School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
Theranostics. 2020 Jul 25;10(21):9544-9560. doi: 10.7150/thno.45788. eCollection 2020.
The developement of oral targeted therapeutics for obesity and obesity-related diseases is challenging, as these diseases involve multiple lesions distributed throughout the whole body. Herein, we report a successful stragety for targeted oral delivery of bindarit to multiple obesity-related lesions including inflamed adipose tissue, fatty liver and atherosclerotic plaques. The computer simulation from atomstic to mesoscale was first applied for designing bindarit-loaded nanoparticles (pBIN) and laminarin-modified bindarit-loaded nanoparticles (LApBIN). Then pBIN were suceesfully prepared using a dialysis procedure, and LApBIN were prepared though the interaction bewtween laminarin and pBIN. The physiochemical properties, and pharmacokinetics, oral targeting capability and in vivo efficacy of LApBIN in various obesity-related diseases were examined. LApBIN were sucessfully designed and prepared. Following oral administration of LApBIN, the nanoparticles could be sucessully orally adsorbed and translocated to monocytes. Contributed by the recruitment of monocytes to multiple obesity-related lesions, LApBIN successfully delivered bindarit to these lesions, and effectively suppressed inflammation there, which exerted successful preventive effects on high-fat-diet-induced obesity, insulin resistance, fatty liver and atherosclerosis. This strategy could represent a promising approach to develop effective oral treatments for obesity and other metabolic diseases.
针对肥胖和肥胖相关疾病的口服靶向治疗的发展具有挑战性，因为这些疾病涉及分布在全身的多个病变。在此，我们报告了一种成功的策略，用于将 bindarit 靶向递送至包括发炎的脂肪组织、脂肪肝和动脉粥样硬化斑块在内的多种肥胖相关病变。我们首次应用从原子到介观的计算机模拟来设计负载 bindarit 的纳米颗粒（pBIN）和藻朊酸钠修饰的负载 bindarit 的纳米颗粒（LApBIN）。然后，通过透析程序成功制备了 pBIN，并且通过藻朊酸钠与 pBIN 的相互作用制备了 LApBIN。我们检测了 LApBIN 用于各种肥胖相关疾病的理化性质、药代动力学、口服靶向能力和体内疗效。成功设计和制备了 LApBIN。口服给予 LApBIN 后，纳米颗粒可以被成功地口服吸收并转移到单核细胞中。由于单核细胞募集到多个肥胖相关病变，LApBIN 成功地将 bindarit 递送至这些病变部位，并有效地抑制了炎症，从而对高脂肪饮食诱导的肥胖、胰岛素抵抗、脂肪肝和动脉粥样硬化产生了成功的预防作用。这种策略可能代表开发用于肥胖和其他代谢性疾病的有效口服治疗方法的一种有前途的方法。
