iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer
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 appro...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for Cancer Research (AACR)
2020
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| Online Access: | https://hdl.handle.net/1721.1/128731 |
| _version_ | 1826191252096286720 |
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| author | Lo, Justin H. Hao, Liangliang Muzumdar, Mandar Raghavan, Srivatsan Kwon, Ester Pulver, Emilia M Hsu, Felicia Aguirre, Andrew J. Wolpin, Brian M. Fuchs, Charles S. Hahn, William C. Jacks, Tyler E Bhatia, Sangeeta N |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Lo, Justin H. Hao, Liangliang Muzumdar, Mandar Raghavan, Srivatsan Kwon, Ester Pulver, Emilia M Hsu, Felicia Aguirre, Andrew J. Wolpin, Brian M. Fuchs, Charles S. Hahn, William C. Jacks, Tyler E Bhatia, Sangeeta N |
| author_sort | Lo, Justin H. |
| collection | MIT |
| description | 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 a v b 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. |
| first_indexed | 2024-09-23T08:53:20Z |
| format | Article |
| id | mit-1721.1/128731 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:53:20Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1287312022-09-30T11:55:41Z iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer Lo, Justin H. Hao, Liangliang Muzumdar, Mandar Raghavan, Srivatsan Kwon, Ester Pulver, Emilia M Hsu, Felicia Aguirre, Andrew J. Wolpin, Brian M. Fuchs, Charles S. Hahn, William C. Jacks, Tyler E Bhatia, Sangeeta N Massachusetts Institute of Technology. Institute for Medical Engineering & Science Koch Institute for Integrative Cancer Research at MIT 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 a v b 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. NCI (Grants P30-CA14051 and U54CA151884) NIH/NIGMS (Grant MSTP T32GM007753) 2020-12-04T20:40:05Z 2020-12-04T20:40:05Z 2018-08 2018-03 2020-12-02T17:36:01Z Article http://purl.org/eprint/type/JournalArticle 1535-7163 1538-8514 https://hdl.handle.net/1721.1/128731 Lo, Justin H. et al. "iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer." Molecular Cancer Therapeutics 17, 11 (August 2018): 2377–88 © 2018 American Association for Cancer Research. en http://dx.doi.org/10.1158/1535-7163.mct-17-1090 Molecular Cancer Therapeutics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Lo, Justin H. Hao, Liangliang Muzumdar, Mandar Raghavan, Srivatsan Kwon, Ester Pulver, Emilia M Hsu, Felicia Aguirre, Andrew J. Wolpin, Brian M. Fuchs, Charles S. Hahn, William C. Jacks, Tyler E Bhatia, Sangeeta N iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer |
| title | iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer |
| title_full | iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer |
| title_fullStr | iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer |
| title_full_unstemmed | iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer |
| title_short | iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer |
| title_sort | irgd guided tumor penetrating nanocomplexes for therapeutic sirna delivery to pancreatic cancer |
| url | https://hdl.handle.net/1721.1/128731 |
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