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. 2008 Aug 27;130(34):11467-76.
doi: 10.1021/ja803036e. Epub 2008 Jul 29.

Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device

Shanta Dhar  1 , Zhuang Liu, Jürgen Thomale, Hongjie Dai, Stephen J Lippard
Affiliations

Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device

Shanta Dhar et al. J Am Chem Soc. .

Abstract

Most low-molecular-weight 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(NH 3) 2Cl 2(O 2CCH 2CH 2CO 2H)(O 2CCH 2CH 2CONH-PEG-FA)] ( 1), containing a folate derivative (FA) at an axial position, was prepared and characterized. Folic acid offers a means of targeting human cells that highly overexpress the folate receptor (FR). Compound 1 was attached to the surface of an amine-functionalized single-walled carbon nanotube (SWNT-PL-PEG-NH 2) 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 reduction of Pt(IV) to Pt(II). The ability of SWNT tethered 1 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 determined by platinum atomic absorption spectroscopy of cell extracts. Formation of the major cisplatin 1,2-intrastrand d(GpG) cross-links on the nuclear DNA was demonstrated by use of a monoclonal antibody specific for this adduct. The SWNT-tethered compound 1 is the first construct in which both the targeting and delivery moieties have been incorporated into the same molecule; it is also the first demonstration that intracellular reduction of a Pt(IV) prodrug leads to the cis-{Pt((NH 3) 2} 1,2-intrastrand d(GpG) cross-link in nuclear DNA.

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Figures

Figure 1
Figure 1
Folate receptor (FR) mediated targeting and SWNT mediated delivery of 1 by endocvtosis and structure of 1
Figure 2
Figure 2
Survival of FR(+) (a) JAR, (b) KB, and FR(−) (c) NTera-2 cells treated with 1 (■), SWNT-1 (▲), or cisplatin (●).
Figure 3
Figure 3
Fluorescence of 2 in (a) FR(+) KB and (b) FR(−) NTera-2 cells.
Figure 4
Figure 4
Visualization of Pt-1,2-d(GpG) intrastrand cross-links in the nuclear DNA of KB cells after treatment (b) SWNT-1 and (c) cis-DDP. (a) Immunofluorescence of untreated KB cells. Nuclei were stained with Hoechst (blue) and Pt-1,2-d(GpG) in DNA were visualized using Mab R-C18 (green).
Scheme 1
Scheme 1
Targeted prodrug-delivery system.
Scheme 2
Scheme 2
Synthetic route to 1.
Scheme 3
Scheme 3
Synthetic procedure for synthesizing 2.
Scheme 4
Scheme 4
Synthetic procedure for synthesizing SWNT-1.
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