胰腺癌（PC）对当前的治疗反应非常差。耐药性的产生是治疗失败的原因之一，对抗耐药性机制而言，PARP1（聚合酶1）是一个相关蛋白质。本研究使用抗坏血酸（AA）作为促氧化剂，将富含磷酸钙的纳米颗粒（NPs）与阿帕尼（OLA，PARP-1抑制剂）功能化，以增强它们个体效应。通过生物模仿法合成了非晶磷酸钙（ACP）NPs，然后将其功能化为OLA和AA（NP-ACP-OLA-AA）。通过评估载药量和释放动力学，细胞毒性，细胞迁移，免疫荧光和基因表达试验，使用胰腺肿瘤细胞系进行了体外研究。在NOD SCID gamma（NSG）小鼠中进行了PANC-1细胞株来源的肿瘤的体内研究。NP-ACP-OLA-AA有效载药率分别为13%wt OLA和1% AA，同时呈现出OLA和AA的逐渐释放，后者在溶液中受到保护以避免降解。这确保OLA和AA在整个体外细胞实验过程（72个小时）中同时可用。体外研究表明，NP-ACP-OLA-AA在人胰腺导管腺癌细胞系中显示出最佳的细胞毒性效应，超越了自由OLA，并表现出更高的基因毒性和经由凋亡介导的细胞毒性效应。有趣的是，使用免疫抑制的PANC-1诱导肿瘤的小鼠进行的体内试验显示，相对于自由OLA，NP-ACP-OLA-AA可产生更高的肿瘤体积减小（59.1%），并增加小鼠的生存率。作为高度生物相容性和可降解系统的磷酸钙NPs在PC中充当了理想载体，相较于自由OLA，它产生了显著的治疗效果，包括细胞毒性、诱导凋亡、抑制细胞迁移、抑制肿瘤生长和延长小鼠生存时间。© 2023 Quiñonero et al.

Pancreatic cancer (PC) shows a very poor response to current treatments. Development of drug resistance is one of the causes of the therapy failure, being PARP1 (poly ADP-ribose polymerase 1) a relevant protein in the resistance mechanism. In this work, we have functionalized calcium phosphate-based nanoparticles (NPs) with Olaparib (OLA, a PARP-1 inhibitor) in combination with ascorbic acid (AA), a pro-oxidative agent, to enhance their individual effects.Amorphous Calcium Phosphate (ACP) NPs were synthesized through a biomimetic approach and then functionalized with OLA and AA (NP-ACP-OLA-AA). After evaluation of the loading capacity and release kinetic, cytotoxicity, cell migration, immunofluorescence, and gene expression assays were performed using pancreatic tumor cell lines. In vivo studies were carried out on tumors derived from the PANC-1 line in NOD SCID gamma (NSG) mice.NP-ACP-OLA-AA was loaded with 13%wt of OLA (75% loading efficiency) and 1% of AA, respectively. The resulting dual nanosystem exhibited a gradual release of OLA and AA, being the latter protected from degradation in solution. This ensured the simultaneous availability of OLA and AA for a longer period, at least, during the entire time of in vitro cell experiments (72 hours). In vitro studies indicated that NP-ACP-OLA-AA showed the best cytotoxic effect outperforming that of the free OLA and a higher genotoxicity and apoptosis-mediated cytotoxic effect in human pancreatic ductal adenocarcinoma cell line. Interestingly, the in vivo assays using immunosuppressed mice with PANC-1-induced tumors revealed that NP-ACP-OLA-AA produced a higher tumor volume reduction (59.1%) compared to free OLA (28.3%) and increased the mice survival.Calcium phosphate NPs, a highly biocompatible and biodegradable system, were an ideal vector for the OLA and AA co-treatment in PC, inducing significant therapeutic benefits relative to free OLA, including cytotoxicity, induction of apoptosis, inhibition of cell migration, tumor growth, and survival.© 2023 Quiñonero et al.