Continuous and aberrant activation of myofibroblasts is the hallmark of pathological fibrosis (e.g., abnormal wound healing). The deposition of excessive extracellular matrix (ECM) components alters or increases the stiffness of tissue and primarily accounts for multiple organ dysfunctions. Among various proteins, Cadherin-11 (CDH11) has been reported to be overexpressed on myofibroblasts in fibrotic tissues. Anti-apoptotic proteins such as (B cell lymphoma-2) (BCL-2) are also upregulated on myofibroblasts. Therefore, we hypothesize that CDH11 could be a targeted domain for cell-specific drug delivery and targeted inhibition of BCL-2 to ameliorate the development of fibrosis in the skin. To prove our hypothesis, we have developed liposomes (LPS) conjugated with CDH11 neutralizing antibody (antiCDH11) to target cell surface CDH11 and loaded these LPS with a BCL-2 inhibitor, Navitoclax (NAVI), to induce apoptosis of CDH11 expressing fibroblasts. The developed LPS were evaluated for physicochemical characterization, stability, in vitro therapeutic efficacy using dermal fibroblasts, and in vivo therapeutic efficacy in bleomycin-induced skin fibrosis model in mice. The findings from in vitro and in vivo studies confirmed that selectivity of LPS was improved towards CDH11 expressing myofibroblasts, thereby improving therapeutic efficacy with no indication of adverse effects. Hence, this novel research work represents a versatile LPS strategy that exhibits promising potential for treating skin fibrosis.

中文翻译：

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Cadherin-11靶向细胞特异性脂质体通过诱导细胞凋亡实现皮肤纤维化治疗


肌成纤维细胞的持续和异常激活是病理性纤维化（例如伤口愈合异常）的标志。过量细胞外基质（ECM）成分的沉积会改变或增加组织的硬度，并主要导致多器官功能障碍。据报道，在各种蛋白质中，钙粘蛋白-11 (CDH11) 在纤维化组织中的肌成纤维细胞上过度表达。抗凋亡蛋白，如 (B 细胞淋巴瘤-2) (BCL-2) 在肌成纤维细胞上的表达也上调。因此，我们假设 CDH11 可能是细胞特异性药物递送和 BCL-2 靶向抑制的靶向结构域，以改善皮肤纤维化的发展。为了证明我们的假设，我们开发了与 CDH11 中和抗体 (antiCDH11) 缀合的脂质体 (LPS)，以靶向细胞表面 CDH11，并在这些 LPS 上负载 BCL-2 抑制剂 Navitoclax (NAVI)，以诱导表达 CDH11 的成纤维细胞凋亡。对所开发的 LPS 的理化特性、稳定性、使用真皮成纤维细胞的体外治疗效果以及博来霉素诱导的小鼠皮肤纤维化模型的体内治疗效果进行了评估。体外和体内研究的结果证实，LPS 对表达 CDH11 的肌成纤维细胞的选择性得到了提高，从而提高了治疗效果，且没有任何不良反应的迹象。因此，这项新颖的研究工作代表了一种多功能的 LPS 策略，在治疗皮肤纤维化方面具有广阔的前景。