Abstract 5413: Double-targeted theranostic gold nanoparticles for treatment of brain tumors

Abstract

Abstract Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient but also nonspecific, thereby posing a major shortcoming in effective treatment of brain cancer. Photodynamic therapy (PDT) is a localized treatment modality, relying on both a photosensitizer and drug activation using a specific wavelength. The widespread use of PDT in brain tumor therapy has been partially hampered by non-targeted phototoxicity towards healthy tissue. The development of nanoparticles selectively targeted to cell surface receptors that can act as drug delivery vehicles is critical for improving the treatment and therapeutic responsiveness in inaccessible tumors, such as glioblastomas. Gold nanoparticles (Au NP) provide an excellent platform with a surface that can be tailored to attach biomolecules for targeted drug delivery and biocompatible coatings that can efficiently encapsulate the hydrophobic photosensitizer drug, Pc 4, thereby reducing off-site cytotoxicity. In this study, we demonstrate a novel double targeted, noncovalent Au NP drug delivery agent, which selectively delivers drugs to brain tumors for PDT. These double-targeted Au NPs loaded with Pc 4 have been compared with previously studied single targeted Au NPs. Hydrophobic Au NPs have been cap exchanged with mono- and bi-functional PEG linkers. Specific targeting of the PEGylated Au NPs to glioma cells is achieved by coupling receptor-binding peptides to the carboxyl moiety of the bi-functional PEG linker. Subsequently, hydrophobic Pc 4 is adsorbed in the PEG corona (mono-functional linker) to form Pc 4 loaded and targeted Au NPs. Packaging of Pc 4 within the PEG core impedes leaching of the drug into the extracellular environment and improves circulation in vivo. UV-Vis absorption measurements indicate encapsulation of Pc 4 within the PEGylated Au NPs. Hydrodynamic diameter of these agents lies well within the limits needed to cross the BBB as determined by dynamic light scattering. In vitro cell uptake studies in glioma cell lines, LN229 and U87, which express differential patterns of the epidermal growth factor (EGF) and transferrin (Tf) receptor targets, show a significant increase in cellular uptake and intracellular localization for double targeted conjugates as compared to either single targeted Au NPs. Titration studies have been carried out in cells to optimize delivery; the optimal concentration for double targeted Au NPs is 500 nM, half of the current clinical standard observed for single targeted Au NPs over the same period of incubation. In vivo imaging utilizing real time, longitudinal fluorescence in mice shows notable accumulation of these agents in the tumor. Co-localization of the targeted Au NPs in regions overexpressing EGF and Tf receptors has been validated by immunohistochemistry. Future experiments involve activation of Pc 4 by PDT after delivery by the double-targeted Au NPs and monitoring tumor cell death. Note: This abstract was not presented at the meeting. Citation Format: Suraj K. Dixit, Yun Zhu, Alfred Moore, Malcolm Kenney, Ann-Marie Broome. Double-targeted theranostic gold nanoparticles for treatment of brain tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5413. doi:10.1158/1538-7445.AM2014-5413