NanoBioPhotonic Platforms for Nanotherapy and Nano-Imaging: Polymer-Encapsulated Metal Clusters, Plasmonic Nanosnakes, and Targeting Enhanced Nanosystems
McLean, Alan
2020
Abstract
Nanoparticle-based technology has reached a threshold where biocompatible NPs with controllable size, morphologies, and functionality are becoming widely fabricated and utilized. This dissertation evaluates new nanobiophotonic platforms for nanotherapy and nanoimaging applications, including polyacrylamide (PAAm)-encapsulated metal clusters, plasmonic nanosnakes, and RGD-targeted fluorescent 8-arm-peg NPs. We first examine biocompatible polyacrylamide (PAAm)-encapsulated Au25Capt18 metal nanoclusters (NCs) for applications in two-photon photodynamic therapy. We demonstrate highly efficacious in vitro two-photon PDT for these PAAm-Au25Capt18 NPs, exhibiting a tremendous enhancement in 2p-PDT-mediated cell death over one-photon PDT-mediated cell death. Furthermore, we show that as a new two-photon photodynamic agent, the Au25Capt18cluster, (a) has a two-photon cross-section 8x larger when compared to 5,10,15,20-Tetrakis(1-methyl-4-pyridinio)porphyrin tetra(p-toluenesulfonate) (TMPYP), the currently most used two-photon photosensitizer, (b) has modest reactive oxygen species (ROS) production (1%) under two-photon excitation, with the potential for this efficiency to be further improved, and (c) when embedded in hydrogel NPs it maintains its unique optical properties while achieving 100% higher tumor uptake and biocompatibility. Next, we fabricate and characterize highly linear plasmonic nanochains of gold nanospheres, which we call “nanosnakes”. These nanosnakes are self-assembled from bare Au nanosphere monomers with virgin surfaces, produced in DI water by laser ablation (a green, chemical-free synthesis). The nanosnakes have several highly desirable properties for biological imaging, including two plasmonic modes, one fixed mode at 525 nm (monomer mode) and a second highly tunable mode. The secondary tunable mode ranges from 590 nm to 640 nm, with tunability precision within 1-2 nm. Such tunability towards the infrared is a highly desirable property in plasmonic imaging, due to these photons’ deeper tissue penetration as well as due to their much reduced background cell fluorescence. We also show that the nanosnakes possess scattering cross-sections up to 40x higher than the Au nanosphere monomers (approximately 3x higher per chain monomer nanosphere), thus making them better contrast agents for imaging applications. Lastly, we demonstrate that the nanosnakes can be easily conjugated with active targeting moieties, for applications such as targeted cancer and heart disease phototherapy, using the RGD peptide as a model system; furthermore, we show that they are also non-toxic to cells, even at very high concentrations (> 0.25 mg/mL, OD 5.0). Overall, the nanosnakes represent a promising new imaging modality for dark-field, SERS, and high resolution microscopy, and have a high potential for in vivo theranostic applications. Lastly, we evaluate fluorescent 8-arm-peg NPs for their RGD-assisted targeting to the age-related macular degeneration (AMD) neovasculature. In vitro experiments reveal a strong, measurable difference between non-targeted and RGD targeted NPs, with the RGD targeted NPs showing nearly a 100 % increase in cellular uptake at the highest incubated NP concentration (3 mg/mL). In vivo experiments at high incubated PEG-RGD concentrations (20 mg/mL injections) show approximately 15-20% enhancement in targeting signal, when compared to non-RGD controls. Overall, we show that 8-arm PEG NPs are a new, readily conjugatable and targetable nanosystem for future optimized AMD diagnosis and therapy, with potential benefits for in vivo theranostic enhancement. Overall, this dissertation evaluates polyacrylamide (PAAm)-encapsulated metal clusters, plasmonic nanosnakes, and RGD-targeted fluorescent 8-arm-peg NPs. These nanobiophotonic platforms are biocompatible, deliverable in vitro and/or in vivo, and exhibit specialized utility, with clear advantages as a new nanomaterial in cancer therapy, plasmonic imaging, and/or disease targeting for applied nanotherapy and nanoimaging.Deep Blue DOI
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nanoscience photodynamic therapy plasmonics active targeting nanoparticle two-photon
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