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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-11, Vol.111 (45), p.16071-16076
• Main Authors: Upadhyay, Urvashi M., Tyler, Betty, Patta, Yoda, Wicks, Robert, Spencer, Kevin, Scott, Alexander, Masi, Byron, Hwang, Lee, Grossman, Rachel, Cima, Michael, Brem, Henry, Langer, Robert
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological Sciences; Brain; Brain neoplasms; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Breast cancer; Cancer; Capsules; Caspase 3 - metabolism; Chemotherapy; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Doxorubicin - pharmacology; Drug trafficking; Female; Humans; Kinetics; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Metastasis; Neoplasm Metastasis; Neoplasm Proteins - metabolism; Physical Sciences; Polymers; Rats; Rats, Inbred F344; Rodents; Tissues; Toxicity; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1313420110

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. Significance Brain metastases represent the most common intracranial tumors in adults. Adequate chemotherapy delivery to the CNS is hindered by the blood–brain barrier. Efforts in intracranial chemotherapy delivery aim to maximize CNS levels while minimizing systemic toxicity; however, the success has been limited thus far. In this work, intracranial implanted doxorubicin and temozolomide microcapsules are compared with systemic administration in a novel rodent model of breast adenocarcinoma brain metastases. These microcapsules are versatile and efficacious, but that efficacy may depend on the ability of the chemotherapy to diffuse in brain tissue. These insights apply to other non-CNS applications of local drug delivery, and drugs should be e