Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain

Authors

• Urvashi M. Upadhyay, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA 02115; urvashi.m.upadhyay@gmail.com rlanger@mit.edu.
• Betty Tyler, Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
• Yoda Patta, Departments of Materials Science and Engineering and.
• Robert Wicks, Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
• Kevin Spencer, Departments of Materials Science and Engineering and.
• Alexander Scott, Departments of Materials Science and Engineering and.
• Byron Masi, Chemical Engineering and.
• Lee Hwang, Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
• Rachel Grossman, Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
• Michael Cima, Departments of Materials Science and Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
• Henry Brem, Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231; Departments of Oncology and Biomedical Engineering, Johns Hopkins University Hospital, Baltimore, MD 21205.
• Robert Langer, Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and urvashi.m.upadhyay@gmail.com rlanger@mit.edu.

Document Type

Article

Abstract

Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.

Medical Subject Headings

Adenocarcinoma (drug therapy, metabolism, pathology); Animals; Antineoplastic Combined Chemotherapy Protocols (pharmacology); Brain Neoplasms (drug therapy, metabolism, pathology, secondary); Capsules; Caspase 3 (metabolism); Dacarbazine (analogs & derivatives, pharmacology); Doxorubicin (pharmacology); Female; Humans; Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology); Neoplasm Metastasis; Neoplasm Proteins (metabolism); Rats; Rats, Inbred F344; Temozolomide

Publication Date

11-11-2014

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

E-ISSN

1091-6490

Volume

111

Issue

45

First Page

16071

Last Page

6

PubMed ID

25349381

Digital Object Identifier (DOI)

10.1073/pnas.1313420110

Recommended Citation

Upadhyay, Urvashi M.; Tyler, Betty; Patta, Yoda; Wicks, Robert; Spencer, Kevin; Scott, Alexander; Masi, Byron; Hwang, Lee; Grossman, Rachel; Cima, Michael; Brem, Henry; and Langer, Robert, "Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain" (2014). Neurosurgery. 2314.
https://scholar.barrowneuro.org/neurosurgery/2314