Abstract 3911: Imaging and treatment of brain metastatic tumors using nanopolymers.
Authors: Ljubimova Julia Y. , Patil Rameshwar , Gangalum Pallavi , Wagner Shawn , Inoue Satoshi , Ding Hui , Portilla-Arias Jose , Rekechenetskiy Arthur , Konda Bindu , Markman Janet , Chesnokova Alexandra , Black Keith L. , Holler Eggehard 
Published: August 2014

A significant clinical problem with brain metastatic (BM) tumors is drug delivery and diagnostic imaging to verify MRI enhancement(s) for planning treatment. MRI enhancement in cancer patient's brain may result from infection after chemotherapy that impairs immune system; metastasis from primary lung/breast cancer; or a new primary brain tumor. Unlike lung/breast, brain biopsies are often technically impossible. Most drugs or monoclonal antibodies (mAb) are effective for primary tumors but cannot penetrate blood brain barrier (BBB) failing to treat brain metastasis.

We used a natural nanobiopolymer, polymalic acid (PMLA), as a platform for the tumor-targeted PolycefinTM drugs for differential brain tumor imaging and treatment.

Three xenogeneic orthotropic human brain metastatic tumors, MDA-MB-474, HER2+ breast cancer; A549 lung cancer, and MDA-MB-468, triple negative breast cancer (TNBC), both EGFR+, were injected into the brain of mice.

For imaging, PolycefinTM had a covalently attached MRI tracer Gadolinium (Gd-DOTA). Antisense oligonucleotides (AON) were conjugated to PolycefinTM to inhibit gene/protein expression to block tumor growth. The combination of cell surface targeting mAbs, including anti-transferrin receptor (TfR) mAb for drug BBB transcytosis, and AONs to multiple tumor markers on the same delivery polymer was used for tumor treatment.

MRI 1H imaging was performed on a 9.4-Tesla MRI system. Treatment groups of animals included (1) HER2+ MDA-MB-474 breast cancer metastases targeted with PMLA-Gd-DOTA/Trastuzumab/TfR mAb; (2) EGFR+ MDA-MB-468 TNBC metastases targeted with PMLA-Gd-DOTA/Cetuximab/TfR mAb; and (3) Controls inoculated with PMLA-IgG mAb and clinical Gd.

Imaging: Specific tumor imaging was shown for brain-implanted lung and breast tumors: the inverse of T1-1 relaxation time proportional to Gd concentration was measured in healthy brain and in the tumor. T1-1 time dependence for Gd-DOTA-Polycefin (T1-1 ratio tumor/normal brain) was compared with clinical Gd, MultiHance®. After reaching a maximum, high T1-1 relative values prevailed for several hours for Gd-DOTA-mAb-Polycefin, but declined rapidly for Gd. High contrast for Gd was seen in 20 min, whereas that for Gd-DOTA-Polycefin peaked in 45-60 min, and remained for up to 3 hrs. By differential MRI with anti-HER2 (Trastuzumab) or anti-EFGR (Cetuximab) mAb attached to the nanoplatform, we were able to differentiate HER2+ from EGFR+ metastatic brain tumors.

Treatment: Animal survival after Polycefin treatment was significantly higher than in untreated or mAb (Herceptin or Cetuximab) treated animals. Survival increases were as follows: 66% for lung cancer, 47% for HER2+ breast cancer, and 81% for TNBC.

We developed a system for differential imaging and successful systemic treatment of various metastatic brain tumors based on specific metastasis targeting, and inhibition of expression of tumor-specific genes/proteins.

Citation Format: Julia Y. Ljubimova, Rameshwar Patil, Pallavi Gangalum, Shawn Wagner, Satoshi Inoue, Hui Ding, Jose Portilla-Arias, Arthur Rekechenetskiy, Bindu Konda, Janet Markman, Alexandra Chesnokova, Keith L. Black, Eggehard Holler. Imaging and treatment of brain metastatic tumors using nanopolymers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3911. doi:10.1158/1538-7445.AM2013-3911