Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Department of Chemistry, Boston University, Boston, MA 02215, USA.
Sci Transl Med. 2022 Oct 12;14(666):eabo3357. doi: 10.1126/scitranslmed.abo3357.
Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology-the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.
生物疗法在肌肉骨骼疾病方面的进展明显不足。肌肉骨骼疾病在生物力学上较为复杂且具有局部性，这凸显出需要新型疗法来解决这些问题。关节纤维化是一种使人衰弱的肌肉骨骼疾病，所有一线治疗选择都无法治疗这种疾病的病因——关节腔内纤维组织的积累。对于每年数以百万计的患者来说，缺乏现代有效的治疗方法需要手术，以试图恢复关节活动范围（ROM）并摆脱长期疼痛。人类松弛素-2（RLX）是一种具有抗纤维化和抗纤维变性活性的内源性肽类激素，是肌肉骨骼纤维化的一种很有前途的生物治疗候选药物。然而，由于药代动力学障碍，RLX 此前已在多个临床项目中失败。在这里，我们描述了一种用于 RLX 持续释放的定制药物输送系统的设计和体外表征。载药聚合物微球在数周的时间内释放 RLX，而不会改变肽结构或生物活性。在体内，微球在大鼠关节内给药导致 RLX 的局部浓度延长，同时减少了全身药物暴露。此外，单次注射 RLX 载药微球可恢复关节 ROM，并以临床衍生的终点恢复关节纤维性关节炎大鼠模型中的关节结构。最后，在与关节纤维性关节炎相关的多种人体组织中确认 RLX 受体表达 RXFP1，表明 RLX 以持续和靶向的方式给药时具有临床转化潜力。
