Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

Abstract

The creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 min in vitro. Furthermore, asymmetric delivery was shown to concentrate drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.

Figure 1

A) Schematic representation of spherical particles and microdevice interface with intestinal epithelial cell surface. This illustration displays the advantages of a microfabricated drug delivery particle over traditional spherical particles: asymmetric release of drug, multi-site targeting for flow stability, and drug reservoir protection can be engineered into the design of the microdevice. B) Light micrograph of detached SU-8 microdevices without hydrogel. The scale bar represents 150 microns.

Figure 2

A) Process flow overview for fabrication of single layer PEGMA laden SU-8 microdevice. B) A light micrograph of hydrogel laden microdevices. The black box represents an unfilled microdevice. A white box represents a filled microdevice. The line represents 150 microns. C) A fluorescent micrograph of hydrogel laden microdevices with bovine serum albumin conjugated to fluorescein isothiocyanate encapsulated in the hydrogel. The gray box represents an unfilled microdevice.

Figure 3

A) The release of auto-fluorescent chemotherapeutic camptothecin was measured in PBS with a fluorescent spectrometer and reported as concentration in microgram per milliliter. The blank hydrogel represents the amount of camptothecin release for a non-drug loaded hydrogel in a microdevice. B) The permeation of camptothecin through a caco-2 epithelial monolayer on collagen treated Transwells®. The concentration in the bottom well of the Transwell® was normalized to that of the top well. An * indicates statistical significance with respect to the free drug conditions. A # represents significance with respect to drug filled hydrogels. All data is presented as average ± standard deviation.

Figure 4

A) Process flow overview for fabrication of multi-layer PEGMA laden SU-8 microdevice. B) A fluorescent micrograph composite of a layered hydrogel prepared with DNP-BSA, FITC-BSA and Texas-red-BSA (from outmost layer to inmost). The grey dotted-line box highlights the reservoir area and the red dotted-line box the outer area of the microdevice. C) A fluorescent micrograph of each individual filter for the labeled BSA is presented for three unique hydrogel-filled microdevices.

Figure 5

A) The release of fluorescently labeled BSA from a layered hydrogel was prepared with DNP-BSA, FITC-BSA and Texas-red-BSA. A * indicates significance with respect to the FITC-BSA release, and a # with respect to Texas-red-BSA. B) The release of both therapeutic proteins (insulin) and small chemicals (camptothecin) is shown over time. All data is presented as average ± standard deviation.