Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19713, United States.
Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716, United States.
Mol Pharm. 2023 Aug 7;20(8):3895-3913. doi: 10.1021/acs.molpharmaceut.3c00009. Epub 2023 Jul 17.
Overexpression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) is correlated with poor survival outcomes in triple-negative breast cancer (TNBC), making Bcl-2 inhibition a promising strategy to treat this aggressive disease. Unfortunately, Bcl-2 inhibitors developed to date have limited clinical success against solid tumors, owing to poor bioavailability, insufficient tumor delivery, and off-target toxicity. To circumvent these problems, we loaded the Bcl-2 inhibitor ABT-737 in poly(lactic--glycolic acid) (PLGA) nanoparticles (NPs) that were wrapped with phospholipid membranes derived from 4T1 murine mammary cancer cells, which mimic the growth and metastasis of human TNBC. We show that the biomimetic cancer cell membrane coating enabled the NPs to preferentially target 4T1 TNBC cells over noncancerous mammary epithelial cells and significantly increased NP accumulation in orthotopic 4T1 tumors in mice after intravenous injection by over 2-fold compared to poly(ethylene glycol)-poly(lactide--glycolic) (PEG-PLGA) copolymer NPs. Congruently, the ABT-737 loaded, cancer cell membrane-wrapped PLGA NPs (ABT CCNPs) induced higher levels of apoptosis in TNBC cells than ABT-737 delivered freely or in PEG-PLGA NPs. When tested in a syngeneic spontaneous metastasis model, the ABT CCNPs significantly increased apoptosis (evidenced by elevated active caspase-3 and decreased Bcl-2 staining) and decreased proliferation (denoted by reduced Ki67 staining) throughout tumors compared with saline or ABT-loaded PEG-PLGA NP controls. Moreover, the ABT CCNPs did not alter animal weight or blood composition, suggesting that the specificity afforded by the TNBC cell membrane coating mitigated the off-target adverse effects typically associated with ABT-737. Despite these promising results, the low dose of ABT CCNPs administered only modestly reduced primary tumor growth and metastatic nodule formation in the lungs relative to controls. We posit that increasing the dose of ABT CCNPs, altering the treatment schedule, or encapsulating a more potent Bcl-2 inhibitor may yield more robust effects on tumor growth and metastasis. With further development, drug-loaded biomimetic NPs may safely treat solid tumors such as TNBC that are characterized by Bcl-2 overexpression.
抗凋亡蛋白 B 细胞淋巴瘤 2（Bcl-2）的过表达与三阴性乳腺癌（TNBC）的不良生存结果相关，因此抑制 Bcl-2 成为治疗这种侵袭性疾病的一种有前途的策略。不幸的是，迄今为止开发的 Bcl-2 抑制剂在治疗实体瘤方面临床效果有限，这归因于生物利用度差、肿瘤传递不足和脱靶毒性。为了规避这些问题，我们将 Bcl-2 抑制剂 ABT-737 载入聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒（NPs）中，这些 NPs 被源自 4T1 鼠乳腺癌细胞的磷脂膜包裹，这种膜模拟了人类 TNBC 的生长和转移。我们表明，仿生癌细胞膜涂层使 NPs 能够优先靶向 4T1 TNBC 细胞，而不是非癌性乳腺上皮细胞，并且与聚乙二醇-聚乳酸-乙醇酸（PEG-PLGA）共聚物 NPs 相比，在静脉注射后显著增加了 NP 在小鼠原位 4T1 肿瘤中的积累，增加了两倍以上。一致地，载有 ABT-737 的、被癌细胞膜包裹的 PLGA NPs（ABT CCNPs）在 TNBC 细胞中诱导的细胞凋亡水平高于自由递送的 ABT-737 或在 PEG-PLGA NPs 中递送的 ABT-737。当在同种异体自发转移模型中进行测试时，与盐水或载有 ABT 的 PEG-PLGA NP 对照相比，ABT CCNPs 显著增加了肿瘤中的细胞凋亡（通过升高的活性 caspase-3 和降低的 Bcl-2 染色来证明）和降低了增殖（通过减少 Ki67 染色来证明）。此外，ABT CCNPs 没有改变动物体重或血液成分，表明 TNBC 细胞膜涂层提供的特异性减轻了与 ABT-737 相关的脱靶不良影响。尽管取得了这些有希望的结果，但与对照组相比，ABT CCNPs 的低剂量仅适度降低了原发性肿瘤生长和肺部转移结节的形成。我们假设增加 ABT CCNPs 的剂量、改变治疗方案或封装更有效的 Bcl-2 抑制剂可能会对肿瘤生长和转移产生更显著的效果。随着进一步的发展，载药仿生 NPs 可能安全地治疗以 Bcl-2 过表达为特征的 TNBC 等实体瘤。
