Department of Chemistry

Abstract

Most low-mol.-wt. platinum anticancer drugs have short blood circulation times that are reflected in their reduced tumor uptake and intracellular DNA binding. A platinum(IV) complex of the formula c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)(O2CCH2CH2CONH-PEG-FA)] (I), contg. a folate deriv. (FA) at an axial position, was prepd. and characterized. Folic acid offers a means of targeting human cells that highly overexpress the folate receptor (FR). Compd. I was attached to the surface of an amine-functionalized single-walled carbon nanotube (SWNT-PL-PEG-NH2) through multiple amide linkages to use the SWNTs as a "longboat delivery system" for the platinum warhead, carrying it to the tumor cell and releasing cisplatin upon intracellular redn. of Pt(IV) to Pt(II). The ability of SWNT tethered I to destroy selectively FR(+) vs. FR(-) cells demonstrated its ability to target tumor cells that overexpress the FR on their surface. That the SWNTs deliver the folate-bearing Pt(IV) cargos into FR(+) cancer cells by endocytosis was demonstrated by the localization of fluorophore-labeled SWNTs using fluorescence microscopy. Once inside the cell, cisplatin, formed upon reductive release from the longboat oars, enters the nucleus and reacts with its target nuclear DNA, as detd. by platinum at. absorption spectroscopy of cell exts. Formation of the major cisplatin 1,2-intrastrand d(GpG) crosslinks on the nuclear DNA was demonstrated by use of a monoclonal antibody specific for this adduct. The SWNT-tethered compd. I is the first construct in which both the targeting and delivery moieties have been incorporated into the same mol.; it is also the first demonstration that intracellular redn. of a Pt(IV) prodrug leads to the cis-{Pt(NH3)2} 1,2-intrastrand d(GpG) crosslink in nuclear DNA. [on SciFinder(R)]