Biguanide-anchored albumin-based nanoplatform inhibits epithelial-mesenchymal transition and reduces the stemness phenotype for metastatic cancer therapy
Biguanide-anchored albumin-based nanoplatform inhibits epithelial-mesenchymal transition and reduces the stemness phenotype for metastatic cancer therapy
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DOI：
10.1016/j.actbio.2023.09.017
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发表时间：
2023-10-23
影响因子：
9.7
通讯作者：
Chen，Jun
中科院分区：
文献类型：
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作者：
Jiang，Tianze;Wang，Jiahao;Chen，Jun
在临床化疗中，白蛋白结合型紫杉醇（Abraxane）可以提高紫杉醇（PTX）对原位恶性肿瘤的肿瘤靶向性和治疗效果。然而，转移性癌症患者的预后较差，可能是由于白蛋白结合紫杉醇的不稳定性、化疗耐药性以及无法改变肿瘤微环境。在这里，我们提出了一种新的双胍修饰的基于白蛋白的纳米平台，该平台封装了紫杉醇，可有效治疗转移性癌症。 PTX 封装在聚（乳酸-乙醇酸）核心中，并涂有双胍修饰白蛋白 (HSA-NH)。功能化纳米颗粒（HSA-NH NP）表现出显着的稳定性和低药物释放（与 Abraxane 相比，P < 0.05），靶向肿瘤组织，抑制上皮间质转化（EMT）事件以实现抗转移作用，并减少癌症干细胞的表型。因此，HSA-NH NPs 不仅可以抑制原发性肿瘤的生长，还可以抑制转移，从而有效延长动物的生存期（55 天）。这项研究提供了概念证明，即封装 PTX 的双胍锚定白蛋白纳米平台是治疗转移性癌症的一种强大、安全和临床转化策略。意义声明白蛋白结合紫杉醇 (Abraxane) 可以提高紫杉醇在临床癌症治疗（如乳腺癌）中的肿瘤靶向性和治疗效果。然而，白蛋白结合紫杉醇的不稳定性、化疗耐药性和缺乏肿瘤微环境调节可能导致转移性癌症患者的治疗效果不佳。在这里，我们开发了双胍锚定的基于白蛋白的纳米平台，该平台封装了用于转移性癌症治疗的紫杉醇（HSA-NH NP）。封装紫杉醇的聚乳酸-乙醇酸 (PLGA) 核可提高 HSA-NH NP 的稳定性。基于二甲双胍的活性，吸附在PLGA核心上的双胍锚定白蛋白可提高紫杉醇疗效，抑制上皮-间质转化过程中的各种异常变化，并降低肿瘤细胞干性。封装 PTX 的双胍锚定白蛋白纳米平台可以作为转移性癌症治疗的有效、安全和临床转化方法。
In clinical chemotherapy, albumin-bound paclitaxel (Abraxane) can improve the tumor targeting property and therapeutic efficacy of paclitaxel (PTX) against orthotopic malignancies. However, patients with metastatic cancer have a poor prognosis, probably due to the instability, chemoresistance, and inability of albumin-bound paclitaxel to alter the tumor microenvironment. Here we propose a new biguanide-modified albumin-based nanoplatform that encapsulates paclitaxel for the effective treatment of metastatic cancer. The PTX is encapsulated in poly (lactic-co-glycolic acid) cores coated with biguanide-modified albumin (HSA-NH). The functionalized nanoparticles (HSA-NH NPs) exhibit a remarkable stable profile with low drug release (P< 0.05 versus Abraxane), target tumor tissues, suppress epithelial-mesenchymal transition (EMT) events for anti-metastatic effects, and reduce the phenotype of cancer stem cells. As a result, HSA-NH NPs effectively prolong animal survival (55 days) by inhibiting not only primary tumor growth but also metastasis. This study provides proof of concept that the biguanide-anchored albumin-based nanoplatform encapsulating PTX is a powerful, safe, and clinically translational strategy for the treatment of metastatic cancer.Statement of significanceAlbumin-bound paclitaxel (Abraxane) can increase paclitaxel's tumor targeting and therapeutic efficacy in clinical cancer treatments such as breast cancer. However, the instability, chemoresistance, and lack of tumor microenvironment modulation of albumin-bound paclitaxel may lead to poor therapeutic efficacy in metastatic cancer patients. Here we develop biguanide-anchored albumin-based nanoplatforms that encapsulate paclitaxel (HSA-NH NPs) for metastatic cancer treatment. Poly(lactic-co-glycolic acid) (PLGA) cores encapsulating paclitaxel improve the stability of HSA-NH NPs. Based on the activities of metformin, biguanide-anchored albumin adsorbed on PLGA cores improves paclitaxel efficacy, inhibits various aberrant changes during epithelial-mesenchymal transition, and reduces tumor cell stemness. The biguanide-anchored albumin-based nanoplatform encapsulating PTX can serve as a potent, safe, and clinically translational approach for metastatic cancer therapies.