They improve the effect of an antitumor drug against pancreatic cancer by binding to a calcium phosphate nanoparticle

A team of Andalusian scientists from the Granada Biosanitary Research Institute (ibs.GRANADA) and the University of Granada (UGR) have designed a new effective nanodrug for pancreatic cancer. It is a multidisciplinary investigation that has been developed in recent years through the financing of different competitive projects, both national and regional, in which the researchers Jose Carlos Prados and Consolation Melguizo (Institute for Biosanitary Research ibs.GRANADA and UGR) and Jose Manuel Delgado (Department of Inorganic Chemistry of the UGR).

Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, represents a serious health problem, being the fourth leading cause of cancer death in Western countries, presenting a very low 5-year survival rate (4%). At the time of diagnosis, 80% of patients have locally advanced or metastatic disease. Despite the recent advances in terms of its treatment, there is still no therapy that can significantly improve the results. For this reason, all the improvements directed towards the achievement of new therapeutic alternatives in this pathology are essential to improve the prognosis of patients.

The collaboration of the A01 Technology Applied to Oncology and Gene Therapy groups of the oncology area of the ibs.GRANADA (Oncology Area) and the FQM-368 Group (Bionanometals) of the UGR have shown that the use of olaparib, an agent used in pancreatic cancer, combined with a calcium phosphate nanoparticle significantly reduces tumor volume and increases survival in pancreatic cancer.

Olaparib is a known resistance mechanism blocking agent that is capable of significantly potentiating the effect of gemcitabine, an agent commonly used in unresectable pancreatic tumors. In vitro assays using cell cultures determined the relevance of resistance mediated by an enzyme that is involved in many cellular functions, including DNA damage, called PRP1, in the development and treatment of pancreatic cancer. In addition, in vivo analysis, using mice with induced pancreatic tumors, demonstrated lower lethality when a combination of both agents was used.

These good results with olaparib observed by this team of scientists from Granada have led them to design nano-formulations that improve the effects of this agent. These calcium phosphate nanoparticles associated with olaparib incorporate ascorbic acid, an agent described as a pro-oxidant in pancreatic cancer cells.

The in vitro results determine a synergistic and potentiating effect of the nanodrug that significantly exceeds that obtained with olaparib in isolation. Surprisingly, in vivo tests using mice with induced pancreatic tumors reveal that the nanodrug was able to reduce tumor volume to a greater extent, by 59,1%, compared to the free drug (28,3%) and that the Mice survival after treatment was significantly increased, 78% versus 44% with olaparib treatment.

These results have been the subject of a patent from the ibs.GRANADA and the UGR that is based on the use of a highly biocompatible and biodegradable system for the treatment of pancreatic cancer. These results show a more promising path to design innovative and more efficient therapies against pancreatic cancer. The results of this line of work have given rise to two publications in the prestigious magazine Biomedicine and Pharmacotherapy and another under review that have subsequently allowed the preparation of patent P202231095.

About the research group

The Research Group on Technology Applied to Oncology and Gene Therapy A01 of the Cancer Area of the ibs.GRANADA, has been consolidated over the last few years thanks to the continuous expansion of its research staff and personnel in training. Its objective in recent years has focused on the development of new strategies for the treatment of cancer at an experimental level but with a clear purpose of clinical application, including the application of nanotechnological systems, the study of cancer stem cells, their mechanisms of resistance and its relevance as a target for new therapies, the determination of new molecules/extracts of plant or animal origin with therapeutic or preventive capacity against cancer and progress in aspects related to regenerative biomedicine, especially in the nervous and musculoskeletal systems. In addition, a central line of his research is based on the development of cancer diagnostic systems based on new technologies, including the determination of gene, protein and metabolomics-based markers.

More information about the group at https://www.ibsgranada.es/grupos-de-investigacion/a01-tecnologia-aplicada-a-oncologia-y-terapia-genica/

Bibliographic reference and patent

Quiñonero F, Mesas C, Muñoz-Gámez JA, Jiménez-Luna C, Perazzoli G, Prados J, Melguizo C, Ortiz R. “PARP1 inhibition by Olaparib reduces the lethality of pancreatic cancer cells and increases their sensitivity to Gemcitabine”. Biomed Pharmacother. 2022, 155:113669. doi: 10.1016/j.biopha.2022.113669. J. Prados, JM. Delgado, F. Quiñonero, B. Parra, G. Ramírez, C. Melguizo, R. Ortiz, C. “Nanoparticles to improve the effects of drugs for treatment of cancer”. P202231095

Image: The UGR research team (from left to right): JC Prados, C. Melguizo, R. Ortiz, C. Mesas, F. Quiñonero, G. Ramírez, B. Parra, JM. Slim