P-糖蛋白（P-gp / ABCB1）介导的多药耐受性（MDR）严重限制了肿瘤化疗的疗效。我们最近报道了磷脂酰肌醇 3-激酶（PI3K）110α和110β亚单位可以是逆转P-gp介导的MDR的肿瘤治疗新靶点，BAY-1082439作为针对PI3K 110α和110β亚单位的抑制剂可通过下调癌细胞中P-gp表达来逆转P-gp介导的MDR。但是，BAY-1082439的溶解度非常低，半衰期短且体内清除速率高。迄今为止，未报道具有靶向PI3K P110α和P110β的功能并逆转P-gp介导的MDR的肿瘤纳米系统。在我们的研究中，建立了一种肿瘤靶向药物传递纳米系统PBDF，它由生物可降解的PLGA-SH纳米粒子（NPs）分别封装了阿霉素（DOX）和BAY-1082439，并被连接到黄金纳米棒（Au NRs）上，并修饰有FA-PEG-SH，以增强逆转P-gp介导的MDR的效果和靶向肿瘤细胞的能力，进一步增强对P-gp过度表达的MDR肿瘤的抑制效率。体外实验表明，与自由DOX和自由BAY-1082439相比，PBDF NPs极大地增强了DOX的摄取量，改善了逆转MDR的活性，抑制了细胞增殖，并在KB-C2细胞中诱导了S期阻滞和凋亡。体内实验进一步证明，PBDF NPs提高了DOX的抗肿瘤能力并抑制了KB-C2肿瘤的发展。值得注意的是，PBDF NPs处理可以抑制裸鼠肝脏和肺脏中KB-C2细胞的转移，显示出无明显的体外或体内毒性。 版权所有 © 2023 Elsevier B.V. 发布。

P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR) in cancers severely limit chemotherapeutic efficacy. We recently reported that phosphatidylinositol-3-kinase (PI3K) 110α and 110β subunits can be novel targets for reversal of P-gp mediated MDR in cancers, and BAY-1082439 as an inhibitor specific for PI3K 110α and 110β subunits could reverse P-gp-mediated MDR by downregulating P-gp expression in cancer cells. However, BAY-1082439 has very low solubility, short half-life and high in-vivo clearance rate. Till now, nano-system with the functions to target PI3K P110α and P110β and reverse P-gp mediated MDR in cancers has not been reported. In our study, a tumor targeting drug delivery nano-system PBDF was established, which comprised doxorubicin (DOX) and BAY-1082439 respectively encapsulated by biodegradable PLGA-SH nanoparticles (NPs) that were grafted to gold nanorods (Au NRs) modified with FA-PEG-SH, to enhance the efficacy to reverse P-gp mediated MDR and to target tumor cells, further, to enhance the efficiency to inhibit MDR tumors overexpressing P-gp. In-vitro experiments indicated that PBDF NPs greatly enhanced uptake of DOX, improved the activity to reverse MDR, inhibited the cell proliferation, and induced S-phase arrest and apoptosis in KB-C2 cells, as compared with free DOX combining free BAY-1082439. In-vivo experiments further demonstrated that PBDF NPs improved the anti-tumor ability of DOX and inhibited development of KB-C2 tumors. Notably, the metastasis of KB-C2 cells in livers and lungs of nude mice were inhibited by treatment with PBDF NPs, which showed no obvious in-vitro or in-vivo toxicity.Copyright © 2023. Published by Elsevier B.V.