Targeting of primary breast cancers and metastases in a transgenic mouse model using rationally designed
Forrest M Kievit1, Zachary R Stephen, Omid Veiseh
1Department of Materials Science & Engineering, University of Washington, Seattle, Washington 98195, USA.
Abstract:
Breast cancer remains one of the most prevalent and lethal malignancies in women. The inability to diagnose small volume metastases early has limited effective treatment of stage 4 breast cancer. Here we report the rational development and use of a multifunctional superparamagnetic iron oxide nanoparticle (SPION) for targeting metastatic breast cancer in a transgenic mouse model and imaging with magnetic resonance (MR). SPIONs coated with a copolymer of chitosan and polyethylene glycol (PEG) were labeled with a fluorescent dye for optical detection and conjugated with a monoclonal antibody against the neu receptor (NP-neu). SPIONs labeled with mouse IgG were used as a nontargeting control (NP-IgG). These SPIONs had desirable physiochemical properties for in vivo applications such as near neutral zeta potential and hydrodynamic size around 40 nm and were highly stable in serum containing medium. Only NP-neu showed high uptake in neu expressing mouse mammary carcinoma (MMC) cells which was reversed by competing free neu antibody, indicating their specificity to the neu antigen. In vivo, NP-neu was able to tag primary breast tumors and significantly, only NP-neu bound to spontaneous liver, lung, and bone marrow metastases in a transgenic mouse model of metastatic breast cancer, highlighting the necessity of targeting for delivery to metastatic disease. The SPIONs provided significant contrast enhancement in MR images of primary breast tumors; thus, they have the potential for MRI detection of micrometastases and provide an excellent platform for further development of an efficient metastatic breast cancer therapy.
Insights
Researchers developed targeted superparamagnetic iron oxide nanoparticles (SPIONs) to detect metastatic breast cancer. These novel nanoparticles successfully targeted and imaged primary tumors and distant metastases in mice, offering a promising tool for early diagnosis and therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Breast cancer is a leading cause of death in women, with late-stage diagnosis of metastases hindering effective treatment.
- Early detection of small-volume metastases is crucial for improving outcomes in stage 4 breast cancer.
Purpose of the Study:
- To develop and evaluate multifunctional superparamagnetic iron oxide nanoparticles (SPIONs) for targeted imaging and potential therapy of metastatic breast cancer.
- To assess the specificity and efficacy of SPIONs in a transgenic mouse model of metastatic breast cancer.
Main Methods:
- Superparamagnetic iron oxide nanoparticles (SPIONs) were coated with chitosan-polyethylene glycol (PEG) and conjugated with anti-neu antibodies (NP-neu) or control IgG (NP-IgG).
- Physicochemical properties, cellular uptake in neu-expressing cells, and in vivo targeting of primary tumors and metastases in mice were evaluated.
- Magnetic resonance (MR) imaging was used to assess contrast enhancement in primary tumors.
Main Results:
- NP-neu exhibited specific binding to neu-expressing breast cancer cells, confirmed by competition assays.
- In vivo, NP-neu selectively targeted primary tumors and spontaneous metastases in liver, lung, and bone marrow.
- SPIONs significantly enhanced MR imaging contrast of primary tumors, demonstrating potential for micrometastasis detection.
Conclusions:
- Targeted SPIONs (NP-neu) show high specificity and efficacy for detecting primary breast tumors and metastatic lesions in a relevant mouse model.
- These SPIONs offer a promising platform for developing advanced diagnostic and therapeutic strategies for metastatic breast cancer.
- The developed SPIONs have potential for early MRI detection of micrometastases, paving the way for improved breast cancer treatment.
