MRI Virtual Biopsy and Treatment of Brain Metastatic Tumors with Targeted Nanobioconjugates: Nanoclinic in the Brain

Abstract

Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which 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 noninvasive MRI diagnostic method, we have engineered a new class of poly(β-L-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood–brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative “MRI virtual biopsy” method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive 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 a significant increase in 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.

HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug

“…1–3 In mouse models we have shown that the efficacy for the treatment of human HER2-positive breast cancer with free trastuzumab alone could be significantly increased when the antibody was co-liganded with poly(β-Lrange-malic acid and an antisense oligonucleotide (AON) targeting HER2-mRNA. 4,5 After the successful use of trastuzumab with affinity in the low nanomolar range, 6,7 peptides with affinities in the high nanomolar region 7–9 and affibodies with affinities in the picomolar to low nanomolar regions have been developed and successfully used for tumor imaging. 10,11 Examples of targeted therapy using anti-HER2/neu peptide (AHNP) or affibodies alone or in combination with other molecules have demonstrated variable degrees of tumor-specific growth inhibition.…”

“…However, their sizes cannot be reduced below diameters of 15 to 25 nm due to the sizes of the antibodies that are attached for specific targeting. 4, 5 On the basis of hydrodynamic considerations, elongated nanomolecules would be superior in quickly “shuffling” their way through dense areas (e.g. intercellular matrix) in comparison to spherically shaped molecules of similar size.…”

“…The combination of trastuzumab with PMLA has enabled a novel, unprecedentedly effective treatment of HER2-positive breast cancer. 4,5 The biodegradable, nontoxic, and non-immunogenic platform of PMLA offers a multitude of pendant carboxylic groups that can be functionalized with (pro)drug(s), prodrug activating groups, targeting peptide(s), protective polyethylene glycol (PEG), membrane destabilizing peptides, and dyes for imaging. 4,5,18–20 …”

In vitro screening of nanomedicines through the blood brain barrier: A critical review

“…Therefore, the evaluation of the permeability of CNS drug delivery systems with in vitro BBB models is of great importance: it allows an estimation of their biodistribution that may well steer the optimization of physicochemical parameters of nanocarriers to achieve more favorable drug pharmacokinetic and distribution profiles for both brain imaging diagnosis [84][85][86][87][88][89][90] and optimum therapy of CNS pathologies [91] M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT (such as neurodegenerative disorders [92][93][94][95][96][97], ischemic strokes [98], brain tumors [99][100][101][102][103] or viral infections [104]). …”

Anti‐Metastatic and Anti‐Angiogenic Activities of Core–Shell SiO2@LDH Loaded with Etoposide in Non‐Small Cell Lung Cancer

“…Based on earlier findings, nanoparticle application may be considered as a potential method in anti‐metastasis research 5. Nanoparticles have captured much attention, for example, their use as gene transporters, drug carriers, radioactive tracers, and therapies in medicine and other relevant fields 6, 7, 8.…”