MRI Virtual Biopsy and Treatment of Brain Metastatic Tumors with Targeted Nanobioconjugates

Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy that can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise non-invasive MRI diagnostic method, we have engineered a new class of poly(β-L-malic acid) polymeric nano-imaging agents (NIA). The NIA carrying attached MRI tracer are able to pass through blood brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative “MRI virtual biopsy” method is based on nanoconjugate carrying MRI contrast agent Gadolinium-DOTA and antibodies recognizing tumor specific markers and extravasating through BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this non-invasive method allowed differential diagnosis of HER2- and EGFR- expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in significant increase of animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.