Vaughan Hannah J, Zamboni Camila G, Radant Nicholas P, Bhardwaj Pranshu, Revai Lechtich Esther, Hassan Laboni F, Shah Khalid, Green Jordan J
Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mol Ther Oncolytics. 2021 Apr 16;21:377-388. doi: 10.1016/j.omto.2021.04.004. eCollection 2021 Jun 25.
Despite initial promise, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based approaches to cancer treatment have yet to yield a clinically approved therapy, due to delivery challenges, a lack of potency, and drug resistance. To address these challenges, we have developed poly(beta-amino ester) (PBAE) nanoparticles (NPs), as well as an engineered cDNA sequence encoding a secretable TRAIL (sTRAIL) protein, to enable reprogramming of liver cancer cells to locally secrete TRAIL protein. We show that sTRAIL initiates apoptosis in transfected cells and has a bystander effect to non-transfected cells. To address TRAIL resistance, NP treatment is combined with histone deacetylase inhibitors, resulting in >80% TRAIL-mediated cell death in target cancer cells and significantly slowed xenograft tumor growth. This anti-cancer effect is specific to liver cancer cells, with up to 40-fold higher cell death in HepG2 cancer cells over human hepatocytes. By combining cancer-specific TRAIL NPs with small-molecule-sensitizing drugs, this strategy addresses multiple challenges associated with TRAIL therapy and offers a new potential approach for cancer treatment.
尽管肿瘤坏死因子相关凋亡诱导配体（TRAIL）在癌症治疗方面最初显示出前景，但由于递送挑战、效力不足和耐药性等问题，基于TRAIL的癌症治疗方法尚未产生临床上获批的疗法。为应对这些挑战，我们开发了聚（β-氨基酯）（PBAE）纳米颗粒（NPs）以及一种编码可分泌TRAIL（sTRAIL）蛋白的工程化cDNA序列，以使肝癌细胞重编程以局部分泌TRAIL蛋白。我们表明，sTRAIL在转染细胞中引发凋亡，并对未转染细胞具有旁观者效应。为解决TRAIL耐药性问题，将纳米颗粒治疗与组蛋白脱乙酰酶抑制剂相结合，导致靶癌细胞中超过80%的细胞因TRAIL介导而死亡，并且异种移植肿瘤生长显著减缓。这种抗癌作用对肝癌细胞具有特异性，HepG2癌细胞的细胞死亡比人肝细胞高40倍。通过将癌症特异性TRAIL纳米颗粒与小分子增敏药物相结合，该策略解决了与TRAIL治疗相关的多个挑战，并为癌症治疗提供了一种新的潜在方法。
