Brain metastasis (BM) is still hard to treat and is a devastating cause of death from breast and lung cancer. HER2/neu positive and triple negative cancers (TNBC; progesterone, estrogen and HER2 receptors negative) often develop BM. Our proposal on new nano drug delivery for effective BM imaging and treatment fits FOA PAR-13-185, The innovating research in image-guided drug delivery (IGDD) for cancer and other diseases. Magnetic Resonance Imaging (MRI) enhancement in the brain might result from a primary or recurrent brain tumor, radiation necrosis, metastasis from primary cancer (e.g., lung, breast), etc. Despite stereotactic biopsy techniques, biopsies in a non-eloquent part of the brain can still carry a 1.2-8% risk of complications. We hypothesize that our new nanoimaging targeted nanoconjugates can pass through BBB/BTB and specifically recognize brain tumor type. With covalently attached contrast agent Gd-DOTA, nanoconjugates would differentiate enhancements on brain MRI distinguishing types of brain lesions/tumors when it is difficult to perform brain tissue biopsy. We also hypothesize that similar nanoconjugates can treat breast cancer BMs. Combining precise diagnostic approach and antitumor therapy, which are both specific to tumor biomarkers, could help eliminate brain BMs more efficiently. The nanoimaging agents (NIA) specific to brain tumor type will be used in addition for treatment monitoring of EGFR-, HER2-, or PDGFRa-positive (primary gliomas) brain tumors. We are going to develop the NIA delivery system with fast clearance in order to perform several diagnostic injections when needed for in/out patients for precise diagnosis and/or tumor treatment monitoring.
Aim 1. Synthesize and optimize a nanoscale contrast agent for brain lesion verification. NIAs will be synthesized to differentiate MRI enhancements due to primary brain tumors and metastases from breast or lung cancer. Nano-MRI resolution will be tested with several versions of conjugates in order to obtain the highest enhancement with minimum time of exposure and toxicity. Nanodrugs will be tested for stability, physico-chemical properties and synthesis reproducibility. Quantitative analysis of MRI contrast with anti- EGFR, anti-HER2 or anti-PDGFRa mAbs will be done.
Aim 2. Treat metastatic brain tumors in vivo with nanoconjugates. Examine molecular mechanisms in vitro and in vivo for BM inhibition with selection of lead nanodrugs. Nanodrugs for effective metastasis inhibition through EGFR or HER2 will be synthesized, characterized, and tested in BM mouse models.
Aim 3. Toxicity study of nanoconjugates for brain BM imaging, treatment and treatment monitoring. Nanoconjugates with covalently attached cyclic-Gd-DOTA or Star-Gd-DOTA as MRI contrast agents will be made for imaging, and similar versions for multiple treatment of BM. Lead imaging and treatment nanoconjugates will be tested for pharmacodynamic, pharmacokinetic, and toxicity parameters, as well as biodistribution. The drugs will bear the same targeting mAbs and tumor marker inhibitors as for treatment.

Public Health Relevance

Despite progress in breast cancer treatment, brain metastasis (BM) is still hard to treat and remains the most devastating cause of death for HER2/neu positive and triple negative (TNBC; progesterone, estrogen and HER2 receptors negative) breast cancer types. Currently marketed therapeutic monoclonal antibodies (mAbs) are used for primary tumor treatment but are ineffective against BM, as they cannot penetrate blood brain barrier (BBB) and blood tumor barrier (BTB). We propose to develop diagnostic and treatment (theranostic) nanoconjugates capable of passing BTB and effective targeting and inhibition of metastatic tumor growth; our proposal directly fits NCI's specific area of focus: Nanotechnology-based techniques enabling understanding, prevention, detection, and elimination of metastases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA188743-02
Application #
9054815
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zhang, Huiming
Project Start
2015-04-15
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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