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Carrier-Free Gambogic Acid Dimer Self-Assembly Nanomedicines for Rheumatoid Arthritis Treatment

INTRODUCTION: The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits i...

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Detalles Bibliográficos
Autores principales: Liu, Yuling, Nie, Xin, Wu, Yihan, Lin, Longfei, Liao, Qian, Li, Jingjing, Lee, Simon Ming-Yuen, Li, Hui, Zhang, Jinming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522496/
https://www.ncbi.nlm.nih.gov/pubmed/37771407
http://dx.doi.org/10.2147/IJN.S422096
Descripción
Sumario:INTRODUCTION: The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits its clinical application. Self-assembly of drug dimers into carrier-free nanoparticles (NPs) has become a straightforward and attractive approach to develop nanomedicines for RA treatment. Herein, homodimers of GBA were designed to form the carrier-free NPs by self-assembly for RA treatment. METHODS: The synthetic gambogic acid dimers (GBA(2)) were self-assembled into NPs using a one-step solvent evaporation method. The size distribution, morphology, drug-loading efficiency (DLE) and storage stability were evaluated. A molecular dynamic simulation was conducted to gain further insight into the self-assembly mechanisms of GBA(2)/NPs. Besides, we investigated the cytotoxicity, apoptosis and cellular uptake profiles of GBA(2)/NPs in macrophages and osteoclasts. Finally, the specific biodistribution on the ankles of adjuvant-induced arthritis (AIA) mice, and the anti-RA efficacy of the AIA rat model were assessed. RESULTS: GBA(2)/NPs exhibited the uniform spherical structure, possessing excellent colloidal stability, high self-assembly stability, high drug loading and low hemolytic activity. Comparing with GBA, GBA(2)/NPs showed higher cytotoxicity, cellular uptake and apoptosis rate against osteoclasts. In addition, GBA(2)/NPs exhibited much higher accumulation in ankle joints in vivo. As expected, the systematic administration of GBA(2)/NPs resulted in the greater alleviation of arthritic symptoms, cartilage protection, and inflammation, notably the reduced systemic toxicity compared to free GBA. CONCLUSION: GBA(2)/NPs formed GBA dimers exhibited the superior accumulation in the inflamed joint and anti-RA activity, potentially attributing to the similar extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (“ELVIS”) effects in inflamed joint and the enhanced cellular uptake in macrophages and osteoclasts. Our findings provide substantial evidence that self-assembly of GBA(2)/NPs would be a promising therapeutic alternative for RA treatment.