Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model - PubMed (original) (raw)

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

Byron C Masi et al. Biomaterials. 2012 Aug.

Abstract

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.

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Figures

Figure 1. Color photograph of the device (A) and a CAD render of the LCP reservoir (B)

Photograph of the fully assembled device. The white LCP reservoir is capped by the purple and gold microchip. The 3 green squares on the microchip are the suspended nitride membranes. The polyimide coated copper leads protrude from the device (A). The reservoir dimensions are 3.7 by 3.2 × 2.2 mm. The total drug payload is 10 milligrams of TMZ. The 200 μm shelf is visible on the interior face of the reservoir walls. This shelf serves a seat for the chip and as an upper boundary for drug during the loading process. A lead-way was designed in the top perimeter of the chip to allow the polyimide leads to project out from the device (B).

Figure 2

Release curves for TMZ filled devices releasing into 37°C water. Devices (n=3) with 3, 2, 1 or 0 membranes activated were placed in stirred baths and sampled for TMZ content. The errors bars are the standard error. Release is a function of the number of activated membranes and release does not occur unless the device is activated.

Figure 3. Graphical presentation of normalized animal weight as a function of time

All animals displayed minimal weight loss during the acute phase, and animal 5 displayed robust weight gain over the chronic time scale

Figure 4. Kaplan Meier survival curves

Animals receiving no treatment or un-activated devices had a median survival of 13 and 16 days respectively. (A) Impact of drug release rate on survival. Animals that received activated devices on day 0 had median survivals of 40 (42.8 % LTS), 28 (28.5 % LTS), and 21 (12.5 % LTS) days for 3, 2, and 1 membranes activated respectively. (B) Impact of drug release time on survival. Animals that had all 3 membranes activated day 0, 3, or 5 had median survivals of 40 (42.8 % LTS), 24 (12.5 % LTS) and 23 days. (C) Comparison between microchip and polymer-based delivery methods. Those animals that received two TMZ:polymer wafers on day 5 had a median survival of 34 days, while those that had all 3 membranes opened on day 5 had median survival of 23 days.

Figure 5. Immunohistological results of Ki67 staining

(A) Ki67 positive cells are green and cell nuclei are blue. Each panel is a representative image from each efficacy study group. The 3M0D (3 membranes activated on day 0) panel contains the fewest number of Ki67 positive cells. (B) Quantitative results obtained by averaging 3 representative images from each group. The two longest surviving groups, wafer and 3M0D, have the lowest levels of Ki67 positive cells.

Figure 6. Immunohistological results of caspase-3 staining

(A) Caspase-3 positive cells are green and cell nuclei are blue. Each panel is a representative image from each efficacy study group. (B) Quantitative results obtained by averaging 3 representative images from each group. The 3M0D (3 membranes activated on day 0) panel contains the second highest number of caspace-3 positive cells.

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Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model - PubMed (original) (raw)