Robust drug bioavailability and safety for rheumatoid arthritis therapy using D-amino acids-based supramolecular hydrogels.
Robust drug bioavailability and safety for rheumatoid arthritis therapy using D-amino acids-based supramolecular hydrogels.
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使用基于 D-氨基酸的超分子水凝胶治疗类风湿性关节炎具有强大的药物生物利用度和安全性。
DOI：
10.1016/j.mtbio.2022.100296
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发表时间：
2022-06
影响因子：
8.2
通讯作者：
Lu, Yao
中科院分区：
文献类型：
--
作者：
Ma, Shaodan;Gu, Shunan;Zhang, Jinwei;Qi, Weizhong;Lin, Zhaowei;Zhai, Weicheng;Zhan, Jie;Li, Qi;Cai, Yanbin;Lu, Yao
长期使用改善病情的抗风湿药物（DMARD）如甲氨蝶呤（MTX）对类风湿关节炎（RA）治疗显示出临床益处。然而，人们越来越关注全身给药的不良反应。因此，迫切需要一种可以提高药物生物利用度同时最小化副作用的策略，但这仍然是RA治疗的挑战。为此，在这里，我们共轭MTX与超分子自组装水凝胶组成的d-氨基酸序列的GDFDFDY。结果表明，MTX-GDFDFDY水凝胶表现出良好的药物选择性行为，它们增加了MTX对RA滑膜细胞的毒性，但降低了对正常细胞的毒性。MTX-GDFDFDY水凝胶不仅能有效抑制RA滑膜细胞的增殖和迁移，还能抑制促炎性M1型巨噬细胞的极化，减轻炎症反应。在将水凝胶关节内注射到佐剂诱导的关节炎（AIA）小鼠的关节中后，我们发现与L-构型MTX-GFFY水凝胶和游离MTX相比，MTX-GDFDDY水凝胶显著减轻关节肿胀和发热的RA综合征。此外，MTX-GDFDFDY水凝胶成功地保护了软骨，抑制了滑膜侵袭和炎症，而没有引起全身性副作用。因此，d-氨基酸超分子水凝胶可作为一种高效、安全的药物释放系统，在改善类风湿关节炎治疗方面具有广阔的应用前景。以D-氨基酸为原料制备了甲氨蝶呤（MTX）超分子水凝胶，用于类风湿关节炎（RA）的治疗。所得到的MTX-GDFDFDY水凝胶对RA滑膜细胞而不是正常细胞表现出选择性细胞毒性。它们还可以抑制M1型巨噬细胞的极化。因此，MTX-GDFDFDY水凝胶在体内成功地减少了滑膜增生和关节破坏，导致了有效和安全的RA治疗。
Long-term use of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) shows clinical benefits for rheumatoid arthritis (RA) treatment. However, there are growing concerns over the adverse effects of systemic drug administration. Therefore, a strategy that can enhance drug bioavailability while minimizing side effects is urgently needed, but remains a challenge in RA therapy. To this end, here we conjugated MTX with a supramolecular self-assembling hydrogel composed of d-amino acids with a sequence of GDFDFDY. It was shown that MTX-GDFDFDY hydrogels exhibited a favorable drug selectivity behavior that they increased MTX toxicity toward RA synoviocytes, but reduce toxicity toward normal cells. Moreover, MTX-GDFDFDY hydrogels not only effectively inhibited the proliferation and migration of RA synoviocytes, but also inhibited the polarization of proinflammatory M1 type macrophages to reduce inflammation. After intra-articularly injected the hydrogels into the joints of adjuvant induced arthritis (AIA) mice, we found that MTX-GDFDFDY hydrogels significantly alleviated RA syndromes of joint swelling and fever compared to L-configuration MTX-GFFY hydrogels and free MTX. Furthermore, MTX-GDFDFDY hydrogels successfully protected cartilage though inhibiting synovial invasion and inflammation without causing systematic side effects. Therefore, d-amino acids supramolecular hydrogels can serve as an efficient and safe drug delivery system, showing a promising potential to improve RA therapy. Methotrexate (MTX) loaded supramolecular hydrogels was prepared using d-amino acids for rheumatoid arthritis (RA) therapy. The resultant MTX-GDFDFDY hydrogels exhibited selective cytotoxicity on RA synoviocytes rather than normal cells. They can also inhibit the polarization of M1 type macrophages. Therefore, MTX-GDFDFDY hydrogels successfully reduce synovial hyperplasia and joint destruction in vivo, leading to an efficient and safe RA therapy.
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影响因子：
5
作者：
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通讯作者：
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影响因子：
120.7
作者：
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17.1
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作者：
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