Hairpin Oligonucleotide Can Functionalize Gold Nanorods for in Vivo Application Delivering Cytotoxic Nucleotides and Curcumin: A Comprehensive Study in Combination with Near-Infrared Laser.

Abstract

We prepared a multimodality nanocomplex by functionalizing gold nanorods (GNRs) with a cytotoxic nucleoside, 5-fluoro-2′-deoxyuridine (FdU) containing a DNA hairpin, along with complexation of pleiotropic molecule curcumin. Conjugates were investigated for anti-tumor activity using an Ehrlich carcinoma model in combination with 808 nm laser irradiation. We demonstrated that hairpin-functionalized GNRs are suitable for intravenous administration, including delivery of cytotoxic nucleotides and curcumin. Curcumin binding with FdU-hairpin-functionalized GNRs displayed improved anti-tumor activity in part by inducing a lymphocyte-mediated immune response. The complex showed notable photothermal activity in vitro; however, 808 nm laser irradiation of the tumor following treatment with the complex did not increase the anti-tumor effect significantly. Biodistribution studies depicted that the nanoconjugates localized primarily in the sinusoidal structures of the liver and spleen with minimal tumor accumulation. Curcumin complexation alleviated the reduction in the RBC count that was observed for the conjugate without curcumin, especially in combination with laser irradiation. Localization of FdU-hairpin-GNR conjugates in the liver and spleen evoked an inflammatory response, which was mitigated by curcumin complexation. However, no functional abnormality was found in the liver in any case. Curcumin binding also notably decreased nanoconjugate accumulation in lungs and significantly reduced inflammation. Biodistribution studies were consistent with previous reports, suggesting that optimization of the GNR size and surface coating is required for more efficient tumor localization via the enhanced permeability and retention (EPR) effect. Our studies demonstrate that DNA/RNA hairpins are suitable for GNR surface functionalization and enable delivery of cytotoxic nucleotides as well as curcumin in vivo with potential for synergistic anti-cancer therapy.