Re-engineered theranostic gold nanoparticles for targeting tumor hypoxia

Developing nanovehicles for selective delivery of a radiation dose/drug to hypoxic tumors is a present-day clinical requirement for effective treatment of cancer. Herein, we describe our attempt to re-engineer the earlier reported lipoic acid-capped Lu-177-labeled nitroimidazole-decorated gold nanoparticles to favorably modulate their pharmacokinetics to reduce uptake in the reticuloendothelial system while retaining the uptake in tumors. Towards this, gold nanoparticles with PEG-chains terminated with 2-nitroimidazole and Bz-DOTA were synthesized [(DOTA)AuNP-PEG-2K-(2-NIM)]. Surface modification of the gold nanoparticles with PEG-2K and 2-nitroimidazole was confirmed through infrared spectroscopy. The conjugation of Bz-DOTA on the nanoparticle surface was confirmed by UV-Vis spectroscopy, which showed a peak at 260-280 nm corresponding to Bz-DOTA. The DLS analysis of gold nanoparticles showed an effective hydrodynamic diameter of 28.9 +/- 1.50 nm with a zeta potential value of -20.62 +/- 0.05 mV at pH 7.4. The nanoparticles were radiolabeled with lutetium-177 with >98% radiochemical purity. In vitro studies using radiolabeled nanoparticles ([Lu-177]Lu-(DOTA)AuNP-PEG-2K-(2-NIM)) in CHO cells showed their 2-fold uptake under hypoxic conditions (at 4 h post incubation) compared to the radiolabeled nanoparticles without nitroimidazole units. The hypoxia selective uptake of the nanoparticles was further confirmed by flow cytometry using a fluorescent analogue (DOTA)AuNP-PEG-2K-(2-NIM)(FITC). It was, however, observed that hypoxic cell uptake of the PEG-2K capped nanoparticles was lower than that of their lipoic acid capped counterpart. In vivo biodistribution studies in tumor bearing Swiss mice demonstrated that PEGylation of nanoparticles could significantly reduce the uptake in the RES while retaining uptake in tumors albeit to a lesser extent.