白蛋白是开发新型治疗药物的有吸引力的载体候选。吉西他滨已经获得美国食品和药品管理局批准用于实体瘤的治疗；然而，目前还没有用于临床的能够优化吉西他滨输送的新药物。本研究的目的是测试一种新型的包裹在白蛋白内的吉西他滨前药JNTX-101的疗效，并研究Cav-1表达是否能够预测JNTX-101的治疗效果。我们首先确定了JNTX-101在一系列胰腺/肺癌细胞系中的治疗有效性，并发现Cav-1 表达增加导致白蛋白摄取的增加，而Cav-1 缺乏则减弱了细胞对JNTX-101的敏感性。此外，Cav-1表达的降低明显减少了一系列细胞在低血清条件下JNTX-101诱导的凋亡细胞死亡。此外，我们在异种移植模型中测试了JNTX-101的治疗效果以及Cav-1在JNTX-101敏感性中的作用，使用了Tet-on诱导的体内肿瘤模型。我们的数据表明，JNTX-101有效抑制了细胞的存活和肿瘤的生长，并且Cav-1表达决定了对JNTX-101的最佳敏感性。这些数据表明Cav-1与JNTX-101的敏感性相关，尤其在营养匮乏条件下，并支持Cav-1作为白蛋白包裹类治疗药物如JNTX-101的预测生物标志物的角色。© 2023 作者。

Albumin is an attractive candidate carrier for the development of novel therapeutic drugs. Gemcitabine has been FDA approved for the treatment of solid tumors; however, new drugs that optimize gemcitabine delivery are not available for clinical use. The aim of this study was to test the efficacy of a novel albumin-encapsulated gemcitabine prodrug, JNTX-101, and investigate whether Cav-1 expression predicts the therapeutic efficacy of JNTX-101. We first determined the treatment efficacy of JNTX-101 in a panel of pancreatic/lung cancer cell lines and found that increases in Cav-1 expression resulted in higher uptake of albumin, while Cav-1 depletion attenuated the sensitivity of cells to JNTX-101. In addition, decreased Cav-1 expression markedly reduced JNTX-101-induced apoptotic cell death in a panel of cells, particularly in low-serum conditions. Furthermore, we tested the therapeutic efficacy of JNTX-101 in xenograft models and the role of Cav-1 in JNTX-101 sensitivity using a Tet-on-inducible tumor model in vivo. Our data suggest that JNTX-101 effectively inhibits cell viability and tumor growth, and that Cav-1 expression dictates optimal sensitivity to JNTX-101. These data indicate that Cav-1 correlates with JNTX-101 sensitivity, especially under nutrient-deprived conditions, and supports a role for Cav-1 as a predictive biomarker for albumin-encapsulated therapeutics such as JNTX-101.© 2023 The Authors.