Posters
Academic Level (Author 1)
Staff
Discipline/Specialty (Author 1)
Cancer and Immunology
Discipline Track
Translational Science
Abstract
Introduction: About 95% of tumor arises from epithelial cell lining ducts known to be pancreatic ductal adenocarcinomas, with less than 5-7% survival rate. Unfortunately, little progress has been seen in the outcomes of patients with PDAC as tumor develops high desmoplasia and chemo-resistance to chemotherapeutic drugs, such as gemcitabine (Gem). Immunotherapy has shown promising results in other cancers but limited response in pancreatic cancer due to desmoplasia and fibrotic tumor microenvironment. A recently identified mucin, MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas. Due to its high membrane expression, MUC13 may serve as an excellent target for PanCa treatment. Our recently published studies demonstrate a unique ability of our novel patented superparamagnetic iron oxide nanoparticles (SPIONS) of curcumin (Indian spice with high medicinal value) to inhibit desmoplasia and make the drug more bioavailable (1,2). Therefore, our objective is to conjugate SPION -curcumin with MUC13 antibody to directly target the pancreatic tumors and to improve immunotherapies by targeting tumor stroma.
Methodology: Patented SPION1 particle was used for loading curcumin and later conjugated with MUC13 for directly targeting the pancreatic tumor. We characterized (size, zeta potential, charge and Dynamic light scattering), optimized and validated the uptake (Prussian blue staining and flow cytometer) of the formulation in invitro using ASPC1, HPAF, Panc 1, Panc M13 cell lines. Targeting efficiency of MNP-Anti-MUC13 particles in Panc-1-M13 and Panc-1 pancreatic cancer cells was done by immunofluorescence using flow cytometer and confocal microscopy. Cells treated with formulation were investigated for effect on PDAC cells and desmoplasia using Western blotting, qPCR, and immunofluorescence.
Results: Our results demonstrate optimal particle size and zeta potential of SPION formulation. MUC13 conjugated SPIONS can efficiently internalize the PDAC cells and target immune checkpoint inhibitors, PDL-1 and CTLA4. MUC13-SPION formulation led to an enhanced uptake in MUC13 positive (MUC13+) PanCa cells as compared with MUC13 null (MUC13-) cells as demonstrated by immunofluorescence, Prussian blue staining and flow cytometry experiments. Interestingly, the formulation resulted in sustained delivery of CUR, enhanced inhibition of cell proliferation, migration and invasion in MUC13+ cells as compared with MUC13- cells, which suggests the targeting efficacy of the formulation. Additionally, the treatment of cells with the formulation inhibited the tumor spheroid formation and growth. The formulation softens up the tumors for therapies that can result in improved response to checkpoint immunotherapies.
Conclusion: This study indicates high therapeutic significance of MUC13-SPIONS for achieving pancreatic tumor specific delivery of drugs. Therefore, the efficient MUC13 conjugated SPION-curcumin can potentiate checkpoint immunotherapies, inhibit tumor growth and its progression. This study has a potential to reduce morbidity and mortality caused by the disease and improve survival in patients.
Presentation Type
Talk
Recommended Citation
Shaji, Poornima Devi; Martinez Bulnes, Ana; Dan, Nirnoy; Chauhan, Subhash C.; Khan, Sheema; and Yallapu, Murali M., "Development of Targeted Drug Delivery System To Improve Immunotherapy In Pancreatic Cancer" (2023). Research Colloquium. 34.
https://scholarworks.utrgv.edu/colloquium/presentation/poster/34
Included in
Cancer Biology Commons, Immunotherapy Commons, Nanomedicine Commons
Development of Targeted Drug Delivery System To Improve Immunotherapy In Pancreatic Cancer
Introduction: About 95% of tumor arises from epithelial cell lining ducts known to be pancreatic ductal adenocarcinomas, with less than 5-7% survival rate. Unfortunately, little progress has been seen in the outcomes of patients with PDAC as tumor develops high desmoplasia and chemo-resistance to chemotherapeutic drugs, such as gemcitabine (Gem). Immunotherapy has shown promising results in other cancers but limited response in pancreatic cancer due to desmoplasia and fibrotic tumor microenvironment. A recently identified mucin, MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas. Due to its high membrane expression, MUC13 may serve as an excellent target for PanCa treatment. Our recently published studies demonstrate a unique ability of our novel patented superparamagnetic iron oxide nanoparticles (SPIONS) of curcumin (Indian spice with high medicinal value) to inhibit desmoplasia and make the drug more bioavailable (1,2). Therefore, our objective is to conjugate SPION -curcumin with MUC13 antibody to directly target the pancreatic tumors and to improve immunotherapies by targeting tumor stroma.
Methodology: Patented SPION1 particle was used for loading curcumin and later conjugated with MUC13 for directly targeting the pancreatic tumor. We characterized (size, zeta potential, charge and Dynamic light scattering), optimized and validated the uptake (Prussian blue staining and flow cytometer) of the formulation in invitro using ASPC1, HPAF, Panc 1, Panc M13 cell lines. Targeting efficiency of MNP-Anti-MUC13 particles in Panc-1-M13 and Panc-1 pancreatic cancer cells was done by immunofluorescence using flow cytometer and confocal microscopy. Cells treated with formulation were investigated for effect on PDAC cells and desmoplasia using Western blotting, qPCR, and immunofluorescence.
Results: Our results demonstrate optimal particle size and zeta potential of SPION formulation. MUC13 conjugated SPIONS can efficiently internalize the PDAC cells and target immune checkpoint inhibitors, PDL-1 and CTLA4. MUC13-SPION formulation led to an enhanced uptake in MUC13 positive (MUC13+) PanCa cells as compared with MUC13 null (MUC13-) cells as demonstrated by immunofluorescence, Prussian blue staining and flow cytometry experiments. Interestingly, the formulation resulted in sustained delivery of CUR, enhanced inhibition of cell proliferation, migration and invasion in MUC13+ cells as compared with MUC13- cells, which suggests the targeting efficacy of the formulation. Additionally, the treatment of cells with the formulation inhibited the tumor spheroid formation and growth. The formulation softens up the tumors for therapies that can result in improved response to checkpoint immunotherapies.
Conclusion: This study indicates high therapeutic significance of MUC13-SPIONS for achieving pancreatic tumor specific delivery of drugs. Therefore, the efficient MUC13 conjugated SPION-curcumin can potentiate checkpoint immunotherapies, inhibit tumor growth and its progression. This study has a potential to reduce morbidity and mortality caused by the disease and improve survival in patients.