title: Investigation of the drug binding properties and cytotoxicity of DNA-capped nanoparticles designed as delivery vehicles for the anticancer agents doxorubicin and actinomycin D.
abstract: Oligonucleotide-functionalized gold nanoparticles (AuNP) were designed and synthesized to be delivery vehicles for the clinically used anticancer drugs doxorubicin (DOX) and actinomycin D (ActD). Each vehicle contains a tailorable number of DNA duplexes, each possessing three high-affinity sequences for the intercalation of either DOX or ActD, thus allowing for control of drug loading. Drug binding was evaluated by measuring changes to DNA melting temperature, T(m), hydrodynamic diameter, D(h), and surface plasmon resonance wavelength, λ(spr), with drug loading. These studies indicate that DOX intercalates at its high-affinity sequence bound at the AuNP, and that ActD exhibits relatively weaker binding to its preferred sequence. Agarose gel electrophoresis further confirmed drug binding and revealed that particle mobilities inversely correlate with D(h). The equilibrium binding constant, K, and dissociation rate constant, β, were determined by dialysis. Results indicate that the high negative electrostatic potential within the DNA shell of the particle significantly decreases β and enhances K for DOX but has little effect on K and β for ActD. The cytotoxicity of the vehicles was studied, with IC(50) = 5.6 ± 1.1 μM and 46.4 ± 9.3 nM for DOX-DNA-AuNP and IC(50) = 0.12 ± 0.07 μM and 0.76 ± 0.46 nM for ActD-DNA-AuNP, in terms of drug and particle concentrations, respectively.
authors.affiliation: Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY 13244-4100, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Alexander
authors.forename: James C
authors.initials: JC
authors.lastname: Dabrowiak
authors.forename: Mathew M
authors.initials: MM
authors.lastname: Maye
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D003609:Dactinomycin / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry*; D006046:Gold / Q000737:chemistry; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D009691:Nucleic Acid Denaturation; D044366:Transition Temperature
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D003609:Dactinomycin; D006046:Gold; D004317:Doxorubicin; D004247:DNA