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

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.National Institutes of Health (U.S.) (Grant R01 EB006365-06)Brain Science Foundation (Private Grant 106708

Developing and applying a miniaturized active microchip device

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 108-112).Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Treatment of GBM is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved moderate success in treating GBM. Depot devices have been limited due to the relatively narrow drug distribution profile they achieve. Convection enhanced delivery has demonstrated that broad distribution is key, but is limited due to uncertain spatial distribution and serious side effects. Miniaturized depot devices, implanted into the tissue surrounding the tumor resection site, could achieve a broad aggregate distribution profile. The capabilities of localized delivery can be enhanced by utilizing microelectromechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a 9L rodent glioma model. An activation mechanism based on thermally induced membrane failure was developed and incorporated. The kinetics of TMZ release were validated and quantified in vitro. The safety of implanting the device intracranially was confirmed. The impact of TMZ release kinetics on survival was investigated by comparing the effects of drug release rates and timing. TMZ delivered from the device prolonged animal survival. The results from the in vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. This miniaturized MEMS device holds tremendous potential for the treatment of GBM and related diseases. Circuit diseases are neurological disorders that arise from the dynamic miscommunication within a neural circuit. Anxiety, mood disorders, and the chronic effects of traumatic brain injury (e.g. Parkinsonism) are prevalent, and are circuit diseases. Circuit diseases could be clinically addressed by a technology capable of electrical, and chemical neuro-modulation. A catheter based device capable of simultaneous infusion of multiple fluids and electrical stimulation was designed and fabricated. Preliminary in vitro infusion studies indicate that the reliable and reproducible infusion of multiple fluids is possible. Future work will focus on improving the biocompatibility of the device and studying the performance of the device in non-human primate models of neurological disorders.by Byron C. Masi.Ph.D

Correction for Upadhyay et al., Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain

Correction for “Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain,” by Urvashi M. Upadhyay, Betty Tyler, Yoda Patta, Robert Wicks, Kevin Spencer, Alexander Scott, Byron Masi, Lee Hwang, Rachel Grossman, Michael Cima, Henry Brem, and Robert Langer, which appeared in issue 45, November 11, 2014, of Proc Natl Acad Sci USA (111:16071–16076; first published October 27, 2014, 10.1073/pnas.1313420110)