Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model.

Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mirco-electro-mechanical 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 rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in vitro. The safety of implanting the device intracranially was confirmed with preliminary in vivo studies. The impact of TMZ release kinetics was investigated by conducting in vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. 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. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.

[1]  Michael J Cima,et al.  Microsystem technologies for medical applications. , 2011, Annual review of chemical and biomolecular engineering.

[2]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[3]  M. Cima,et al.  A controlled-release microchip , 1999, Nature.

[4]  Vanessa S. Rothholtz,et al.  Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration , 2000, Brain Research.

[5]  C. Magee,et al.  Local Intracerebral Administration of Paclitaxel with the Paclimer® Delivery System: Toxicity Study in a Canine Model , 2005, Journal of Neuro-Oncology.

[6]  R. Grossman,et al.  A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats. , 2010, Journal of neurosurgery.

[7]  R Langer,et al.  Microchips as Controlled Drug-Delivery Devices. , 2000, Angewandte Chemie.

[8]  Henry Brem,et al.  Recent Advances in Brain Tumor Therapy: Local Intracerebral Drug Delivery by Polymers , 2004, Investigational New Drugs.

[9]  W. Mark Saltzman,et al.  New Methods for Direct Delivery of Chemotherapy for Treating Brain Tumors , 2006, The Yale journal of biology and medicine.

[10]  W. Pardridge,et al.  Drug Delivery to the Brain , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  H. Brem,et al.  Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. , 2005, Anticancer research.

[12]  V. Tse,et al.  Recurrent glioblastoma multiforme: a review of natural history and management options. , 2006, Neurosurgical focus.

[13]  Robert Langer,et al.  In vivo release from a drug delivery MEMS device. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[14]  John T Santini,et al.  Electrothermally activated microchips for implantable drug delivery and biosensing. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[15]  A. Nomeir,et al.  High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma. , 1997, Journal of chromatography. B, Biomedical sciences and applications.

[16]  Yihai Cao,et al.  PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells , 2011, Nature Medicine.

[17]  John T Santini,et al.  Chronic, programmed polypeptide delivery from an implanted, multireservoir microchip device , 2006, Nature Biotechnology.

[18]  M. McGirt,et al.  Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. , 2009, Journal of neurosurgery.

[19]  R. Puri,et al.  Distribution kinetics of targeted cytotoxin in glioma by bolus or convection-enhanced delivery in a murine model. , 2004, Journal of neurosurgery.

[20]  Manfred Westphal,et al.  A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. , 2003, Neuro-oncology.

[21]  N M Elman,et al.  Medical applications of implantable drug delivery microdevices based on MEMS (Micro-Electro-Mechanical-Systems). , 2010, Current pharmaceutical biotechnology.

[22]  Henry Brem,et al.  Intracranial microcapsule drug delivery device for the treatment of an experimental gliosarcoma model. , 2011, Biomaterials.

[23]  E S Newlands,et al.  Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. , 1997, Cancer treatment reviews.

[24]  Robert Langer,et al.  In vivo delivery of BCNU from a MEMS device to a tumor model. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[25]  Timothy C Ryken,et al.  Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001. , 2006, Neurosurgical focus.

[26]  H. Brem,et al.  Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model , 2007, Cancer Chemotherapy and Pharmacology.

[27]  N M Elman,et al.  The Next Generation of Drug‐Delivery Microdevices , 2009, Clinical pharmacology and therapeutics.

[28]  Michael J Cima,et al.  Microchip technology in drug delivery , 2000, Annals of medicine.

[29]  H Kalimo,et al.  Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. , 1997, Neurosurgery.

[30]  Henry Brem,et al.  Targeted therapy for brain tumours , 2004, Nature Reviews Drug Discovery.

[31]  N M Elman,et al.  An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care , 2009, Biomedical microdevices.

[32]  Robert Langer,et al.  First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip , 2012, Science Translational Medicine.

[33]  N M Elman,et al.  Electro-thermally induced structural failure actuator (ETISFA) for implantable controlled drug delivery devices based on micro-electro-mechanical-systems. , 2010, Lab on a chip.

[34]  M. Berger,et al.  Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies. , 2006, Neurosurgical focus.

[35]  Raghu Raghavan,et al.  Convection-enhanced delivery of therapeutics for brain disease, and its optimization. , 2006, Neurosurgical focus.

[36]  Raphael Pfeffer,et al.  Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. , 2004, Journal of neurosurgery.