Abstract
BackgroundThere is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors.MethodsPhospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model.ResultsThe average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle.ConclusionsThe Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.
Highlights
20–30 % of breast cancer patients are diagnosed with Her-2-positive breast cancers, which are associated with resistance to some chemotherapeutic agents and poor disease-free survival [1,2,3]
A significantly larger number of monoclonal antibody (mAb)-modified nanobubbles conjugated with Herceptin (NBs-Her) adhered to the SK-BR3 cells than to the MDA-MB-231 cells, suggesting that the adhesion of NBs to Her-2-positive breast cancer cells is due to the antigen– antibody reaction
Noninvasive and inexpensive sonography combined with Herceptin-targeted NBs may be a promising tool for diagnosing and evaluating the treatment response of Her-2-positive breast cancer
Summary
20–30 % of breast cancer patients are diagnosed with Her-2-positive breast cancers, which are associated with resistance to some chemotherapeutic agents and poor disease-free survival [1,2,3]. Diagnosis is critical for successful treatment and improved prognosis of Her-2-positive breast cancer. Cytotoxic chemotherapy remains the mainstay treatment for breast cancer [4, 5]. Neoadjuvant chemotherapy was established for breast cancer. These treatments aim to Breast Cancer (2016) 23:445–455 increase tumor respectability and allow breast-conserving therapies [6]. The combination of trastuzumab ( known as Herceptin), a humanized monoclonal antibody (mAb) against the Her-2 receptor [7], and neoadjuvant chemotherapy has improved the response rate for breast cancers that overexpress Her-2. There is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, Her-2-expressing cancers. We characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors.
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