Osteoarthritis (OA) is a joint disease characterized by progressive damage of articular cartilage and the adjoining subchondral bone. Chondrocytes, the primary cells of the cartilage, have limited regenerative capacity and when they undergo stress due to trauma or with aging, they senesce or become apoptotic. Rapamycin, a potent immunomodulator, has shown promise in OA treatment. It activates autophagy and is known to prevent senescence. However, its clinical translation for OA is hampered due to systemic toxicity as high and frequent doses are required. Here, we have fabricated rapamycin encapsulated poly(lactic-co-glycolic acid) (PLGA) based carriers that induced autophagy and prevented cellular senescence in human chondrocytes. The microparticle (MP) delivery system showed sustained release of the drug for several weeks. Rapamycin microparticles protected in vitro cartilage mimics (micromass cultures) from degradation, allowing sustained production of sGAG, and demonstrated a prolonged senescence preventive effect under oxidative and genomic stress conditions. These microparticles also exhibited a residence time of ∼30 days after intra-articular injections in murine knee joints. Such particulate systems are promising candidates for intra-articular delivery of rapamycin for the treatment of osteoarthritis.

中文翻译：

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雷帕霉素-PLGA微粒可防止衰老，在压力下维持软骨基质的产生，并在小鼠关节中表现出长期保留。

骨关节炎（OA）是一种关节疾病，其特征是关节软骨和相邻的软骨下骨逐渐受损。软骨细胞是软骨的主要细胞，其再生能力有限，当它们由于外伤或衰老而承受压力时，它们会感觉衰老或凋亡。雷帕霉素是一种有效的免疫调节剂，已在OA治疗中显示出希望。它可以激活自噬，并且可以防止衰老。然而，由于全身毒性，OA的临床翻译受到阻碍，因为需要高剂量和频繁剂量。在这里，我们雷帕霉素封装聚（乳酸-制造合作-乙醇酸（PLGA）为基础的载体，可诱导自噬并阻止人类软骨细胞的细胞衰老。微粒（MP）输送系统显示药物持续释放了数周。雷帕霉素微粒可保护体外软骨模拟物（微团培养物）免于降解，从而持续产生sGAG，并在氧化和基因组应激条件下表现出延长的衰老预防作用。这些微粒在鼠膝关节中关节内注射后还表现出约30天的停留时间。这样的微粒系统有望用于雷帕霉素的关节内递送以治疗骨关节炎。