Gold nanostars (GNS) have increasingly seen usage in photothermal treatment of diseases such as cancer. Owing to their flexible synthesis, GNS can be easily tuned to absorption wavelengths that bypass the absorption of non-target tissue. The particles can also be easily coupled with other sensing modalities such as molecular imaging using surface-enhanced Raman spectroscopy (SERS) and Immunotherapy in a synergistic manner. We have developed a combination treatment for cancer therapy called Synergistic Immuno Photo Nanotherapy (SYMPHONY) effectively uses photothermal heating as an adjunct treatment with immune check-point inhibitors. Here we develop several methods to simulate and analyze the optical and thermal effects of GNS absorption. In particular, the optimal conditions of GNS heating are investigated for understanding specific targeted therapy with limitations surrounding tissue absorption.
Surface-enhanced Raman scattering (SERS) is emerging as an alternative non-invasive detection method in many applications. We recently show the use of SERS nanoprobes to detect tumors in vivo in mice, as well as the use of SERS sensors in vivo in plants for the detection of mIRNA. In spite of these advancements, the translation of SERS to real-world settings has been limited due to issues with observing Raman signal over complex background. For example, it remains challenging to observe SERS under sunlight or under strong illumination (e.g., operating room), using a conventional Raman setup. To this end, we combined a Raman setup with a newly developed dual-wavelength laser to perform shifted-excitation Raman difference spectroscopy (SERDS). Using SERDS, we demonstrate that the use of SERS sensors to detect miRNA in live plants inside a growth chamber, under full illumination. Additionally, we show that SERDS can be used to accurately identify tumors in mice, under ambient light. In both these applications, we demonstrate that the combination of SERS with SERDS improves the sensitivity and accuracy. This work will aid the translation of Raman and SERS to real-world settings.
The discovery of new treatments for cancer is imperative. Recently, we showed in a proof-of-concept study that SYnergistic IMmuno PHOtothermal NanotherapY (SYMPHONY) is a powerful treatment for metastatic bladder cancer and brain tumor in mouse models. Our work has recently demonstrated that combining immunotherapy checkpoint inhibitors and gold nanostar (AuNS) photothermal therapy (PTT) is more effective in killing primary tumors and activating the immune system to eradicate tumors at distant sites, than each individual treatment alone. When the tumor is being ablated via PTT in mice models, using low intensity heat from a near infrared laser, the dying tumor releases proteins that trigger the immune system to destroy remaining tumor cells. Immune checkpoint inhibitors prevent the tumor cells from hiding from the immune system’s mechanisms; thus, the immune system becomes capable of attacking distant secondary tumors, after the primary tumor has been eradicated using AuNS mediated PTT. The data shows that after the cured mice were rechallenged with bladder cancer cells, no tumor formation was observed after 60 days; hence these results indicate that the SYMPHONY treatment can function as a cancer vaccine and lead to long-lasting immunity.
Biocompatible gold nanostars (GNS) with tip-enhanced electromagnetic and optical properties have been developed and applied for multifunctional cancer diagnostics and therapy (theranostics). Their multiple sharp branches acting like “lightning rods” can convert safely and efficiently light into heat. As with other nanoparticles, GNS sizes can be controlled so that they passively accumulate in tumors due to the enhanced permeability and retention (EPR) effect of tumor vasculature. This feature improves tumor-targeting precision and permits the use of reduced laser energy required to destroy the targeted cancer cells. The ability to selectively heat tumor areas where GNS are located while keeping surrounding healthy tissues at significantly lower temperatures offers significant advantages over other thermal therapies. GNS-mediated photothermal therapy combined with checkpoint immunotherapy was shown to reverse tumor-mediated immunosuppression, leading to the treatment of not only primary tumors but also cancer metastasis as well as inducing effective long-lasting immunity, i.e. an anticancer ‘vaccine’ effect.
Surface-enhanced Raman scattering (SERS) provides a non-destructive sensing method with high sensitivity and multiplex detection capability since SERS takes advantage of high enhancement from surface plasmon resonance and unique “fingerprint” spectral signature using Raman spectroscopy. Our group has developed a unique plasmonics-active nanoparticle, gold nanostars, with tunable plasmonics in near-infrared (NIR) “tissue optical window” without using toxic surfactant. We present their applications for chemical and biological sensing with SERS method as well as theoretical studies to investigate and confirm experimentally measured SERS results.
Cancer has become one of most significant death reasons and causes approximately 7.9 million human deaths worldwide each year. The challenge to detect cancer at an early stage makes cancer-related biomarkers sensing attract more and more research interest and efforts. Surface-enhanced Raman scattering (SERS) provides a promising method for various biomarkers (DNA, RNA, protein, et al.) detection due to its high sensitivity, specificity and capability for multiple analytes detection. Raman spectroscopy is a non-destructive photon-scattering technique, which provides molecule-specific information on molecular vibrational energy levels. SERS takes advantage of plasmonic effects and can enhance Raman signal up to 1015 at “hot spots”. Due to its excellent sensitivity, SERS has been capable of achieving single-molecule detection limit. Local pH environment has been identified to be a potential biomarker for cancer diagnosis since solid cancer contains highly acidic environments. A near-infrared (NIR) SERS nanoprobe based on gold nanostars for pH sensing is developed for future cancer detection. Near-infrared (NIR) light is more suitable for in vivo applications because of its low attenuation rate and tissue auto fluorescence. SERS spectrum of pH reporter under various pH environments is monitored and used for pH sensing. Furthermore, density functional theory (DFT) calculation is performed to investigate Raman spectra changes with pH at the molecular level. The study demonstrates that SERS is a sensitive tool to monitor minor molecular structural changes due to local pH environment for cancer detection.
Nanotechnology provides tremendous biomedical opportunities for cancer diagnosis, imaging, and therapy. In contrast to
conventional chemotherapeutic agents where their actual target delivery cannot be easily imaged, integrating imaging
and therapeutic properties into one platform facilitates the understanding of pharmacokinetic profiles, and enables
monitoring of the therapeutic process in each individual. Such a concept dubbed “theranostics” potentiates translational
research and improves precision medicine. One particular challenging application of theranostics involves imaging and
controlled delivery of nanoplatforms across blood-brain-barrier (BBB) into brain tissues. Typically, the BBB hinders
paracellular flux of drug molecules into brain parenchyma. BBB disrupting agents (e.g. mannitol, focused ultrasound),
however, suffer from poor spatial confinement. It has been a challenge to design a nanoplatform not only acts as a
contrast agent but also improves the BBB permeation. In this study, we demonstrated the feasibility of plasmonic gold
nanoparticles as both high-resolution optical contrast agent and focalized tumor BBB permeation-inducing agent. We
specifically examined the microscopic distribution of nanoparticles in tumor brain animal models. We observed that
most nanoparticles accumulated at the tumor periphery or perivascular spaces. Nanoparticles were present in both
endothelial cells and interstitial matrices. This study also demonstrated a novel photothermal-induced BBB permeation.
Fine-tuning the irradiating energy induced gentle disruption of the vascular integrity, causing short-term extravasation of
nanomaterials but without hemorrhage. We conclude that our gold nanoparticles are a powerful biocompatible contrast
agent capable of inducing focal BBB permeation, and therefore envision a strong potential of plasmonic gold
nanoparticle in future brain tumor imaging and therapy.
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