Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy
Lingegowda S. Mangala, … , David G. Gorenstein, Anil K. Sood
Lingegowda S. Mangala, … , David G. Gorenstein, Anil K. Sood
Published October 20, 2016
Citation Information: JCI Insight. 2016;1(17):e87754. https://doi.org/10.1172/jci.insight.87754.
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Research Article Angiogenesis Oncology

Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy

Abstract

Current antiangiogenesis therapy relies on inhibiting newly developed immature tumor blood vessels and starving tumor cells. This strategy has shown transient and modest efficacy. Here, we report a better approach to target cancer-associated endothelial cells (ECs), reverse permeability and leakiness of tumor blood vessels, and improve delivery of chemotherapeutic agents to the tumor. First, we identified deregulated microRNAs (miRs) from patient-derived cancer-associated ECs. Silencing these miRs led to decreased vascular permeability and increased maturation of blood vessels. Next, we screened a thioaptamer (TA) library to identify TAs selective for tumor-associated ECs. An annexin A2–targeted TA was identified and used for delivery of miR106b-5p and miR30c-5p inhibitors, resulting in vascular maturation and antitumor effects without inducing hypoxia. These findings could have implications for improving vascular-targeted therapy.

Authors

Lingegowda S. Mangala, Hongyu Wang, Dahai Jiang, Sherry Y. Wu, Anoma Somasunderam, David E. Volk, Ganesh L. R. Lokesh, Xin Li, Sunila Pradeep, Xianbin Yang, Monika Haemmerle, Cristian Rodriguez-Aguayo, Archana S Nagaraja, Rajesha Rupaimoole, Emine Bayraktar, Recep Bayraktar, Li Li, Takemi Tanaka, Wei Hu, Cristina Ivan, Kshipra M Gharpure, Michael H. McGuire, Varatharasa Thiviyanathan, Xinna Zhang, Sourindra N. Maiti, Nataliya Bulayeva, Hyun-Jin Choi, Piotr L. Dorniak, Laurence J.N. Cooper, Kevin P. Rosenblatt, Gabriel Lopez-Berestein, David G. Gorenstein, Anil K. Sood

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Figure 3

Delivery of CH/Endo28-NPs to tumor vasculature.

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Delivery of CH/Endo28-NPs to tumor vasculature. Tumors and organs were h...
Tumors and organs were harvested 6 hours after a single intravenous injection of CH-Endo28-NPs (150 pmol/mouse) into HeyA8 tumor–bearing mice and stained with anti-CD31 antibody to detect blood vessels. (A) Representative tumor sections showing binding of CH/Endo28-NPs to tumor vasculature. Nuclei are shown in blue, blood vessels in green, and CH-Endo28-NPs in red (Cy3). CH/Endo28-NPs, chitosan/Endo28-nanoparticles. (B) Representative tumor sections showing colocalization of CH-Endo28-NPs (red) with blood vessels (green). Arrows in A and B denote colocalization of Endo28 (red) and CD31 (green). (C) Representative tumor sections showing delivery of Alexa 488–conjugated siRNA using CH/Endo28-NPs into tumor cells (blue indicates nuclei, green indicates Alexa 488–conjugated siRNA, and red indicates CH-Endo28-NPs). CH/R4-NPs, chitosan/R4-nanoparticles. Arrows denote colocalization of CH/Endo28 (red) and Alexa 488 siRNA (green).(D) Representative tumor sections showing that annexin A2 silencing reduced delivery of CH/Endo28-NPs to the tumor vasculature. Mice were treated with either CH/control siRNA or CH/mouse annexin A2 (CH/mAnnexin A2) siRNA for 48 hours before a single intravenous injection of CH/R4-NPs or CH/Endo28-NPs. Tumors were harvested 24 hours after NP injection and stained with anti-CD31 antibody to visualize blood vessels. Scale bars: 50 μm. (E) Distribution of CH/Endo28-NPs in tumor cells and organs, examined using IVIS imaging (see Supplemental Methods). Optical imaging of organs and tumors from HeyA8 tumor–bearing mice treated with CH-NPs or CH/R4-NPs or CH/Endo28-NPs shows fluorescence intensity overlaid on white light images of different mouse organs and tumor.