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Hydrogel Filled Micro-Engineered Particles for Oral Delivery of Chemotherapeutic In Shear Conditions

Kristy M. Ainslie, Department of Bioengineering and Therapeutic Sciences, UCSF, 1700 4th Street, Byers Hall Room 203; Box 2520, San Francscio, CA 94158, Casey M. Kraning, Chemistry, Butler University, Indianapolis, IN 46208, and Tejal Desai, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 1700-4th Street, Box 2520, QB3 203, Mission Bay Campus, San Francisco, CA 94143-2520.

Hydrogel laden micro-engineered particles were used to create a novel oral drug delivery device to control the release of the chemotherapeutics. Delivery via these microdevices is advantageous because they deliver drug only in the direction of the cell layer, in contrast to spherical particles that deliver drug radially. The devices are fabricated through multi-layered photolithography. The attachment and release of these devices in vitro under physiologically relevant shear conditions was observed.

Cancer is the second leading cause of death in the United States. Chemotherapeutic delivery is challenged due to drug hydrophobicity, therapeutic degradation and/or lethal toxicity affecting healthy cells. A well engineered chemotherapeutic oral delivery device can help overcome these obstacles. Additionally, oral delivery is preferred over other invasive methods (e.g. intravenous) because it can be self-administered, leading to reduced delivery costs and increased patience compliance. Our laboratory has developed a micro-engineered oral drug delivery device (termed microdevice) that incorporates flat geometry allowing two-dimensional drug release, planar attachment to the intestinal wall and minimal resistance to mechanical forces generated by peristalsis in the intestine. The microdevice consists of a 150x150x8 micron-cubed flat polymer with a walled reservoir.

The microdevice is microfabricated with SU-8 through multi-layered photolithography steps. A poly(ethylene glycol) dimethacrylate (PEGDA) based hydrogel was added into the reservoir through additional photolithography. Acrylate functional groups have been shown to covalently bind to the free-radical groups present on SU-8 and we have shown long-scale binding of the hydrogels to the devices in physiological relevant conditions. Proteins and chemotherapeutics can easily be incorporated into the hydrogel, for controlled release of therapeutics from the device over the course of hours, as is relevant for intestinal delivery. Furthermore, layers with unique therapeutics incorporated in each can be fabricated into the device, allowing for incorporation of combinatorial therapy, such as applied in traditional cancer treatment. The bioactivity of chemotherapeutics released from the hydrogel was measured in vitro. Permeation of drug through intestinal epithelial cells was increased over 400% with the microdevices, compared to bare hydrogels. Chemotherapeutic loaded microdevices placed on a monolayer superior to a culture with colon cancer cells showed a decrease in cancer cell proliferation and viability while not adversely affecting the epithelial cell monolayer.

For specific attachment of the device to the intestinal epithelium, tomato lectin was covalently attached to the hydrogel layer. An acrylate- N-hydroxysuccinimide (Acr-NHS) cross-linker functionalized with avidin was introduced into the hydrogel. The addition of biotinalyted tomato lectin resulted in increased face-down attachment to an in vitro intestinal cell epithelial cell layer under physiologically relevant shear conditions. The percentage of adherent microdevices was shown to be dependent on the synergistic effect of tomato lectin and acrylate-avidin concentration. Drug release and diffusion through an intestinal monolayer was also measured in shear conditions. This work characterizes the further development of a novel micro-engineered oral drug delivery device.