Posters
Presenting Author Academic/Professional Position
Staff
Discipline/Specialty (Author 1)
Immunology and Microbiology
Discipline/Specialty (Author 2)
Immunology and Microbiology
Discipline/Specialty (Author 3)
Immunology and Microbiology
Discipline/Specialty (Author 4)
Immunology and Microbiology
Discipline/Specialty (Author 5)
Immunology and Microbiology
Presentation Type
Oral Presentation
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Pancreatic cancer (PanCa) is characterized by a lack of early diagnosis, poor response to available therapeutic modalities, and chemoresistance. Gemcitabine (GEM) is currently considered the most effective therapy for PanCa; however, it shows only a marginal survival benefit of 6 months. This poor drug response has been attributed to desmoplasia, causes suboptimal drug delivery, alters tumor microenvironment (TME), which includes tumor surrounding blood vessels, fibroblasts, immune cells, extracellular matrix, and other signaling molecules and induces chemo-resistance in tumors. To overcome these existing issues associated with chemotherapy, the identification and development of novel therapeutic modalities are a pressing need. Piperlongumine (PL) is a natural alkaloid isolated from the long pepper, Piper longum L., and has shown substantial cancer-preventive and therapeutic efficacy against various cancers. However, delivering its effective concentration in pancreatic tumors has been challenging. We have recently engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized, and poly-L-lysine coated piperlongumine loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PLGA-PL), which effectively inhibits the growth of PanCa cells. This study demonstrates that PLGA-PL effectively sensitizes tumor cells to GEM via decreased desmoplasia, altered TME, SHH/CXCL12/CXCR4, and immune surveillance. Our findings show that PLGA-PL synergizes with GEM in inhibiting PanCa cell (HPAF-II and Panc-1) growth, migration, and invasion compared to free PL. Mechanistically, PLGA-PL targets the TME by inhibiting the sonic hedgehog (SHH) pathway and oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cell interaction. We have also found that PLGA-PL alone and in combination with GEM targets cancer stem cells by inhibiting pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc, CD133, and Oct-4) as determined by qRT-PCR, Western blotting, and immunofluorescence analysis, and further confirmed by restricting tumor sphere formation. Furthermore, PLGA-PL also effectively targets tumor-associated macrophages (TAM) by repolarizing M2 into M1 phenotype via inhibiting the expression of M2 markers and an increase in M1 markers in mouse macrophage cell line RAW264.7. M2 polarization of RAW264.7 cells was induced by culture with IL-4 (20 ng/mL) in the presence of PLGA-PL or vehicle control. In addition, PLGA-PL effectively increases phagocytic capacity in murine macrophages as determined by phagocytosis assay (Vybrant Phagocytosis Assay Kit). In conclusion, we observed that PLGA-PL effectively targets TME and facilitates GEM uptake by inhibiting the activation of CXCR4/CXCL12/SHH signaling and reprograming tumor immune surveillance. This study suggests that PLGA-PL has great potential for future clinical use in the management of PanCa.
Recommended Citation
Kashyap, Vivek K.; Mandes, Reinaldo; Chauhan, Neeraj; Zubieta, Daniel; Sikander, Mohammed; Ghali, Eswara N.H.K; Hafeez, Bilal B.; Yallapu, Murali M.; and Chauhan, Subhash C., "Novel nanoformulation of piperlongumine attenuates pancreatic tumor desmoplasia and modulates tumor immune responses" (2025). Research Symposium. 133.
https://scholarworks.utrgv.edu/somrs/2025/posters/133
Included in
Biology Commons, Biotechnology Commons, Laboratory and Basic Science Research Commons, Medicine and Health Sciences Commons
Novel nanoformulation of piperlongumine attenuates pancreatic tumor desmoplasia and modulates tumor immune responses
Pancreatic cancer (PanCa) is characterized by a lack of early diagnosis, poor response to available therapeutic modalities, and chemoresistance. Gemcitabine (GEM) is currently considered the most effective therapy for PanCa; however, it shows only a marginal survival benefit of 6 months. This poor drug response has been attributed to desmoplasia, causes suboptimal drug delivery, alters tumor microenvironment (TME), which includes tumor surrounding blood vessels, fibroblasts, immune cells, extracellular matrix, and other signaling molecules and induces chemo-resistance in tumors. To overcome these existing issues associated with chemotherapy, the identification and development of novel therapeutic modalities are a pressing need. Piperlongumine (PL) is a natural alkaloid isolated from the long pepper, Piper longum L., and has shown substantial cancer-preventive and therapeutic efficacy against various cancers. However, delivering its effective concentration in pancreatic tumors has been challenging. We have recently engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized, and poly-L-lysine coated piperlongumine loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PLGA-PL), which effectively inhibits the growth of PanCa cells. This study demonstrates that PLGA-PL effectively sensitizes tumor cells to GEM via decreased desmoplasia, altered TME, SHH/CXCL12/CXCR4, and immune surveillance. Our findings show that PLGA-PL synergizes with GEM in inhibiting PanCa cell (HPAF-II and Panc-1) growth, migration, and invasion compared to free PL. Mechanistically, PLGA-PL targets the TME by inhibiting the sonic hedgehog (SHH) pathway and oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cell interaction. We have also found that PLGA-PL alone and in combination with GEM targets cancer stem cells by inhibiting pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc, CD133, and Oct-4) as determined by qRT-PCR, Western blotting, and immunofluorescence analysis, and further confirmed by restricting tumor sphere formation. Furthermore, PLGA-PL also effectively targets tumor-associated macrophages (TAM) by repolarizing M2 into M1 phenotype via inhibiting the expression of M2 markers and an increase in M1 markers in mouse macrophage cell line RAW264.7. M2 polarization of RAW264.7 cells was induced by culture with IL-4 (20 ng/mL) in the presence of PLGA-PL or vehicle control. In addition, PLGA-PL effectively increases phagocytic capacity in murine macrophages as determined by phagocytosis assay (Vybrant Phagocytosis Assay Kit). In conclusion, we observed that PLGA-PL effectively targets TME and facilitates GEM uptake by inhibiting the activation of CXCR4/CXCL12/SHH signaling and reprograming tumor immune surveillance. This study suggests that PLGA-PL has great potential for future clinical use in the management of PanCa.
