Plasmonic Nanostructures for Controlled Drug Delivery
Goodman, Amanda M
Halas, Naomi J
Doctor of Philosophy
Drug delivery and photothermal ablation based on resonant illumination of near-infrared-absorbing noble metal nanoparticles that have accumulated in tumors are highly promising cancer therapies. Crucial aspects of these therapies include the nanoparticle size and biocompatibility, and the ability to remotely trigger the release of therapeutic cargo, once the particles have relocated to the tumor site. Yet, maximizing tumor uptake, reducing non-specific toxicity, and achieving flexible drug loading and release strategies remain challenges in developing a nanocarrier system. Here, a class of nanoparticles known as hollow Au nanoshells (HGNS) is investigated because near-IR resonances are achievable in this system with diameters less than 100 nm. However, we report a surprising finding that in vivo HGNS are unstable, fragmenting with the Au and remnants of the sacrificial Ag core accumulating differently in various organs. Stability studies across a wide range of pH environments and in serum confirmed HGNS fragmentation. These results demonstrate the importance of tracking both materials of a galvanic replacement in biodistribution studies and of performing thorough nanoparticle stability studies prior to any intended in vivo applications. Using biocompatible nanoshells, near-IR light-induced DNA release was studied as a platform for controlled drug delivery wherein therapeutic drugs can be released from a DNA host. Yet, tailorability of this system is limited. Understanding the mechanism of DNA release will allow easier control of release for various molecular cargos. Our studies have shown that under irradiation by a continuous wave (CW) laser, nanoparticle heating, as opposed to hot electrons, is responsible for DNA dehybridization and is highly dependent on nanoparticle concentration, requiring the bulk solution temperature to rise above the DNA dehybridization temperature to induce release at particle concentrations feasible in tumors. Alternatively, DNA release due to femtosecond irradiation can be achieved by breaking the Au-S bond via a hot-electron transfer process without any considerable bulk temperature increase. This is critically important for cancer treatment, as the cellular environment is very sensitive to temperature fluctuations and nanoparticle uptake in tumors is highly variable. Remotely triggering release of host DNA with no bulk temperature increase can enable selective drug release, drastically reducing the nonspecific side effects of typical chemotherapy treatments. Intracellular light-triggered release of chemotherapy drugs was investigated using low levels of CW and pulsed NIR light from both DNA and protein scaffolds. The results showed a higher percent cytotoxicity for CW laser-induced release from a DNA scaffold. Using the protein scaffold, increased cytotoxicity was observed for release using pulsed light in cancerous cells, while non-cancerous cells were unaffected. These results show that light-triggered drug release is an effective non-toxic drug delivery vehicle to selectively kill cancers cells. Furthermore, by simply exchanging the chemotherapy drug, this system can be extended to treatments for many cancer types. Achieving the flexible loading and release strategies shown here will allow release to be more easily controlled and tailored for various chemotherapeutic drugs and cancer types.