VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation
The availability of nanoparticles (NPs) to deliver small interfering RNA (siRNA) has significantly expanded the specificity and range of ‘druggable’ targets for precision medicine in cancer. This is especially important for cancers such as triple negative breast cancer (TNBC) for which there are no...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/6/1260 |
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| author | Shanshan Tan Zhihang Chen Yelena Mironchik Noriko Mori Marie-France Penet Ge Si Balaji Krishnamachary Zaver M. Bhujwalla |
| author_facet | Shanshan Tan Zhihang Chen Yelena Mironchik Noriko Mori Marie-France Penet Ge Si Balaji Krishnamachary Zaver M. Bhujwalla |
| author_sort | Shanshan Tan |
| collection | DOAJ |
| description | The availability of nanoparticles (NPs) to deliver small interfering RNA (siRNA) has significantly expanded the specificity and range of ‘druggable’ targets for precision medicine in cancer. This is especially important for cancers such as triple negative breast cancer (TNBC) for which there are no targeted treatments. Our purpose here was to understand the role of tumor vasculature and vascular endothelial growth factor (VEGF) overexpression in a TNBC xenograft in improving the delivery and function of siRNA NPs using in vivo as well as ex vivo imaging. We used triple negative MDA-MB-231 human breast cancer xenografts derived from cells engineered to overexpress VEGF to understand the role of VEGF and vascularization in NP delivery and function. We used polyethylene glycol (PEG) conjugated polyethylenimine (PEI) NPs to deliver siRNA that downregulates choline kinase alpha (Chkα), an enzyme that is associated with malignant transformation and tumor progression. Because Chkα converts choline to phosphocholine, effective delivery of Chkα siRNA NPs resulted in functional changes of a significant decrease in phosphocholine and total choline that was detected with <sup>1</sup>H magnetic resonance spectroscopy (MRS). We observed a significant increase in NP delivery and a significant decrease in Chkα and phosphocholine in VEGF overexpressing xenografts. Our results demonstrated the importance of tumor vascularization in achieving effective siRNA delivery and downregulation of the target gene Chkα and its function. |
| first_indexed | 2024-03-09T22:45:13Z |
| format | Article |
| id | doaj.art-2267f31d38b94590a7896d820d1eb352 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:45:13Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2267f31d38b94590a7896d820d1eb3522023-11-23T18:30:51ZengMDPI AGPharmaceutics1999-49232022-06-01146126010.3390/pharmaceutics14061260VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene DownregulationShanshan Tan0Zhihang Chen1Yelena Mironchik2Noriko Mori3Marie-France Penet4Ge Si5Balaji Krishnamachary6Zaver M. Bhujwalla7Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USADivision of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USAThe availability of nanoparticles (NPs) to deliver small interfering RNA (siRNA) has significantly expanded the specificity and range of ‘druggable’ targets for precision medicine in cancer. This is especially important for cancers such as triple negative breast cancer (TNBC) for which there are no targeted treatments. Our purpose here was to understand the role of tumor vasculature and vascular endothelial growth factor (VEGF) overexpression in a TNBC xenograft in improving the delivery and function of siRNA NPs using in vivo as well as ex vivo imaging. We used triple negative MDA-MB-231 human breast cancer xenografts derived from cells engineered to overexpress VEGF to understand the role of VEGF and vascularization in NP delivery and function. We used polyethylene glycol (PEG) conjugated polyethylenimine (PEI) NPs to deliver siRNA that downregulates choline kinase alpha (Chkα), an enzyme that is associated with malignant transformation and tumor progression. Because Chkα converts choline to phosphocholine, effective delivery of Chkα siRNA NPs resulted in functional changes of a significant decrease in phosphocholine and total choline that was detected with <sup>1</sup>H magnetic resonance spectroscopy (MRS). We observed a significant increase in NP delivery and a significant decrease in Chkα and phosphocholine in VEGF overexpressing xenografts. Our results demonstrated the importance of tumor vascularization in achieving effective siRNA delivery and downregulation of the target gene Chkα and its function.https://www.mdpi.com/1999-4923/14/6/1260choline kinasenanoparticlessiRNA deliverytriple negative breast cancervascularization |
| spellingShingle | Shanshan Tan Zhihang Chen Yelena Mironchik Noriko Mori Marie-France Penet Ge Si Balaji Krishnamachary Zaver M. Bhujwalla VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation Pharmaceutics choline kinase nanoparticles siRNA delivery triple negative breast cancer vascularization |
| title | VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation |
| title_full | VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation |
| title_fullStr | VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation |
| title_full_unstemmed | VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation |
| title_short | VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation |
| title_sort | vegf overexpression significantly increases nanoparticle mediated sirna delivery and target gene downregulation |
| topic | choline kinase nanoparticles siRNA delivery triple negative breast cancer vascularization |
| url | https://www.mdpi.com/1999-4923/14/6/1260 |
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