Targeting pancreatic cancer stem cells via Anti-RON Immunoliposomes

dc.contributor.committeeChairWang, Ming-Hai
dc.contributor.committeeMemberAhsan, Fakhrul
dc.contributor.committeeMemberSrivastava, Sanjay
dc.contributor.committeeMemberWeidanz, Jon
dc.creatorPadhye, Snehal -- Pharmaceutical Sciences
dc.description.abstractCancer stem cells (CSC) contribute to pancreatic cancer tumorigenesis through tumor initiation, drug resistance, and metastasis. Currently, therapeutics targeting pancreatic CSC are under intensive investigation. This study tested a novel strategy that utilizes RON receptor as a drug delivery moiety for increased therapeutic activity against pancreatic CSC. CD24+CD44+ESA+ triple-positive pancreatic CSC (CSC+24/44/ESA) were obtained from spheroids of pancreatic L3.6pl cancer cells by sequential magnetic cell sorting method. These cells displayed typical spheroid growth pattern, expressed unique self-renewal marker Bmi-1, re-differentiated into an epithelial phenotype, acquired an epithelial to mesenchymal phenotype, and caused tumor formation in animal model. Among several receptor tyrosine kinases examined, RON was highly expressed and sustained by CSC+24/44/ESA. This feature provided the cellular basis for validating the therapeutic effectiveness of anti-RON antibody Zt/c9-directing doxorubicin-immunoliposomes (Zt/c9-Dox-IL). Zt/c9-Dox-IL specifically interacted with CSC+24/44/ESA and rapidly caused RON internalization, which led to uptake of liposomal doxorubicin. Moreover, Zt/c9-Dox-IL was effective in reducing viability of L3.6pl cells and CSC+24/44/ESA. The IC50 values between free Dox (62.0±3.1 μM) and Zt/c9-Dox-IL (95.0 ±6.1 μM) treated CSC+24/44/ESA were at relatively comparable levels. In addition, Zt/c9-Dox-IL in combination with small molecule inhibitors lapatinib, sunitinib, or dasatinib further reduced viability of CSC+24/44/ESA. In conclusion, RON expression by CSC+24/44/ESA is a suitable molecule for targeted delivery of chemoagents. Thus anti-RON antibody-directed delivery of chemotherapeutics is effective in reducing viability of pancreatic CSC
dc.subjectStem cells
dc.subjectDrug delivery devices
dc.titleTargeting pancreatic cancer stem cells via Anti-RON Immunoliposomes