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Mol Cancer Ther. 2018 Nov;17(11):2377-2388. doi: 10.1158/1535-7163.MCT-17-1090. Epub 2018 Aug 10.

iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer.

Lo JH#1,2, Hao L#1,2, Muzumdar MD1, Raghavan S3,4,5, Kwon EJ1, Pulver EM1, Hsu F1, Aguirre AJ3,4,5, Wolpin BM3,5, Fuchs CS6, Hahn WC3,4,5, Jacks T1,7, Bhatia SN8,2,3,4,7,9.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts.
2
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.
3
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
4
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Yale Cancer Center, New Haven, Connecticut.
7
Howard Hughes Medical Institute, Cambridge, Massachusetts.
8
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts. sbhatia@mit.edu.
9
Marble Center for Cancer Nanomedicine, Massachusetts Institute of Technology, Cambridge, Massachusetts.
#
Contributed equally

Abstract

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 αvβ3/5 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. Mol Cancer Ther; 17(11); 2377-88. ©2018 AACR.

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