Medical devices for delivery of siRNA
Medical devices that incorporate siRNA are provided. 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 fabricated on a surface of the microneedle to project outward from the surface of the microneedle, the nanostructures being arranged in a predetermined pattern, wherein at least a portion of the nanostructures have a cross-sectional dimension of less than 500 nanometers and greater than 5 nanometers, a height of from 10 nanometers to 1 micrometer and an aspect ratio of from 0.2 to 5, and wherein the microneedle further contains a channel; and
a reservoir that is in fluid communication with the channel of the microneedle and that contains an siRNA construct.
2. The device of claim 1 , wherein the pattern 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 400 nanometers and greater than 10 nanometers.
5. The device of claim 1 , wherein at least a portion of the nanostructures have a center-to-center spacing of from 50 nanometers to 1 micrometer.
6. The device of claim 1 , wherein at least a portion of the nanostructures have a height of from 100 nanometers to 700 nanometers.
7. The device of claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from 0.5 to 3.5.
8. The device of claim 1 , wherein the siRNA agent includes a duplexed region of between 20 and 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 according to claim 1 , wherein the pattern has a fractal dimension of greater than 1 and up to 5.
18. The device according to claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of from 100 to 300 nanometers.
19. The device according to claim 1 , wherein the nanostructures have approximately the same cross-sectional dimension.
20. The device according to claim 1 , wherein the ratio of the cross sectional dimension of two adjacent nanostructures to the center-to-center spacing between those two structures is between 1:1 and 1:4.
21. The device according to claim 1 , wherein at least a portion of the nanostructures have an equidistant spacing.
22. The device according to claim 1 , wherein at least a portion of the nanostructures are in the form of pillars.
23. The device according to claim 1 , wherein the channel has a cross-sectional dimension of from 1 to 100 micrometers.
24. The device according to claim 23 , wherein the channel has a length of from 10 to 800 micrometers.
25. The device according to claim 1 , wherein the device contains a microneedle array that contains the microneedle.
26. The device according to claim 25 , wherein the array contains a base having an aperture, wherein the aperture is in at least partial alignment with the channel of the microneedle.
27. The device according to claim 26 , wherein the reservoir is attached to a substrate upon which the array is located.
28. The device according to claim 26 , wherein the reservoir is removably connected to the array.
29. 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 fabricated in a predetermined pattern to project outward from the surface of the microneedle, wherein at least a portion of the nanostructures have a cross-sectional dimension of less than 500 nanometers and greater than 5 nanometers, a height of from 10 nanometers to 1 micrometer and an aspect ratio of from 0.2 to 5, 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.