Development of nanoparticle-based approaches for the treatment and imaging of pancreatic cancer

1 online resource (193 pages) : PDF

2020

University of North Carolina at Charlotte

Pancreatic ductal adenocarcinoma (PDAC) is a type of exocrine pancreatic cancer which accounts for over 90% of cases. PDAC is the fourth-leading cause of cancer-related mortality in the United States with a 5-year survival rate of 9% with little to no change in the last 40 years. The high mortality and poor prognosis of PDAC can be attributed to multifactorial reasons including late diagnosis, intrinsic and acquired resistant behavior, early micrometastatic dissemination, desmoplastic effect, and heterogeneities in tumors, rendering the current treatments rather ineffective. Hence, it is imperative to focus on improved methods for the detection and treatment of PDAC. Mesoporous silica nanoparticles (MSN)-based modalities can be a promising approach for PDAC treatment, owing to their outstanding properties. Research in this Thesis focuses on the development of novel MSN-based modalities to address many of the drawbacks impeding the success of current PDAC therapies. In Chapter 2, MSNs were used to achieve high drug loading and provide synergistic co-delivery of Gem/cisPt. The MSN platform was functionalized with a novel tMUC1-specific antibody (TAB004) for targeted drug delivery. The TAB004-Gem-cisPt-MSNs showed increased accumulation in the tumors, which therapeutically outperformed the untargeted MSN material as well as free Gem/cisPt. The carrier design using chemical conjugation of drugs to MSNs along with stimuli-responsive behavior eliminated systemic drug release and off-target toxicities in KCM syngeneic mice. For Chapter 3, sequential therapy was designed to combat the stromal barrier via SHh inhibition using cyclopamine (CyP). The time-staggered sequential combination therapy of CyP-MSNs plus Gem-cisPt-MSNs showed increased tumor inhibition in aggressive HPAF II tumor-bearing mice and showed changes in the tumor stroma. Chapter 4 addresses the early diagnosis of PDAC which is essential to improve PDAC prognosis. In this direction, target specific TAB004-MSNs was used as an imaging and diagnostic probe. TAB004-MSNs demonstrated increased selectivity in tMUC1-expressing PDAC cells. More importantly, TAB004-MSNs could selectivity accumulate in the pancreas at an early PanIN lesion stage. The versatile uses of MSNs and their thorough investigation in KCM, syngeneic mice, HPAF II xenograft mice, and transgenic PDA.MUC1 mice demonstrate safety, bioimaging, and therapeutic performance of MSNs. Overall, the data in this Thesis provides evidence for successful multi-modal applications of MSNs and provides proof for the clinical translation of our platform.

doctoral dissertations

Nanoscience
Chemistry

Ph.D.

Cancer Therapy
Drug Delivery
Mesoporous Silica Nanoparticles
Pancreatic Cancer
Tumor Stroma

Chemistry

Vivero-Escoto, Juan

Mukherjee, Pinku
Dréau, Didier
Afonin, Kirill
Troutman, Jerry

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2020.

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