Download 2016 department of medicine research day

2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: Co-administration of iRGD peptide enhances the efficacy of irinotecan
silicasome in KPC- and patient-derived pancreatic cancer mouse models
Presenter: Xiangsheng Liu
Division: Nanomedicine
☐Faculty ☐Fellow ☐Resident ☒Post-doc Research Fellow ☐Graduate Student ☐Medical Student ☐Other
Principal Investigator/Mentor: Andre E. Nel and Huan Meng Co-Investigators: Yanan Kang, Katie Rose Villabroza,
Paulina Lin, Ian Perrett, Yupei Liao, Chong Hyun Chang, Nanping Wu, Timothy Donahue, Erkki Ruoslahti
Thematic Poster Category:
Pharmacology and Drug Development
Abstract
Because pancreatic cancer (PDAC) is an incurable cancer with a 5-year survival rate of 6%, urgent
intervention is required to improve survival. GEM and FOLFIRINOX were approved in 1996 and early
2000s, respectively. No new therapy was approved until “nanomedicine” emerges. We have developed
a multifunctional lipid-coated mesoporous silica nanoparticle (LB-MSNP), which is now called
“Silicasome”. An irinotecan silicasome has been showed improved efficacy and safety over irinotecan
MM398 mimicking liposome (Onivyde®, developed by Merrimack) in PDAC treatment in our previous
study. Given this background, we hypothesize that active targeting could further enhance tumor
biodistribution and efficacy of our pre-clinically proven and PDAC-specific silicasome. Here, we
demonstrate an easy approach through the use of an iRGD peptide, which enhanced the
chemotherapeutic efficacy of chemo-delivery silicasome and inhibited PDAC metastases in a Kras
orthotopic PDAC mouse model. Electron tomography was used to capture the transportation of
silicasome, from the tumor blood vessel lumen  intermediary step during the transcytosis process in
endothelial cells  ultimately in tumor interstitium, an ultrastructural feature that has not previously
been accomplished. This provided the insight to the commentary tumor targeting mechanism that
tumor vascular endothelial cells displayed a network of tubular vesicles (a.k.a. the vesico-vacuolar
organelle or VVO), which controlled vascular access of nanocarriers. Because the targeting mechanism
is supposed to be the exposed “CendR” motif, upon cleavage from the iRGD peptide, interacts with
NRP-1 kinase receptor, which is capable of triggering transcytosis of nanocarriers. We continued to
demonstrate the contrasting effect of iRGD in patient derived PDAC models with high vs low NRP-1
levels, which conceptualized our personalized nano engineered approach for PDAC.