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Novel Synthesis of Platinum Complexes and Their Intracellular Delivery to Tumor Cells by Means of Magnetic Nanoparticles

Novel Synthesis of Platinum Complexes and Their Intracellular Delivery to Tumor Cells by Means of Magnetic Nanoparticles

Alessandra Quarta, Manuel Amorín, María José Aldegunde, Laura Blasi, Andrea Ragusa, Simone Nitti, Giammarino Pugliese, Giuseppe Gigli, Juan R Granja, Teresa Pellegrino

Nanoscale. 2019 Dec 28;11(48):23482-23497.

PMID: 31808496

Abstract:

Platinum-based drugs are popular in clinics as chemotherapeutic agents to treat solid tumors. However, severe side effects such as nephro- and neurotoxicity impose strict dosage limitations that can lead to the development of drug resistance and tumor relapse. To overcome these issues Pt(iv) prodrugs and platinum delivery systems might represent the next generation of platinum-based drugs. In this study four novel Pt(ii) complexes (namely, PEG-Glu-Pt-EDA, PEG-Glu-Pt-DACH, PEG-Mal-Pt-EDA and PEG-Mal-Pt-DACH) were synthesized and a general strategy to covalently bind them to iron oxide nanoparticles was developed. The intracellular uptake and cell distribution studies of Pt-tethered magnetic nanoparticles on breast and ovarian cancer cell line models indicate that binding of the Pt complexes to the nanoparticles facilitates, for all the complexes, cellular internalization. Moreover, the magnetic nanoparticles (MNPs), as shown in a magnetofection experiment, enhance the uptake of MNP-Pt conjugates if a magnet is placed beneath the culture dish of tumor cells. As shown by a Pt release experiment, intranuclear platinum quantification and TEM analysis on cell sections, the presence of a pH-sensitive dicarboxylic group coordinating the Pt complex, triggers platinum dissociation from the NP surface. In addition, the triazole moiety facilitates endosomal swelling and the leakage of platinum from the endosomes with intranuclear localization of platinum release by the NPs. Finally, as assessed by MTT, caspase, calcein/ethidium bromide live/dead assays, among the four NP-Pt conjugates, the NP-Glu-Pt-EDA complex having a glutamate ring and ethylenediamine as a chelating amine group of the platinum showed higher cytotoxicity than the other three MNP-platinum conjugates.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP13455124	Platinum(II) bromide		13455-12-4	Price

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