Contacts:
Tel: 0039 3283512110
e-mail: arianna.mancini3@gmail.com
Supervisors:
Prof. Elena Dreassi; Prof. Tiziano Tuccinardi
PhD project Title:
In vivo MRI evaluation of pharmacokinetics and biodistribution of new pyrazolo[3,4-d]pyrimidine derivatives delivered by targeted liposomes
Research summary:
This Ph.D. project includes the preclinical development and characterization of novel pyrazolo[3,4-d]pyrimidine-structure based anticancer agents, identified as potent tyrosine kinase inhibitors. Some members of this family showed a good activity against two nervous system cancers, neuroblastoma and glioblastoma. These compounds could represent a new and improved step toward targeted nervous system cancer therapy, that has the potential for avoiding some of the drawbacks associated with cytotoxic chemotherapy. The most promising compounds are selected, formulated, and characterized for their pharmacokinetic, toxicological and pharmacodynamic properties both in vitro and in vivo. First, properties such as aqueous solubility, permeability and metabolic stability, plasma protein binding are assessed, then the inhibitory properties of drugs on cytochrome P450 enzymes, hERG channel and P-glycoprotein are evaluated. By means of pharmacokinetic tests in healthy mice, important parameters such as plasma half-life, clearance, oral bioavailability and brain penetration are estimated. Formulation studies comprises the development of long circulating nano-systems for their use against solid cancers. Liposomes are essential tools in drug delivery, tumor targeting and molecular imaging. Exploiting the possibility of engineering liposomes surface to make them specific for tumor cells, the project includes the preparation of pyrazolo[3,4-d]pyrimidines-loaded liposomes coupled with the antibody anti-disialoganglioside-2 (anti-GD-2), with the aim of targeting its epitope, which is abundantly expressed at neuroblastoma cells surface. Liposomes coupled with anti-GD2 can improve drug delivery and cellular uptake, enhancing the efficacy of the drug toward experimental models of human neuroblastoma. In addition, liposomes could be an effective platform for MRI contrast agent to allow that distribution and drug release can be fully visualized using molecular imaging. In order to make liposomes MRI-sensitive, they are co-loaded with the anticancer compound and contrast agent Gd-DTPA, thus making them observable in MR images.
Publications:
Poster communications at congress:
Mancini, A.; Fallacara, A. L.; Zamperini, C.; Iovenitti, G.; Rango, E.; Angelucci, A.; Schenone, S.; Botta, M. Preclinical Development of Novel Pyrazolo[3,4-d]Pyrimidine Structure-Based TKIs for the Treatment of Glioblastoma. AACR Annual Meeting. 2019 March 29, Atlanta, Georgia, USA. (https://www.abstractsonline.com/pp8/#!/6812/presentation/5462)
Mancini, A.; Iovenitti, G.; Zamperini, C.; Calandro, P.; Schenone, S.; Botta, M. Plasmin-Binding Tripeptide-Decorated Liposomes Loading Pyrazolo[3,4-d]Pyrimidines for Targeting Hepatocellular Carcinoma. European Workshop in Drug Synthesis. 2018 May 20, Siena, Italy.
Mancini, A.; Iovenitti, G.; Vignaroli, G.; Calandro, P.; Zamperini, C.; Coniglio, F.; Tavanti, M.; Colecchia, D.; Dreassi, E.; Valoti, M.; Schenone, S.; Chiariello, M.; Botta, M. Improvement of Pyrazolo[3,4-d]Pyrimidines Pharmacokinetic Properties: Nanosystem Approaches for Drug Delivery. 13th International Conference and Exhibition on Nanomedicine and Pharmaceutical Nanotechnology. 2017 July 24, Rome, Italy.