Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1α with Targeted Multifunctional ECO/siRNA Nanoparticles.
Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model. The RGD-targeted ECO/siHIF-1α nanoparticles resulted in over 50% reduction in tumor size after intravenous injection at a dose of 2.0 mg of siRNA/kg every 3 days for 3 weeks compared to a saline control. DCE-MRI revealed significant decline in vascularity and over a 70% reduction in the tumor blood flow, permeability-surface area product, and plasma volume fraction vascular parameters in the tumor treated with the targeted ECO/siHIF-1α nanoparticles. The treatment with targeted ECO/siRNA nanoparticles resulted in significant silencing of HIF-1α expression at the protein level, which also significantly suppressed the expression of VEGF, Glut-1, HKII, PDK-1, LDHA, and CAIX, which are all important players in tumor angiogenesis, glycolytic metabolism, and pH regulation. By possessing the ability to elicit a multifaceted effect on tumor biology, silencing HIF-1α with RGD-targeted ECO/siHIF-1α nanoparticles has great promise as a single therapy or in combination with traditional chemotherapy or radiation strategies to improve cancer treatment.
Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Anthony S
AS
Malamas
Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Erlei
E
Jin
Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Maneesh
M
Gujrati
Case Center for Biomolecular Engineering, Department of Biomedical Engineering, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Zheng-Rong
ZR
Lu
D000818:Animals; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D003287:Contrast Media / Q000032:analysis; D005455:Fluorescent Antibody Technique; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009389:Neovascularization, Pathologic / Q000235:genetics; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics*
D003287:Contrast Media; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering
DCE-MRI; HIF-1; angiogenesis; multifunctional lipid; siRNA