Title

Carboplatin: Exploring mechanism of action and improved drug delivery (1) Role of carbonate in the mechanism of action of carboplatin; (2) Cytotoxicity of mesoporous silica nanomaterials

Date of Award

2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

James C. Dabrowiak

Keywords

Carboplatin, Platinum anticancer drugs, Carbonate, Cytotoxicity, Mechanism of action, Mesoporous silica

Subject Categories

Chemistry | Inorganic Chemistry | Physical Sciences and Mathematics

Abstract

(1) The second generation Pt 2+ anticancer drug carboplatin, cis -[Pt(NH 3 ) 2 (CBDCA- O,O' )], where CBDCA is cyclobutane-1,1-dicarboxylate, is here shown to react with carbonate, which is present in blood, interstitial fluid, cytosol, and culture medium, to produce platinum-carbonato and -hydroxo complexes, using 1D 13 C and 1 H NMR spectroscopy, 2D [ 1 H, 15 N] HSQC NMR spectroscopy and 15 N-labeled carboplatin, an UV-visible spectroscopy. Observed rate constants for the reaction of carboplatin in various media show that CO 3 2- is an important nucleophile for the ring opening of carboplatin, and that this reaction is important in the nucleophile-rich RPMI culture medium. In the presence of Jurkat cells, carboplatin is modified not only by substances present in culture medium, such as carbonate, but also by substances released by the c themselves. Using 13 C NMR, resonances have been detected that, by comparison to previously reported carbonato complexes, are due to carbonato species produced when carboplatin is allowed to react in carbonate buffer. This corroborates [ 1 H, 15 N] HSQC NMR, which shows the formation of carbonato and hydroxo complex cis -[Pt(NH 3 ) 2 (CO 3 )(OH)] - . The products formed in this reaction are taken up by cells a interact with critical cellular components. Aging carboplatin in carbonate buffer produces species that are more toxic toward human neuroblastoma, renal proximal tubule, and Namalwa-luc Burkitt's lymphoma cells, than is intact carboplatin. When exposed to carboplatin or carboplatin aged in carbonate, normal Jurkat cells take up/bind approximately the same amount of Pt, while cisplatin-resistant Jurkat cells take up/bind less Pt when exposed to the latter. Collectively, the studies presented here show that carbonate may play an important role in the mechanism of action of carboplatin in vivo.

(2) Mesoporous silica MCM-41 is here shown to adsorb carboplatin, using UV-visible spectroscopy, and [ 1 H, 15 N] HSQC NMR spectroscopy and 15 N-labeled carboplatin. The toxicity of MCM-41, two of its functionalized analogs, and spherical silica nanoparticles, toward human neuroblastoma cells was also investigated. Cytotoxicity, reported in terms of the number of particles required to inhibit normal cell growth by 50%, appears related to the adsorptive surface area of the particle; however, factors such as size and shape also appear to be important. Collectively, these studies explore the suitability of mesoporous silica nanomaterials as vehicles for drug delivery.

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