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Supplemental Video 1. Intravital imaging of iRGD TPNs in a xenograft model of pancreatic cancer from iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer

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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

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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.

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