Signal Transducer and Activator of Transcription 3 (STAT3), a common oncogenic mediator, is constitutively activated in many types of human cancers and plays a critical role in tumor growth and cancer immune evasion. The focus of this dissertation is the delivery of STAT3 inhibitor cucurbitacins to tumors using polymeric nano-carriers for the inhibition of tumor growth and modulation of tumor-induced immunosuppression.
The anticancer and immunomodulatory activity of STAT3 inhibitor JSI-124 (cucurbitacin I) was studied in mice carrying B16 tumor. The results showed that JSI-124 + CpG or 7-acyl lipid A combination therapy modulated immunosuppression in tumor environment and generated superior anti-tumor effects compared to monotherapy. In further studies, a sensitive and reproducible liquid chromatography-mass spectroscopy (LC-MS) method was developed and validated for quantitative analysis of STAT3 inhibitor cucurbitacins in vitro and in biological samples. Moreover, nano-delivery systems based on poly(ethylene oxide)-block-poly(-caprolactone) (PEO-b-PCL) micelles and its analogues containing physically encapsulated cucurbitacin and poly(D,L -lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing chemically conjugated JSI-124 for the delivery of STAT3 inhibitor to tumor and dendritic cells (DCs) were developed and characterized. Polymeric micelles of different PCL based core structure were able to significantly increase the water solubility of STAT3 inhibitor cucurbitacins, and slow the rate of drug release by a diffusion dependent mechanism. The chemical structure of the micellar core was found to control the release rate of cucurbitacin from the micelles. PLGA NPs containing conjugated JSI-124, on the other hand, demonstrated a degradation dependent drug release profile over a 1-month period. Both nanoparticulate formulations exhibited potent anticancer and STAT3 inhibitory activity against B16 cancer. Moreover PLGA-JSI-124 NPs suppressed STAT3 activation in immunosuppressed p-STAT3highDCs and significantly improved their function in stimulating T cell proliferation in vitro. These findings show that JSI-124 esters of PLGA NPs can potentially provide a useful platform for JSI-124 delivery to tumor and its targeted delivery to DCs.
The results of this research not only proved the principle of STAT3 inhibition in tumors as an efficient intervention for enhancing the therapeutic efficacy of TLR ligand-based cancer immunotherapy, but led to development of nano-delivery systems with potential application in cancer chemo-and immunotherapy. / Pharmaceutical Sciences
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/634 |
| Date | 11 1900 |
| Creators | Molavi, Ommoleila |
| Contributors | Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences), Lai, Raymond (Department of Laboratory Medicine and Pathology), Suresh, Mavanur (Faculty of Pharmacy and Pharmaceutical Sciences), El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences), Anderson, Colin (Department of Surgery), Prakash, Satya (Department of Biomedical Engineering, Mcgill University) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Format | 3968283 bytes, application/pdf |
| Relation | Molavi et al, CSPS (2006), http://www.ualberta.ca/~csps/JPPS9_2/John_Samuel/MS_502.htm, Molavi et al, ELSEVIER (2008), http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2663961, Molavi et al, Nature (2008), http://www.nature.com/icb/journal/v86/n6/abs/icb200827a.html, Molavi et al, Informa, (2008), http://www.informahealthcare.com/doi/abs/10.1080/08923970802380452 |
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