Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1α with Targeted Multifunctional ECO/siRNA Nanoparticles

Abstract

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.

RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

“…28 Some integrins, including αvβ3 and αvβ5, are overexpressed in neovasculature and some tumors including ovarian cancer (OvCa). 29–31 Since the RGD motif is recognized by half integrins, RGD-containing peptides have been widely used as targeting ligand for cancer diagnosis 32–35 and therapy 36–40 .…”

Recent Progress in the Design of Hypoxia‐Specific Nano Drug Delivery Systems for Cancer Therapy

“…A multifunctional, pH-sensitive, cationic lipid carrier (1aminoethyl) imino bis[N-(oleicylcysteinyl-1-amino-ethyl) propionamide] (ECO) was synthesized for the systemic and targeted delivery of HIF-1α siRNA. [79] Tumor-targeted ECO/siRNA nanoparticles were formed by conjugating cRGD-PEG to the complex of ECO and HIF-1α siRNA. The pH-sensitive amphiphilicity of ECO facilitated endosomal escape and avoided degradation of the siRNA cargo within the acidic environment.…”

“…Systemic administration of ECO/siHIF-1α nanoparticles at a dose of 2.0 mg of siRNA kg −1 every 3 days for 3 weeks resulted in >50% reduction in tumor size compared to a saline control. [79] Liu et al reported a cationic mixed micellar nanoparticle (MNP) consisting of two amphiphilic di-block copolymers, poly(ε-caprolactone)-block-poly(2aminoethylethylene phosphate) (PCL 29 -b-PPEEA 21 ) and poly(εcaprolactone)-block-poly(ethylene glycol) (PCL 40 -b-PEG 45 ) for the treatment of hypoxic tumors. [80] MNP formed a nanocomplex of 58.0 ± 3.4 nm after binding with HIF-1α siRNA.…”

Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles

“…Preclinical studies in various different tumor models have demonstrated siRNA nanoparticles to be effective in inhibiting tumor growth (Parvani et al 2015; Su, et al 2015; Zhang, et al 2016), metastasis (Parvani et al 2015; Zhao, et al 2015), angiogenesis (Liu, et al 2015; Malamas, et al 2016), and drug resistance (Deng et al 2013; Zhang et al 2016). These studies have paved the way for various ongoing clinical trials, which are summarized in Table 2.…”