Polyvalent oligonucleotide gold nanoparticle conjugates as delivery vehicles for platinum(IV) warheads.
Amine-functionalized polyvalent oligonucleotide gold nanoparticles (DNA-Au NPs) were derivatized with a cisplatin prodrug, and the resulting DNA-Au NP conjugates were used to internalize multiple platinum centers. A platinum(IV) complex, c,c,t-[Pt(NH(3))(2)Cl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)], was tethered to the surface of DNA-Au NPs through amide linkages. The platinum-tethered gold nanoparticles were taken into several cancer cells. The drop in intracellular pH facilitated reductive release of cisplatin from the prodrug, which then formed 1,2-d(GpG) intrastrand cross-links in the cell nuclei, as confirmed by an antibody specific for this adduct. The cytotoxicity of the platinum(IV) complex increases significantly in several cancer cell lines when the complex is attached to the surface of the DNA-Au NPs and in some instances exceeds that of cisplatin.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Shanta
S
Dhar
Weston L
WL
Daniel
David A
DA
Giljohann
Chad A
CA
Mirkin
Stephen J
SJ
Lippard
D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry
D004337:Drug Carriers; D009841:Oligonucleotides; D011355:Prodrugs; D010984:Platinum; D006046:Gold; D004247:DNA