Polymorphism in Cisplatin Anticancer Drug

Abstract

This study reports a combined experimental and theoretical study of the solid-state polymorphism of the anticancer agent cisplatin. A complete assignment was performed for the inelastic neutron scattering (INS) and Raman spectra collected simultaneously for cisplatin, at different temperatures, with a view to obtain reliable and definitive evidence of the relative thermal stability of its α and β polymorphic species. A marked temperature-dependent hysteresis was observed, as previously reported in the literature. Theoretical calculations were carried out at the density functional theory level, using a plane-wave basis set approach and pseudopotentials. A detailed comparison with the experimental Raman and INS data showed that the α polymorph is present at the lowest temperatures, whereas the β form occurs near room temperature. Furthermore, regions of coexistence of both forms are identified, which depend on the working mode (heating or cooling). These findings imply that Raman spectroscopy allows clear identification of the α and β polymorphs at a given temperature and can unambiguously discriminate between them. Elucidation of the polymorphic equilibrium of this widely used anticancer drug is paramount for its pharmaceutical preparation and storage conditions.

Comment on “Assessment of new DFT methods for predicting vibrational spectra and structure of cisplatin: Which density functional should we choose for studying platinum(II) complexes?” [Spectrochim. Acta A125 (2014) 431–439]

“…This is shown by the excellent agreement between the observed and calculated geometries we obtain [2,3]. Moreover, although it may be true that periodic-DFT methods are not straightforwardly applied to very large systems, they can already handle up to a few hundred atoms already (e.g.…”

“…Studies by simultaneous Raman and inelastic neutron scattering (INS) techniques allow the observation of all the low energy vibrational modes of these complexes, including the ones of most interest, those involving the metal centre [3]. INS has a further advantage in that it is straightforward to generate a calculated spectrum from only the vibrational transition energies and the atomic displacements, the more complicated (and less reliable) calculation of infrared and Raman intensities is avoided.…”

“…Thus the combination of INS spectroscopy with periodic-DFT calculations provides a much more stringent test of a calculation than consideration of transition energies alone. It should be highlighted that these type of experiments have been performed and published for cisplatin [3], as well as periodic-DFT calculations for solid cisplatin, transplatin and carboplatin [4].…”

Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy

“…This data, coupled to previous INS and EXAFS studies on drug-DNA adducts (carried out at ISIS and DLS 18,21,23,24 ), will pave the way for future work on other promising cisplatin-like anticancer agents (both Pt(II) and Pd(II)) which have been studied by the team in the last few years, as well as on distinct human cancer cells. In addition, experiments are envisaged to monitor the drugs biodistribution within the cell, by differentiating the responses in different subcellular regions as well as through the use of synchrotron radiation FTIR microspectroscopy for obtaining high spatial resolution chemical images on single cells.…”

“…A thorough knowledge of these compounds and of their interactions with their main pharmacological target (DNA), as well as with other biomolecules involved in the drug pharmacokinetics (e.g. glutathione) and pharmacodynamics, has been attained through vibrational spectroscopy (Raman, FTIR and Inelastic Neutron Scattering (INS)) [18][19][20][21][22][23][24] coupled to synchrotron-based Extended X-ray Absorption Fine Structure (EXAFS), 23 as well as by NMR metabolomics 22,25 and electrochemical techniques. 26,27 In order to design such effective chemotherapeutic agents, it is essential not only to determine their effect on cellular growth, metabolism and function, but also to understand the mechanisms (at a molecular level) associated with this biological impact.…”