近 FDA 批准的 Cytalux（FDA 批准用于卵巢癌手术的开创性药物 - 普渡大学新闻）就是一个很好的例子，它是一种叶酸受体靶向的术中近红外（NIR）成像剂，是在我们的实验室中开发的。骨折相关的发病率和死亡率影响了很大一部分世界人口。仅美国、加拿大和欧洲在治疗骨质疏松性骨折方面就花费了 480 亿美元，尽管这个数字还没有算上由于生产力下降而带来的经济负担。据估计，到 2050 年，全球将有 2100 万髋部骨折，这将成为导致过早死亡和残疾的主要原因。尽管需要改善骨折修复的治疗方法，但近几十年来，治疗骨折的方法几乎没有变化。骨折归巢骨合成代谢物的全身给药在这方面具有很大的治疗潜力。在这里，我们报告了一种骨折靶向肽的设计，该肽由一个有效载荷组成，该有效载荷结合并激活甲状旁腺激素受体（PTHR1），并与由 20 个 D-谷氨酸（D-Glu）组成的靶向配体相连，该配体将有效载荷定向积累在骨折部位。这种靶向递药可将骨折愈合时间缩短至<1/2，同时在小鼠中产生的修复骨比盐水处理对照组强 2 倍以上。此外，这种羟基磷灰石靶向肽可以在不引起健康组织毒性或不改变健康骨骼的情况下在狗中给药。此外，由于在骨质疏松和糖尿病骨折的小鼠中也得到了类似的结果，并且这种方法同时加速了疼痛的缓解，因此我们得出结论，这种骨折靶向合成代谢肽具有彻底改变骨折治疗的巨大潜力。
