Oxaliplatin(IV) Prodrugs Functionalized with Gemcitabine and Capecitabine Induce Blockage of Colorectal Cancer Cell Growth—An Investigation of the Activation Mechanism and Their Nanoformulation
Carlo Marotta,
Damiano Cirri,
Ioannis Kanavos,
Luisa Ronga,
Ryszard Lobinski,
Tiziana Funaioli,
Chiara Giacomelli,
Elisabetta Barresi,
Maria Letizia Trincavelli,
Tiziano Marzo,
Alessandro Pratesi
Affiliations
Carlo Marotta
Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy
Damiano Cirri
Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy
Ioannis Kanavos
Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France
Luisa Ronga
Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France
Ryszard Lobinski
Institute of Analytical and Physical Chemistry for the Environment and Materials (IPREM-UMR 5254), Pau University, E2S UPPA, CNRS, 64053 Pau, France
Tiziana Funaioli
Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy
Chiara Giacomelli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Elisabetta Barresi
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Maria Letizia Trincavelli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Tiziano Marzo
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Alessandro Pratesi
Department of Chemistry and Industrial Chemistry, University of Pisa, 56124 Pisa, Italy
The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs. The design, synthesis, and characterization of two novel Pt(IV) prodrugs based on oxaliplatin bearing the anticancer drugs gemcitabine or capecitabine in the axial positions have been reported. These complexes were able to dissociate into their constituents to promote cell death and induce apoptosis and cell cycle blockade in a representative colorectal cancer cell model. Specifically, the complex bearing gemcitabine resulted in being the most active on the HCT116 colorectal cancer cell line with an IC50 value of 0.49 ± 0.04. A pilot study on the encapsulation of these complexes in biocompatible PLGA-PEG nanoparticles is also included to confirm the retention of the pharmacological properties and cellular drug uptake, opening up to the possible delivery of the studied complexes through their nanoformulation.
