Abstract
Molecularly-targeted contrast enhanced ultrasound (US) imaging is a promising imaging strategy with large potential for improving diagnostic accuracy of conventional US imaging in breast cancer detection. Therefore, we constructed a novel dual-targeted nanosized US contrast agent (UCA) directed at both vascular endothelial growth factor receptor 2 (VEGFR2) and human epidermal growth factor receptor 2 (HER2) based on perfluoropropane (C3F8)-filled poly(lactic-co-glycolic acid) (PLGA) (NBs) for breast cancer detection. In vitro, single- or dual-targeted PLGA NBs showed high target specificities and better effects of target enhancement in VEGFR2 or HER2-positive cells. In vivo, US imaging signal in the murine breast cancer model was significantly higher (P < 0.01) for dual-targeted NBs than single-targeted and non-targeted NBs. Small animal fluorescence imaging further confirmed the special affinity of the dual-targeted nanosized contrast agent to both VEGFR2 and HER2. Immunofluorescence and immunohistochemistry staining confirmed the expressions of VEGFR2 and HER2 on tumor neovasculature and tumor cells of breast cancer. In conclusions, the feasibility of using dual-targeted PLGA NBs to enhance ultrasonic images is demonstrated in vitro and in vivo. This may be a promising approach to target biomarkers of breast cancer for two site-specific US molecular imaging.
Highlights
Targeted US contrast agent (UCA) represented by gas-filled microbubbles (MBs) are stabilized by a shell
The goal of this study was to develop a novel dual-targeted UCA directed at both Vascular endothelial growth factor receptor 2 (VEGFR2) and Human epidermal growth factor receptor 2 (HER2) based on poly(lactic-co-glycolic acid) (PLGA) NBs for breast cancer detection
It had been proven that VEGFR2-targeted US molecular imaging could improve the diagnostic accuracy of early breast cancer and distinguish breast cancers with different angiogenesis and aggressiveness
Summary
Targeted UCAs represented by gas-filled microbubbles (MBs) are stabilized by a shell. PLGA hollow or porous MBs have already been proved to be an efficient UCA in previous researches[9,10] They can be modified with monoclonal antibody or polypeptide for targeting US or dual-mode US/MR molecular imaging[11,12]. Only a few studies have developed nanobubble-based specific US imaging agents for improved detection and diagnosis for breast cancer[15,16]. Several studies have shown that US molecular imaging using VEGFR2-targeted MBs allows highly accurate detection of breast cancer, even ductal carcinoma in situ (DCIS)[18,19,20]. Recent researches have described HER2-targeted US, MRI and PET-CT contrast agents for improved detection and diagnosis of breast cancer[1,15,16,24]
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