Department of Orthopedics and Orthopedic Research Center, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan.
Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung City 80424, Taiwan.
Int J Nanomedicine. 2020 May 28;15:3771-3790. doi: 10.2147/IJN.S252223. eCollection 2020.
Rapamycin has been considered as a potential treatment for osteoarthritis (OA). Drug carriers fabricated from liposomes can prolong the effects of drugs and reduce side effects of drugs. Low-intensity pulsed ultrasound (LIPUS) has been found to possess anti-OA effects.
The anti-osteoarthritic effects of liposome-encapsulated rapamycin (L-rapa) combined with LIPUS were examined by culture of normal and OA chondrocytes in alginate beads and further validated in OA prone Dunkin-Hartley guinea pigs.
L-rapa with LIPUS largely up-regulated aggrecan and type II collagen mRNA in human OA chondrocytes (HOACs). L-rapa with LIPUS caused significant enhancement in proteoglycan and type II collagen production in HOACs. Large decreases in both MMP-13 and IL-6 proteins were found in the HOACs exposed to L-rapa with LIPUS. Intra-articular injection of 40 μL L-rapa at both 5 μM and 50 μM twice a week combined with LIPUS thrice a week for 8 weeks significantly increased GAGs and type II collagen in the cartilage of knee. Results on OARSI score showed that intra-articular injection of 5 μM L-rapa with LIPUS displayed the greatest anti-OA effects. Immunohistochemistry revealed that L-rapa with or without LIPUS predominantly reduced MMP-13 in vivo. The values of complete blood count and serum biochemical examinations remained in the normal ranges after the injections with or without LIPUS. These data indicated that intra-articular injection of L-rapa collaborated with LIPUS is not only effective against OA but a safe OA therapy.
Taken together, L-rapa combined with LIPUS possessed the most consistently and effectively anabolic and anti-catabolic effects in HOACs and the spontaneous OA guinea pigs. This study evidently revealed that liposome-encapsulation collaborated with LIPUS is able to reduce the effective dose and administration frequency of rapamycin and further stably reinforce its therapeutic actions against OA.
雷帕霉素已被认为是治疗骨关节炎（OA）的一种潜在药物。脂质体药物载体可以延长药物作用时间，减少药物副作用。低强度脉冲超声（LIPUS）已被发现具有抗 OA 作用。
通过藻酸盐珠中正常和 OA 软骨细胞的培养，进一步在易患 OA 的 Dunkin-Hartley 豚鼠中验证了包载雷帕霉素的脂质体（L-rapa）联合 LIPUS 的抗 OA 作用。
L-rapa 联合 LIPUS 可显著上调人 OA 软骨细胞（HOACs）的聚集蛋白聚糖和 II 型胶原 mRNA。L-rapa 联合 LIPUS 可显著增加 HOACs 中蛋白聚糖和 II 型胶原的产生。暴露于 L-rapa 联合 LIPUS 的 HOACs 中，MMP-13 和 IL-6 蛋白的含量均显著降低。每周两次向关节内注射 40 μL 浓度为 5 μM 和 50 μM 的 L-rapa，联合每周三次 LIPUS 治疗 8 周，可显著增加膝关节软骨中的 GAGs 和 II 型胶原。OARSI 评分结果表明，关节内注射 5 μM L-rapa 联合 LIPUS 显示出最强的抗 OA 作用。免疫组化结果显示，L-rapa 联合或不联合 LIPUS 主要减少了体内 MMP-13 的表达。注射 L-rapa 联合或不联合 LIPUS 后，血常规和血清生化检查值均在正常范围内。这些数据表明，关节内注射 L-rapa 联合 LIPUS 不仅对 OA 有效，而且是一种安全的 OA 治疗方法。
综上所述，L-rapa 联合 LIPUS 在 HOACs 和自发 OA 豚鼠中具有最一致和有效的合成代谢和抗分解代谢作用。本研究清楚地表明，脂质体包封联合 LIPUS 能够降低雷帕霉素的有效剂量和给药频率，并进一步稳定增强其对 OA 的治疗作用。
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