title: Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain.
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.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA 02115; urvashi.m.upadhyay@gmail.com rlanger@mit.edu.
authors.forename: Urvashi M
authors.initials: UM
authors.lastname: Upadhyay
authors.affiliation: Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.affiliation: Departments of Materials Science and Engineering and.
authors.forename: Yoda
authors.initials: Y
authors.lastname: Patta
authors.affiliation: Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
authors.forename: Robert
authors.initials: R
authors.lastname: Wicks
authors.affiliation: Departments of Materials Science and Engineering and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Spencer
authors.affiliation: Departments of Materials Science and Engineering and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scott
authors.affiliation: Chemical Engineering and.
authors.forename: Byron
authors.initials: B
authors.lastname: Masi
authors.affiliation: Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
authors.forename: Lee
authors.initials: L
authors.lastname: Hwang
authors.affiliation: Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
authors.forename: Rachel
authors.initials: R
authors.lastname: Grossman
authors.affiliation: Departments of Materials Science and Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Cima
authors.affiliation: Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231; Departments of Oncology and Biomedical Engineering, Johns Hopkins University Hospital, Baltimore, MD 21205.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D002214:Capsules; D053148:Caspase 3 / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000077204:Temozolomide
chemical_list: D002214:Capsules; D009363:Neoplasm Proteins; D003606:Dacarbazine; D004317:Doxorubicin; C505410:Casp3 protein, rat; D053148:Caspase 3; D000077204:Temozolomide
keywords: brain; chemotherapy; intracranial; metastases; microcapsule