肾脏选择性Bcl-2抑制剂递送改善纤维化治疗
Kidney Selective Bcl2 Inhibitor Delivery Improves Fibrosis Treatment.
摘要(中文译文)
肾纤维化是最致命的疾病之一。由于在疾病进展至晚期之前缺乏症状，肾纤维化常常未被诊断，而一旦进展至晚期，透析或肾移植便成为唯一可行的选择。尽管肾纤维化伴随显著的发病率与死亡率，目前尚无能够高效且有效治疗该疾病的可用疗法。本研究旨在开发一种靶向肾纤维化的纳米颗粒介导的治疗方式，以期改善治疗效果。我们对聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒进行了修饰，使其与血管紧张素2靶向肽（AT2肽）连接，该肽可靶向并结合血管紧张素2受体（AT2R），并负载Bcl-2抑制剂（Navitoclax/Navi），从而将载荷高效且特异性地递送至作用部位。Navi通过抑制抗凋亡蛋白Bcl2诱导细胞凋亡。通过体外和体内模型研究了各种Navi制剂的治疗疗效，并与使用Rho激酶抑制剂法舒地尔（Fasudil）治疗的组进行比较。采用免疫组织化学和分子生物学技术观察发现，与游离Navi或非靶向制剂（NP/Navi）相比，靶向纳米颗粒（TNP/Navi）治疗组小鼠中Bcl2表达显著降低且细胞凋亡上调。在体外和体内模型中，TNP/Navi组的α-SMA和CTGF均显著降低，这明显表明所开发制剂具有治疗潜力。经TNP/Navi治疗的肾脏保持了正常肾脏形态且胶原沉积减少，进一步证实AT2R靶向纳米颗粒介导的细胞凋亡上调具有逆转肾纤维化病理的潜力。
Abstract
Kidney fibrosis is one of the deadliest diseases. Kidney fibrosis often goes undiagnosed due to the absence of symptoms until the disease progresses to advanced stages, at which point dialysis or kidney transplant becomes the only viable options. Despite the significant morbidity and mortality associated with kidney fibrosis, there is currently no treatment available that efficiently and effectively addresses the condition. This study aims to develop a nanoparticle-mediated therapeutic modality targeting kidney fibrosis, anticipating improved therapeutic outcomes. We have modified a poly(lactic-co-glycolic acid) (PLGA) nanoparticle to link with angiotensin 2 targeting peptide (AT2 peptide) that targets and bind with angiotensin targeting 2 receptor (AT2R) and loaded with the Bcl-2 inhibitor (Navitoclax/Navi), to carry the payload to the site of action efficiently and specifically. Navi induces apoptosis by inhibiting the anti-apoptotic protein Bcl2. The therapeutic efficacy of various Navi formulations was investigated by both in vitro and in vivo models and compared to a group treated with Fasudil, a Rho-kinase inhibitor. A significant reduction of the Bcl2 expression and an upregulation of apoptosis were observed in the group of mice treated with targeted nanoparticle (TNP/Navi) when compared to free Navi or nontargeted formulation (NP/Navi), using immunohistochemistry and molecular biology techniques. A significant reduction in α-SMA and CTGF was observed in the TNP/Navi group for both in vitro and in vivo models that demonstrates an obvious indication of therapeutic potential of the developed formulation. Conservation of normal kidney morphology and less collagen deposition in the kidney treated with TNP/Navi further consolidates that AT2R targeted nanoparticle-mediated apoptosis upregulation has the potential to reverse the pathology of kidney fibrosis.
如何引用
AMA
Humayra Afrin, Sayantani Chakraborty, Md Nafiujjaman, Md Nurul Huda, Taeho Kim, Lela Vukovic, et al. Kidney Selective Bcl2 Inhibitor Delivery Improves Fibrosis Treatment.. ACS applied bio materials. 2026; doi:10.1021/acsabm.6c00062.
APA
Humayra Afrin, Sayantani Chakraborty, Md Nafiujjaman, Md Nurul Huda, Taeho Kim, Lela Vukovic, et al (2026). Kidney Selective Bcl2 Inhibitor Delivery Improves Fibrosis Treatment.. ACS applied bio materials. https://doi.org/10.1021/acsabm.6c00062
GB/T 7714
Humayra Afrin, Sayantani Chakraborty, Md Nafiujjaman, Md Nurul Huda, Taeho Kim, Lela Vukovic, et al. Kidney Selective Bcl2 Inhibitor Delivery Improves Fibrosis Treatment.[J]. ACS applied bio materials, 2026 doi:10.1021/acsabm.6c00062.
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