The goal of the proposed research is to control the assembly and fabrication of discrete clusters of anisotropic gold nanostructures, UCNPs, and responsive polymer coatings to obtain ideal theranostics for the imaging and treatment of solid tumors. Theranostics represent an exciting area of cancer research because they allow noninvasive tracking of therapeutics into the tumor environment followed by tumor-specific release. Light in the tissue transparency window of 650-1000 nm can serve as an energy source to perform both of these functions. However, most IR-induced imaging and therapy requires light flux only available at superficial sites and thus cannot be applied to many other cancers. The proposed research will utilize the PIs' knowledge of photophysics, nanoscale assembly, and macromolecules for the rational design of NIR-utilizing nanostructures. The proposed theranostic will produce either visible image contrast or drug release, depending on irradiation intensity. The proposed nanostructures will consist of an anisotropic gold nanostructure for NIR maximum absorption, an upconverting nanoparticle (UCNP) for conversion to visible light, and a stimulus-responsive polymer coating to release drug molecules in response to irradiation. A nanostructure able to perform these functions at non-superficial depths requires both a fundamental understanding of the energy transfer processes occurring at the gold surface and the mechanisms by which this energy can be harvested. This will be accomplished through: 1. Synthesis of precise Au-UCNP nanostructures and characterization of photoluminescence. Recent theoretical studies have shown that local field enhancement can enhance upconverted luminescence output by orders of magnitude if the particles are assembled correctly. Biomolecular assembly techniques will be used to specifically position UCNPs at the tips of anisotropic Au nanorods (AuNRs) and nanostars (AuNSs) to maximize energy transfer. These structures will be validated using both single particle and ensemble luminescence measurements. 2. Synthesis of thermally-responsive and photodegradable polymers and evaluation of their responsiveness to NIR irradiation of Au-UCNP clusters. The deposition of IR energy at the surface of the Au nanostructures will be employed to facilitate drug delivery by surface-grafted polymers via either Au surface heating or generation of singlet oxygen. These studies will be performed using polymers capable of conformational switching or oxidative depolymerization, respectively. 3. Synthesis of optimized Au-UCNP-polymer theranostics and validation in in vitro models. The imaging and therapeutic capabilities of the optimized theranostics will be tested against 4T1 cells grown in a 3D Matrigel substrate to mimic both the structure and heterogeneity of the tumor environment.
One of the major challenges in the treatment of solid tumors is confining therapeutic efficacy to the tumor environment to deliver sufficient drug to the tumor while limiting side effects to the patient. Light-activated theranostics allow both tracking of dru circulation and initiation of chemotherapeutic action, but their efficacy is limited to tumor targes near the skin. The proposed research will develop new structures that can perform this function deeper below the skin, establishing this technology for many other cancer types.
| He, Liangcan; Mao, Chenchen; Brasino, Michael et al. (2018) TiO2-Capped Gold Nanorods for Plasmon-Enhanced Production of Reactive Oxygen Species and Photothermal Delivery of Chemotherapeutic Agents. ACS Appl Mater Interfaces 10:27965-27971 |
| Kumar, Kaushlendra; Castaño, Eduard Jimenez; Weidner, Andrew R et al. (2016) Depolymerizable Poly(O-vinyl carbamate-alt-sulfones) as Customizable Macromolecular Scaffolds for Mucosal Drug Delivery. ACS Macro Lett 5:636-640 |
