Reactions of platinum(II) anticancer drugs. Kinetics of acid hydrolysis of cis-diammine(cyclobutane-1,1-dicarboxylato)platinum(II) “Carboplatin”

Hay, Robert W.; Miller, Samantha

doi:10.1016/s0277-5387(97)00477-4

Cited by 50 publications

(35 citation statements)

References 23 publications

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“…24), and its rate of aquation is much slower (4,5). Here, we report that, despite the differences in chemical properties, carboplatin can be efficiently encapsulated in a lipid formulation by a similar method, resulting in a formulation with a strongly improved cytotoxicity against tumor cells in vitro compared with the free drug.…”

Section: Introductionmentioning

confidence: 89%

“…It was found that modification of cisplatin to contain less labile leaving groups alters the pharmacokinetics and the toxicity profile of the drug. Replacement of the chloride leaving groups with a cyclobutane-dicarboxylato ligand, forming cis -diammine-cyclobutane-1,1-dicarboxylatoplatinum(II) (carboplatin), slowed down the rate of hydrolysis 100-fold, rendering the compound less reactive and reducing systemic toxicities, whereas antitumor activity was retained (1,4,5). At effective doses, carboplatin produced substantially less nausea, vomiting, nephrotoxicity, and neurotoxicity than cisplatin, and bone marrow suppression was its predominant toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Carboplatin nanocapsules: a highly cytotoxic, phospholipid-based formulation of carboplatin

Hamelers

Loenen

Staffhorst

et al. 2006

Molecular Cancer Therapeutics

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Platinum-based drugs are widely used in cancer chemotherapy. However, their clinical use is limited by systemic toxicity, rapid blood clearance, and the occurrence of resistance. Our research is aimed at increasing the therapeutic index of these drugs by encapsulation in a lipid formulation. Previously, we developed a method for efficient encapsulation of cisplatin in a lipid formulation, yielding cisplatin nanocapsules. Here, we show that carboplatin, a cisplatin-derived anticancer drug with different chemical properties, can be efficiently encapsulated in a lipid formulation by a similar method. The carboplatin nanocapsules exhibit a very high cytotoxicity in vitro: the IC 50 value of carboplatin nanocapsules is up to a 1,000-fold lower than that of conventional carboplatin when tested on a panel of carcinoma cell lines. Cellular platinum content analysis and confocal fluorescent imaging of the interaction of the carboplatin nanocapsules with IGROV-1 cells indicate that the improved cytotoxicity is due to increased platinum accumulation in the cells, resulting from uptake of the formulation by endocytosis.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Carboplatin nanocapsules: a highly cytotoxic, phospholipid-based formulation of carboplatin

Hamelers

Loenen

Staffhorst

et al. 2006

Molecular Cancer Therapeutics

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“…We utilised molecular modelling to identify which p-Bel to develop with a view to facilitating complexation to Pt while minimising any negative impact on HDAC inhibitory activity. We anticipated that the dual functioning Pt-p-Bel conjugate would hydrolyse in much the same way as carboplatin in cells [17,18] by releasing the p-Bel derivative to inhibit HDACs and the cytotoxic cis-diammine Pt moiety to bind DNA nucleobases.…”

Section: Introductionmentioning

confidence: 99%

A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

Parker

Nimir

Griffith

et al. 2013

Journal of Inorganic Biochemistry

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“…[31][32][33][34] It has been established that in acidic solution it is likely that the degradation of carboplatin should occur by a biphasic process with a first hydration leading to the ring opening, followed by a second hydration and consequent displacement of the malonate group. [33] A detailed knowledge of all stationary points involved in these reactions is important at this stage, and theoretical methods are a useful tool for obtaining a complete description of the energetics controlling this process.…”

Section: Introductionmentioning

confidence: 99%

On the Hydrolysis Mechanism of the Second-Generation Anticancer Drug Carboplatin

2007

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The hydrolysis reaction mechanisms of carboplatin, a second-generation anticancer drug, have been explored by combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The decomposition of carboplatin in water is expected to take place through a biphasic mechanism with a ring-opening process followed by the loss of the malonato ligand. We have investigated this reaction in water and acid conditions and established that the number of protons present in the malonato ligand has a direct effect on the energetics of this system. Close observation of the optimised structures revealed a necessary systematic water molecule in the vicinity of the amino groups of carboplatin. For this reason we have also investigated this reaction with an explicit water molecule. From the computed potential-energy surfaces it is established that the water hydrolysis takes place with an activation barrier of 30 kcal mol(-1), confirming the very slow reaction observed experimentally. The decomposition of carboplatin upon acidification was also investigated and we have computed a 21 kcal mol(-1) barrier to be overcome (experimental value 23 kcal mol(-1)). We have also established that the rate-limiting process is the first hydration, and ascertained the importance of a water molecule close to the two amine groups in lowering the activation barriers for the ring-opening reaction.

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Reactions of platinum(II) anticancer drugs. Kinetics of acid hydrolysis of cis-diammine(cyclobutane-1,1-dicarboxylato)platinum(II) “Carboplatin”

Cited by 50 publications

References 23 publications

Carboplatin nanocapsules: a highly cytotoxic, phospholipid-based formulation of carboplatin

Carboplatin nanocapsules: a highly cytotoxic, phospholipid-based formulation of carboplatin

A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

On the Hydrolysis Mechanism of the Second-Generation Anticancer Drug Carboplatin

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