Enhanced cellular uptake of platinum by a tetracationic Pt(II) nanocapsule and its implications to cancer treatment (original) (raw)
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Dalton Transactions, 2006
Four-and five-coordinate platinum(II) complexes, cis-[PtCl 2 (A 2 )] (1) and [PtCl 2 (A 2 )(g 2 -ethylene)] (2) {A 2 = 4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BPS (mixture of isomers) (a); 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BCS (mixture of isomers) (b)} have been synthesized and characterized by 1 H, 13 C, and 195 Pt NMR spectroscopy. The stability and high water solubility of complexes 1a, 1b and 2b, due to the presence of the polar SO 3 − groups on the ligands skeleton, allowed to test their in vitro cytotoxicity on HeLa tumour cells in a wide range of drug concentration. At low and medium incubation doses (<200 lM) 1a, 1b and 2b all showed similar in vitro cytotoxicity, negligible or much lower with respect to cisplatin. At doses higher than 200 lM their activity increased and 1b, the most active among the new complexes, exhibited a cytotoxicity comparable, although still lower, with respect to cisplatin. GFAAS Platinum analytical data showed that the tested compounds 1a, 1b and 2b, although carrying sulfonate charged groups, may undergo cellular uptake, which, in the case of 1b and 2b, is even higher with respect to cisplatin. Furthermore, in the case of 1b and 2b it has been possible to compare, for the first time, the cytotoxic activity for square-planar four-coordinate and trigonal-bipyramidal five-coordinate platinum(II) complexes having the same carrier ligand. The tendency of the five-coordinate species 2b to give at longer incubation time similar cytotoxicity with respect to the square-planar compound 1b suggests a possible use of the trigonal-bipyramidal five-coordinate complexes as prodrugs.
Drug Delivery Devices and Targeting Agents for Platinum(II) Anticancer Complexes
Australian Journal of Chemistry, 2008
An ideal platinum-based delivery device would be one that selectively targets cancerous cells, can be systemically delivered, and is non-toxic to normal cells. It would be beneficial to provide drug delivery devices for platinum-based anticancer agents that exhibit high drug transport capacity, good water solubility, stability during storage, reduced toxicity, and enhanced anticancer activity in vivo. However, the challenges for developing drug delivery devices include carrier stability in vivo, the method by which extracellular or intracellular drug release is achieved, overcoming the various mechanisms of cell resistance to drugs, controlled drug release to cancer cells, and platinum drug bioavailability. There are many potential candidates under investigation including cucurbit[n]urils, cyclodextrins, calix[n]arenes, and dendrimers, with the most promising being those that are synthetically adaptable enough to attach to targeting agents.
Novel platinum (II)-based anticancer complexes and molecular hosts as their drug delivery vehicles
Dalton Trans., 2007
Platinum(II)-based DNA intercalators where the intercalating ligand is 1,10-phenanthroline or a phenanthroline derivative and where the ancillary ligand is either achiral (e.g. ethylenediamine) or chiral (e.g. diaminocyclohexane) show a range of cytotoxicities with a defined structure-activity relationship. The most cytotoxic are those that contain methylated-phenanthroline ligands and 1S,2S-diaminocyclohexane (S,S-dach) as the ancillary ligand. We have developed a new purification method using Sep-Pak R C-18 reverse phase columns, which means these metal complexes can be made faster and cheaper compared to published methods. Platinum(II)-based complexes containing imidazole, pyrrole and b-alanine subunits, that are capable of recognising specific DNA base-pair sequences have also been synthesised. These include linear or hairpin polyamide ligands that can recognise DNA sequences up to seven base-pairs in length and contain single platinum centres capable of forming monofunctional adducts with DNA. We have now synthesised and characterised, by 1 H and 195 Pt NMR, ESI-MS and elemental analysis, the first dinuclear platinum(II) DNA sequence selective agent. Finally, using 1 H NMR we have examined the encapsulation of our platinum(II)-based DNA intercalators by cucurbit [6]uril (CB[6]). Encapsulation by CB[6] was found to not significantly change the cytotoxicity of five platinum(II)-based DNA intercalators, indicating it may have utility as a molecular carrier for improved drug delivery. ‡ Electronic supplementary information (ESI) available: 1 H and 195 Pt NMR and ESI-MS of DNHLSP-6. Cytotoxicity of selected platinum(II) DNA intercalators in human cancer cell lines. See
Chemical Engineering Journal, 2018
Cisplatin has been for many years the gold standard chemotherapeutic drug for the treatment of a wide range of solid tumors, even though its use is commonly associated with serious side effects including non-selective toxicity, myelosuppression or development of cisplatin resistance, among others complications. Over the last decade, a number of nanoparticle formulations were developed to reduce its side effects and improve the selectivity and efficacy of this drug. In this study, we have developed a novel nanoparticle platform based on nanoscale coordination polymer named (Zn-Pt(IV)-NCPs) which contains a Pt(IV) prodrug , Zn and the linker ligand 1,4-Bis(imidazol-1-ylmethyl)benzene (bix). The main objective has been to gain insights into the mechanism of action of this nanostructured material in comparison with cisplatin and the free Pt(IV) prodrug in order to stablish a correlation between nanostructuration and therapeutic activity. Zn-Pt(IV)-NCPs nanoparticles displayed an average size close to 200 nm as determined by DLS, a good stability in physiologic environments, and a controlled drug release of Pt. In vitro studies demonstrated that Pt(IV)-NCPs showed an enhanced cytotoxic effect against cell culture of cervical cancer, neuroblastoma and human adenocarcinoma cells in comparison with free Pt(IV) prodrug. Although no difference in cell uptake of Pt was observed for any of the three cell lines assayed, a higher amount of Pt bound to the DNA was found in the cells treated with the nanostructured Pt(IV) prodrug. These studies suggest that the nanostructuration of the prodrug facilitate its activation and induce a change in the mechanism of action related to an increased interaction with the DNA as corroborated by the studies of direct interaction of the Pt(IV) prodrug, nanostructured or not, with DNA.
Scientific reports, 2015
Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2-diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidne...
ACS Omega, 2020
Cancer is a major public health problem being one of the main causes of morbidity and mortality today. Recent advances in catalytic nanomedicine have offered new cancer therapies based on the administration of nanoparticles (NPs) of platinum (Pt) dispersed in catalytic mesoporous nanomaterials (titania, TiO 2) with highly selective cytotoxic properties and no adverse effects. A half maximal inhibitory concentration (IC 50) study was carried out in cancerous cell lines (HeLa, DU-145, and fibroblasts) to evaluate the cytotoxic effect of different nanomaterials [Pt/TiO 2 , TiO 2 , and Pt(acac) 2 ] synthesized by the sol−gel method at concentrations 0−1000 μg/mL. The assays showed that IC 50 values for Pt in functionalized TiO 2 (NPt) in HeLa (53.74 ± 2.95 μg/mL) and DU-145 (75.07 ± 5.48 μg/mL) were lower than those of pure TiO 2 (74.29 ± 8.95 and 82.02 ± 6.03 μg/mL, respectively). Pt(acac) 2 exhibited no cytotoxicity. Normal cells (fibroblasts) treated with NPt exhibited no significant growth inhibition, suggesting the high selectivity of the compound for cancerous cells only. TiO 2 and NPt were identified as antineoplastic compounds in vitro. Pt(acac) 2 is not recommendable because of the low cytotoxicity observed.
Journal of inorganic …, 2009
The utility of p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-[{PtCl(NH 3 ) 2 } 2 l-dpzm] 2+ (di-Pt; where dpzm = 4,4 0 -dipyrazolylmethane) as a model complex, has been examined using 1 H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX[4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX[4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5 0 -guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX . The cytotoxicity of free di-Pt and s-CX[4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC 50 of 100 and 60 lM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 lM, respectively). s-CX displays no cytotoxicity at concentrations up to 1.5 mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 Â 10 4 M À1 ) means the host-guest complex is mostly disassociated at biologically relevant concentrations.
Journal of Inorganic Biochemistry, 2009
The utility of p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-[{PtCl(NH 3 ) 2 } 2 l-dpzm] 2+ (di-Pt; where dpzm = 4,4 0 -dipyrazolylmethane) as a model complex, has been examined using 1 H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX[4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX[4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5 0 -guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX . The cytotoxicity of free di-Pt and s-CX[4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC 50 of 100 and 60 lM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 lM, respectively). s-CX displays no cytotoxicity at concentrations up to 1.5 mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 Â 10 4 M À1 ) means the host-guest complex is mostly disassociated at biologically relevant concentrations.