Medical devices for delivery of siRNA
Disclosed are medical devices that incorporate siRNA. In addition to one or more siRNA constructs, devices include nanostructures fabricated on a surface to form a nanotopography. A random or non-random pattern of structures may be fabricated such as a complex pattern including structures of differing sizes and/or shapes. Microneedles may be incorporated on devices. The pattern including nanostructures may be formed on the surface of the microneedles.
1. A device for delivery of an siRNA construct across a dermal barrier, the device comprising:
a microneedle and a plurality of nanostructures located on a surface of the microneedle to project outward from the surface of the microneedle, the nanostructures being arranged in a pattern that comprises a fractal and/or fractal-like geometry; and
an siRNA construct in fluid communication with the microneedle.
2. The device of claim 1 , wherein the surface of the microneedle further includes microstructures, wherein the nanostructures have a cross-sectional dimension smaller than the microstructures.
3. The device of claim 2 , further comprising second nanostructures having a cross-sectional dimension less than the cross-sectional dimension of the microstructures and greater than the cross-sectional dimension of the first nanostructures.
4. The device of claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of less than about 500 nanometers and greater than about 5 nanometers.
5. The device of claim 1 , wherein at least a portion of the nanostructures have a center-to-center spacing of from about 50 nanometers to about 1 micrometer.
6. The device of claim 1 , wherein at least a portion of the nanostructures have a height of from about 10 nanometers to about 20 micrometers.
7. The device of claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from about 0.15 to about 30.
8. The device of claim 1 , wherein the siRNA agent includes a duplexed region of between about 20 and about 30 pairs.
9. The device of claim 1 , at least one strand of the siRNA including a 3′ overhang of two or three nucleotides.
10. The device of claim 1 , the siRNA agent comprising additional nucleotides or nucleotide analogue.
11. The device of claim 1 , wherein the siRNA agent comprises a nucleotide sequence that is identical to a portion of a targeted gene.
12. The device of claim 1 , wherein the siRNA agent includes insertions, deletions, or single point mutations compared to a portion of a targeted gene.
13. The device of claim 1 , wherein the siRNA agent is a single strand siRNA.
14. The device of any of claim 1 , wherein the siRNA comprises a ligand tethered to the siRNA.
15. The device of claim 1 , wherein the siRNA agent is incorporated into a delivery vehicle.
16. The device of claim 1 , wherein the siRNA construct comprises a vector.
17. The device of claim 1 , wherein the nanostructures are fabricated on a film, and wherein the film is laid over the microneedle.
18. A method for delivering an siRNA construct across a dermal barrier, the method comprising:
penetrating the stratum corneum with a microneedle having a surface on which a plurality of nanostructures are arranged in a pattern that comprises a fractal and/or fractal-like geometry, wherein the nanostructures project outward from the surface of the microneedle, and wherein the microneedle further contains a channel;
transporting an siRNA construct from a reservoir through the channel of the microneedle and across the stratum corneum.