Non-invasive imaging of early signs of inflammation of endocrine pancreas is of importance due to a generally late clinical diagnosis of type 1 diabetes (T1D). Seventy-80% of insulin producing beta-cells could be already lost prior to the onset of clinical symptoms. Therefore, monitoring these early changes including increased vascular permeability of pancreas and activation of pro-inflammatory signaling pathways will aid in early diagnosis and timing of therapy. We have developed and tested superparamagnetic nanoparticles (NPs) with strong photoacoustic signal for detecting potential permeability changes in the pancreas of streptozotocin (STZ)- induced mouse model of T1D. These biocompatible gold/iron-oxide NPs enable application of multi-modality photoacoustic (PA) and magnetic resonance (MR) imaging to investigate the extent of NP accumulation in the pancreas. In addition, we have investigated the spatial distribution of nanoparticles in the endocrine and exocrine of pancreas using electron microscopy techniques. Our initial time-dependent histology results demonstrate the influx of macrophages and neutrophils as the first responders to pancreatic damage as well as activation of the NF-ҡB signaling pathway, which plays a central role in the inflammation of the islets. We recorded a significantly stronger PA signal in the pancreas of STZ-treated mice compared to control mice, which indicate higher accumulation of the NPs in mice with chemically induced diabetes. The potential use of a combination of clinically available imaging modality (MRI) and emerging high-resolution/high sensitivity PA makes this approach feasible for clinical translation. Furthermore, the safety of these imaging modalities makes them ideal for both initial diagnosis of diabetes in individuals at risk of T1D and for longer term noninvasive monitoring of the response to therapy.

Glioblastoma Multiforme (GBM) is an aggressive cancer that originates from astrocytes and spreads to spinal cord and other parts of the brain. Increase in replication of glial cells leads to advantageous mutations in the tumor. According to the cancer statistics from 2015 about 15,320 deaths were reported due to GBM. Five-year survival is less than 5% making GBM a dreadful form of cancer. Current treatment involves complex invasive surgery, followed by chemotherapy and radiation. The goal of this study is to develop a combination therapy to treat GBM using Poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulated with two drugs namely gefitinib and GSK461364, each with a unique target. Gefitinib is a Tyrosine Kinase inhibitor, which competes for ATP-binding site of EGFR-TK. GSK461364 is a Polo-like Kinase (PLK-1) inhibitor that blocks the G2/M transition in tumor cell cycle. These distinct hydrophobic drugs are tested on U-87 MG (human malignant glioma) cell line. PLGA is attached to Polyethylene glycol (PEG), which is conjugated to transferrin receptor binding peptide. These transferrin peptides bind to transferrin receptors (TfR) or CD71 and enable the entry of PLGA-PEG nanoparticles across the Blood Brain Barrier (BBB). Results of characterization, TEM, SEM images, in vitro drug release profiles, stability, cytotoxicity assay, flow cytometry data of uptake of the nanoparticles will be presented.

Triple Negative Breast Cancer (TNBC) has the worst prognosis among all the sub-types of breast cancer. Currently no targeted treatment has been approved for TNBC management. While TNBC does not overexpress hormone receptors, it has been found to over express certain receptors like transferrin (TfR) or folate receptors. The aim of this research is to synthesize targeted polymeric nanoparticles for TNBC. MDA-MB-231 cells are used as a representative TNBC cell line in this study. Active targeting of TNBC is achieved by conjugating the nanoparticles to a peptide (Tr) that binds to the TfR. Photodynamic Therapy (PDT) using polymeric nanoparticles was explored for TNBC treatment. PDT utilizes a secondary form of targeting by remotely triggering benzoporphyrin derivative monoacid (BPD) using near infrared light. When irradiated at 690nm, BPD induces cytotoxicity via generation of reactive oxygen species. The polymeric nanoparticles were characterized for size, zeta potential, and drug release at 37°C. The morphology of the nanoparticles was confirmed using electron microscopy and cell uptake was monitored in vitro using fluorescent microscopy. PDT was carried out at 500nM BPD concentration using a 690nm laser. Cytotoxicity of these targeted polymeric nanoparticles was assessed using a standard colorimetric viability assay (MTT). The nanoparticles synthesized were fairly monodisperse and the release studies demonstrated sustained BPD release from the nanoparticles. Receptor mediated endocytosis of the active nanoparticles was studied by using FITC conjugated peptide and the FITC signal was observed using fluorescent microscopy. Stronger BPD fluorescent signal for the active targeting nanoparticles (PLGA-PEG-Tr) compared to the passive (PLGA-PEG) nanoparticles. Significant cell death following PDT was observed in all the treatment groups, which was also confirmed by imaging the cells post-treatment using standard live-dead stain. PDT is a fairly versatile and non-invasive form of treatment and using targeted nanoparticles it can be adapted for other drugs and diseases.

Glioblastoma Multiforme (GBM) is an aggressive cancer that originates from astrocytes and spreads to spinal cord and other parts of the brain. Increase in replication of glial cells leads to advantageous mutations in the tumor. In 2015 about 15,320 deaths were reported due to GBM. Five-year survival is less than 5% making GBM a dreadful cancer. Current treatment involves complex invasive surgery, followed by chemotherapy and radiation. There is a desperate unmet need for a targeted treatment of GBM with minimum damage to the surrounding normal tissue. Combination treatments are increasingly being used to target multiple hallmarks of cancer. The goal of this study is to develop a combination therapy to treat GBM using Poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulated with three different drugs namely gefitinib, temozolomide (TMZ) and GSK461364 each with a unique target. Nanoparticles facilitate combination of multiple drugs for simultaneous delivery to cancer cells in a single nano-sized platform. Gefitinib is a Tyrosine Kinase inhibitor, which competes for ATP-binding site of EGFR-TK. TMZ methylates DNA of tumor cells, resulting in apoptosis. GSK461364 is a Polo-like Kinase (PLK-1) inhibitor that blocks the G2/M transition in tumor cell cycle. These three distinct hydrophobic drugs are tested on U-87 MG (human malignant glioma) and MDA-MB-231 (triple negative breast cancer) cell lines. PLGA is attached to Polyethylene glycol (PEG), which is conjugated to transferrin receptor (TfR) binding peptide for targeting TfR overexpression, common in GBM. PEG is known to increase the circulation half-life in vivo and improves colloidal stability of nanoparticles. These transferrin peptides bind to TfR (or CD71) and enable the entry of PLGA across Blood Brain Barrier (BBB). Results of characterization, in vitro drug release profiles, stability at 37C and 4C, cytotoxicity assay, electron micrographs of nanoparticles containing drugs and fluorescent imaging will be presented.