Medical devices for delivery of siRNA
View Patent ↗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 and microstructures projecting directly outward from a surface of the microneedle in a predetermined pattern, wherein at least a portion of the microstructures have a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, and 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 and an aspect ratio of from about 0.2 to about 5, 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 , 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.
3. 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.
4. The device of claim 1 , wherein at least a portion of the nanostructures have a height of from about 10 nanometers to about 1 micrometer.
5. The device of claim 1 , wherein at least a portion of the nanostructures have an aspect ratio of from about 0.5 to about 3.5.
6. The device of claim 1 , wherein the siRNA agent includes a duplexed region of between about 20 and about 30 pairs.
7. The device of claim 1 , at least one strand of the siRNA including a 3′ overhang of two or three nucleotides.
8. The device of claim 1 , the siRNA agent comprising additional nucleotides or nucleotide analogue.
9. The device of claim 1 , wherein the siRNA agent comprises a nucleotide sequence that is identical to a portion of a targeted gene.
10. The device of claim 1 , wherein the siRNA agent includes insertions, deletions, or single point mutations compared to a portion of a targeted gene.
11. The device of claim 1 , wherein the siRNA agent is a single strand siRNA.
12. The device of any of claim 1 , wherein the siRNA comprises a ligand tethered to the siRNA.
13. The device of claim 1 , wherein the siRNA agent is incorporated into a delivery vehicle.
14. The device of claim 1 , wherein the siRNA construct comprises a vector.
15. The device according to claim 1 , wherein the pattern has a fractal dimension of greater than about 1.
16. The device according to claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 100 to about 300 nanometers.
17. The device according to claim 1 , wherein the nanostructures have approximately the same cross-sectional dimension.
18. 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 about 1:1 and about 1:4.
19. The device according to claim 1 , wherein at least a portion of the nanostructures have an equidistant spacing.
20. The device according to claim 1 , wherein at a portion of the nanostructures are in the form of pillars.
21. The device according to claim 1 , wherein the channel has a cross-sectional dimension of from about 1 to about 100 micrometers.
22. The device according to claim 21 , wherein the channel has a length of from about 10 to about 800 micrometers.
23. The device according to claim 1 , wherein the device contains a microneedle array that contains the microneedle.
24. The device according to claim 23 , wherein the array contains a base having an aperture, wherein the aperture is in at least partial alignment with the channel of the microneedle.
25. The device according to claim 24 , wherein the reservoir is attached to a substrate upon which the array is located.
26. The device according to claim 24 , wherein the reservoir is removably connected to the array.
27. The device according to claim 1 , wherein at least a portion of the nanostructures have a cross-sectional dimension of from about 20 to about 400 nanometers and at least a portion of the microstructures have a cross-sectional dimension of from about 600 nanometers to about 1.5 micrometers.
28. The device according to claim 1 , wherein at least a portion of the microstructures have an aspect ratio of from about 0.2 to about 5.
29. The device according to claim 1 , wherein the cross-sectional dimension of the microstructures is greater than the height of the microstructures.
30. The device according to claim 29 , wherein at least a portion of the microstructures have an aspect ratio of from about 0.15 to 1.
31. The device according to claim 1 , wherein at least a portion of the nanostructures have a height greater than a cross-sectional dimension.
32. A method for delivering an siRNA construct across a dermal barrier, the method comprising:
penetrating a stratum corneum with a microneedle having a surface on which a plurality of nanostructures and microstructures project directly outward therefrom in a predetermined pattern, wherein the microneedle further contains a channel, wherein at least a portion of the microstructures nave a cross-sectional dimension of greater than about 500 nanometers and less than about 10 micrometers and a height of from about 20 nanometers to about 1 micrometer, and wherein at least a portion of the nanostructures have a cross-section dimension of less than about 500nanometers and greater than about 5 nanometers and an aspect ratio of from about 0.2 to about 5,
transporting an siRNA construct from a reservoir through the channel of the microneedle and across the stratum corneum.