Composition comprising gas-filled microcapsules for ultrasound mediated delivery
Composition comprising gas filled microcapsules and a bioactive agent, useful for an ultrasound-mediated delivery of said bioactive agent. The microcapsules comprise a relatively stiff shell of polymeric or lipid material and have in particular a resistance to a mechanical index of at least 0.15, while the bioactive agent is substantially unbound to the shell of the microcapsules. The composition of the invention is particularly suitable for effectively delivering a genetic material into a cell, upon exposure of the composition to a level of acoustic pressure capable of destroying a portion of the microcapsules and releasing the gas contained therein.
1. A method for delivering a bioactive agent into a cell which comprises:
administering a composition comprising a bioactive agent and a plurality of gas filled microcapsules having a polymeric and/or lipid shell to a body part comprising said cell in a patient in need thereof, said microcapsules having a resistance to a mechanical index of at least 0.15 and not higher than 10, and said bioactive agent being substantially unbound to and located outside of said shell; and
applying an ultrasound wave to said body part, said wave having a frequency of from about 20 kHz to less than about 50 MHz and an acoustic pressure that results in a mechanical index that is capable of destroying a portion of said microcapsules, to effectively deliver said bioactive agent to said cell.
2. The method of claim 1 wherein the shell of said microcapsules comprises a biodegradable physiologically compatible polymer and/or a biodegradable water-insoluble lipid.
3. The method of claim 1 wherein the gas contained in the microcapsules comprises a perfluorinated gas.
4. The method of claim 1 wherein said bioactive agent is a drug or a genetic material.
5. The method of claim 1 wherein said bioactive agent is associated with a carrier.
6. The method of claim 5 wherein said carrier further comprises a targeting ligand.
7. The method of claim 1 , wherein-said microcapsules have a resistance to a mechanical index of at least 0.18 and not higher than 10.
8. The method of claim 7 , wherein-said microcapsules have a resistance to a mechanical index of at least 0.20 and not higher than 10.
9. The method of claim 1 , wherein said acoustic pressure is from 200 kPa to 10 MPa and said frequency is 1.15 MHz.
10. The method of claim 1 , wherein said acoustic pressure is from 300 kPa to 10 MPa and said frequency is 2.25 MHz.
11. The method of claim 1 , wherein said frequency is from about 300 kHz to about 3 MHz.
12. The method of claim wherein said frequency is from about 500 kHz to about 1.5 MHz.
13. The method of claim 1 , wherein said frequency is about 1 MHz.
14. The method of claim 1 , wherein said wave has a spatial-peak time-average intensity of from about 0.5 mW/cm 2 to about 10 W/cm 2 .
15. The method of claim 1 , wherein said wave has a spatial-peak time-average intensity of from about 1 mW/cm 2 to about 3 W/cm 2 .
16. The method of claim 14 , wherein the total energy deposition is below the cytotoxic threshold of said cell.