Browsing by Subject "Photothermal Therapy"

Plasmonic nanoplatforms have fundamentally changed the landscape of biomedical sciences, particularly in the fields of early disease detection and treatment. Metallic nanoparticles with unique geometries and compositions such as gold nanostars (GNS) and nanorattles (NR) have allowed for the development of highly sensitive and effective platforms for detecting early disease biomarkers such as RNA without the need for laboratory-based sample amplification tools such as polymerase chain reaction (PCR). Furthermore, these plasmonics-active particles have also enabled novel optical methods for deep tissue tumor detection without the associated energy concerns and technical complexity of traditional imaging methods such as X-Ray computed tomography (CT) or magnetic resonance imaging (MRI). Finally, these particles can also be used for their effective photon to heat conversion capabilities for highly specific treatment of cancer tissue. The body of work described here is a culmination of several applications of plasmonic nanoparticles ranging from biomarker disease detection to deep tumor localization and photothermal treatment.

Recent advances in the of plasmonic nanoplatforms utilizing gold nanoparticles have resulted in many applications for point-of-care (POC) diagnostics. Upon laser excitation, the surface plasmons on the gold nanoparticles strongly oscillate, generating a strong electromagnetic field (EF) in the vicinity of the nanoparticle surface. This EF field enhancement, often referred to as the plasmonic effect, can be utilized to greatly increase the Raman scattering signal of molecules near the particle’s surface. This phenomenon called Surface-Enhanced Raman Scattering (SERS) can then be utilized for highly specific diagnostic and therapeutic applications. Our group has developed numerous biosensors that take advantage of this unique plasmonic property for use in non-invasive and non-amplifying biomarker detection. Due to its strong SERS signal, the ultrabright SERS nanorattles were developed as a unique sandwich hybridization biosensor for nucleic acid detection. We have demonstrated their successful use in detecting unamplified RNA genetic biomarkers of squamous cell carcinoma (SCC) for Head and Neck Cancers (HNCs) in a joint project with our clinical collaborator, Dr. Walter Lee, MD.

Nanoparticle platforms have also allowed for the development of novel optical and spectroscopic detection of deeply seated tumors. The unique spectroscopic fingerprint of SERS spectra on Raman-labelled GNS can be paired with optical techniques that separate the excitation laser source from the detector, which allows for deep tissue interrogation. approach This Surface-Enhanced Spatially Offset Raman Spectroscopy (SESORS) modality has allowed for the detection of GNS in tissue model systems such as through the centimeter-thick bone of a monkey skull. This spatial offset detection mechanism was further developed into a more general system known as Optical Recognition of Constructs using Hyperspectral Imaging and Detection (ORCHID). This system takes advantage of the two-dimensional charge-coupled detection (CCD) system itself as a means of physical separation between the source and detector, and by binning pixels of specific radial distances, a novel and digital-based spatial offset system can be utilized for probing deep tissue layers.

Finally, nanoparticles are utilized for the improved and highly targeted treatment of cancer tissue by taking advantage of the enhanced permeation and retention (EPR) effect in tumors. The photothermal heat treatment with GNS allows for highly specific targeted treatment of tumor, thereby minimizing off-target healthy tissue heating. We have demonstrated this in a brain tumor in a mouse model in a collaborative project with our clinical collaborator Dr. Peter Fecci, MD. We have also developed several simulation models utilizing Monte Carlo Photon propagation as well as analytical thermal diffusion models to demonstrate this effect in tissue containing GNS accumulated in a tumor volume. These simulations were then complemented with experimental studies showing the extent of heat using MRI heat imaging and direct contact thermocouples.

Bladder cancer has been ranked as one of the top ten and top twenty most commonly occurring cancers in men and women, respectively, with approximately half of the diagnoses being late stage and/or metastatic disease. The current standard-of-care treatment for metastatic bladder cancer is cisplatin-based chemotherapy, but only about 60% of patients qualify for this treatment option and the remaining cohort have few alternatives available. In fact, the only widely considered alternative is immune checkpoint blockades, or immunotherapies, which work to reactivate inhibited functions of immune cells. Unfortunately, these alone have not proven effective against metastatic malignancies. We believe that we can enhance the effects of clinically available immunotherapies with the addition of nanostar mediated photothermal therapy to the primary tumor. In fact, this combination of anti-PD-L1 immune checkpoint blockade and gold nanostar mediated photothermal therapy, henceforth called SYnergistic iMmuno PHOtothermal NanotherapY (SYMPHONY), was previously tested in a pilot study where C57BL/6 mice were injected with MB49 bladder cancer cells at two locations. One of the sites was treated with one of five treatments and the second remained untreated. Both tumor volumes were measured over time and the survival of the mice was also documented. This study resulted in one of the five SYMPHONY mice having complete tumor control after treatment and no other treatment group had this outcome. Upon rechallenge of the same tumor cell line, a tumor did not grow suggesting long-term immunity to this cancer. Along with a proof of concept, these studies were successful in identifying that macrophages and T-cells are associated with the tumor eradication. However, there is still little known about the quantification of the immune response at the distant tumor site after treatment. Our long-term goal is to develop an effective alternative treatment option for patients with metastatic bladder cancer. The overall objective of this application was to quantify the immune response of transgenic mice with fluorescent reporter genes on monocytes, natural killer cells, and dendritic cells undergoing one of four treatments (SYMPHONY, photothermal therapy alone (GNS), immunotherapy alone (anti-PD-L1) or no treatment (control)) as well as identify time points within the week following therapy in which additional studies could be conducted. Our central hypothesis was that mice treated with SYMPHONY would exhibit an elevated immune cell infiltration at the site of the distant tumor within ~48 hours post treatment, and that SYMPHONY will induce a greater immune response at the distant tumor site compared to anti-PD-L1 alone. This hypothesis was tested by implanting a primary flank tumor and a smaller, untreated distant tumor in 14 mice. The distant tumor cells were first stained with a far-red DiD fluorescent dye before injection into the center of a dorsal skinfold window chamber. The primary tumors were treated with one of the four treatment modalities and the window chamber was imaged using intravital microscopy for 7 days after the treatment. From this study, we found that the greatest change in the immune signal for any group occurred in the SYMPHONY group on the day of treatment and this immune signal remained elevated throughout the 7-day imaging period. This change was greater than all other treatment groups, including the anti-PD-L1 group, therefore, we accept our hypothesis. Further work should focus on assessing the immune response in mice on the day of treatment, looking at other immune cell types and by quantifying the effects of laser treatment on this day. It is noted that using the immune signal surrounding the distant tumor to predict an immune response within the tumor requires imaging at intervals more frequent than every 24 hours because of estimated macrophage travel velocity in tissue, where a more suitable frequency would be every 1.5-2 hours.