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posted on 2023-04-03, 16:03 authored by Justin H. Lo, Liangliang Hao, Mandar D. Muzumdar, Srivatsan Raghavan, Ester J. Kwon, Emilia M. Pulver, Felicia Hsu, Andrew J. Aguirre, Brian M. Wolpin, Charles S. Fuchs, William C. Hahn, Tyler Jacks, Sangeeta N. Bhatia Intravital imaging of a subcutaneous pancreatic cancer xenograft (MIA PaCa-2) showing distribution of PEGylated iRGD TPNs (green) in tumor cell compartments surrounding abnormal tumor blood vessels. Collagen visualized through second-harmonic generation is displayed in magenta. Images in this video were captured at a depth of 60 μm from the edge of the exposed tumor. Each frame of 0.25 sec represents 5 min of elapsed time, starting 3 minutes after injection of the particles. Please refer to Figure S5 for reference scale bar.
Funding
NCI
Lustgarten Foundation
National Institute of Environmental Health Sciences
Starr Foundation
Marie-D. & Pierre Casimir-Lambert Fund
MIT-Harvard Center of Cancer Nanotechnology Excellence
National Cancer Institute
Find out more...NIH/NIGMS
Dana-Farber Leadership Council
NIH
American Society of Clinical Oncology/Conquer Cancer Foundation
History
ARTICLE 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.
