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Francisco Quiñonero,1,2,* Belén Parra-Torrejón,3,* Gloria B Ramírez-Rodríguez,3 Victor Garcés,3 José M Delgado-López,3 Cristina Jiménez-Luna,1,2,4 Gloria Perazzoli,1,2,4 Consolación Melguizo,1,2,4 Jose Prados,1,2,4 Raul Ortíz1,2,4 1Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, 18100, Spain; 2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18014, Spain; 3Department of Inorganic Chemistry, Faculty of Science, University of Granada, Granada, 18071, Spain; 4Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18071, Spain*These authors contributed equally to this workCorrespondence: José M Delgado-López, Department of Inorganic Chemistry, Faculty of Science, University of Granada, Granada, 18071, Spain, Email jmdl@ugr.esIntroduction: 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.Methods: 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.Results: 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.Conclusion: 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.Graphical Abstract: Keywords: nanomedicine, calcium phosphate nanocarriers, Olaparib, ascorbic acid, synergistic effect, pancreatic cancer |
