Journal
MOLECULAR CANCER THERAPEUTICS
Volume 17, Issue 11, Pages 2377-2388Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-1090
Keywords
-
Categories
Funding
- Koch Institute Support Grant from the NCI [P30-CA14051]
- Lustgarten Foundation, a Core Center Grant from the National Institute of Environmental Health Sciences [P30-ES002109]
- Starr Cancer Consortium grant from the Starr Foundation
- Marie-D. & Pierre Casimir-Lambert Fund
- MIT-Harvard Center of Cancer Nanotechnology Excellence [NIH U54CA151884]
- Marble Center for Cancer Nanomedicine
- NCI [U01 CA176058]
- NIH/NIGMS [MSTP T32GM007753]
- Ludwig Fellowship for metastasis research
- Koch Institute Quinquennial Cancer Research Fellowship
- NIH [T32 CA009172]
- American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award
- Hope Funds for Cancer Research Postdoctoral Fellowship
- Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research
- Perry S. Levy Endowed Fellowship
- Harvard Catalyst and Harvard Clinical and Translational Science Center [UL1 TR001102]
- Pancreatic Cancer Action Network Samuel Stroum Fellowship
- American Society of Clinical Oncology Young Investigator Award
- Dana-Farber Leadership Council
Ask authors/readers for more resources
Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with alpha(v)beta(3/5) integrins and neuropilin-1, we hypothesized that tandem peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer. (C) 2018 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available