Systems and methods for delivery of a therapeutic agent
View Patent ↗Methods and apparatus are provided for applying an fragment of a neurotoxin such as the active light chain (LC) of the botulinum toxin (BoNT), such as one of the serotype A, B, C, D, E, F or G botulinum toxins, via permeabilization of targeted cell membranes to enable translocation of the botulinum neurotoxin light chain (BoNT-LC) molecule across the targeted cell membrane to the cell cytosol where a therapeutic response is produced in a mammalian system. The methods and apparatus include use of catheter based delivery systems, non-invasive delivery systems, and transdermal delivery systems.
1. A system for delivering toxins to target cells in a mammalian target, said system comprising:
a toxin consisting of a light chain of a neurotoxin fragment;
a catheter or other structure adapted to introduce the toxin to a region adjacent the target cells; and
an energy applicator configured to apply energy to the target cells at a level sufficient to cause pores to form in the cell membranes of the target cells to allow the toxin to pass through said pores into the target cells.
2. A system as in claim 1 , wherein the energy applicator is adapted to selectively apply energy to target cells within the region where toxin has been introduced.
3. A system as in claim 1 , wherein the energy applicator is adapted to apply energy non-selectively within the region where toxin has been introduced.
4. A system as in claim 1 , wherein the toxin is an active toxin fragment.
5. A system as in claim 4 , wherein the active fragment is selected from the group consisting of botulinum toxin fragments, ricin fragments, exotoxin A fragments, diphtheria toxin fragments, cholera toxin fragments, and tetanus toxin fragments.
6. A system as in claim 5 , wherein the active fragment consists of the botulinum light chain (BoNT-LC).
7. A system as in claim 6 , wherein the light chain fragment is derived from at least one of botulinum toxins A, B, C, D, E, F, and G.
8. A system as in claim 1 , wherein the energy applicator is adapted to apply an electric pulse of between 1V and 500V to the target region.
9. A system as in claim 8 , wherein the electric pulse is radio frequency (RF) energy.
10. A system as in claim 9 , wherein the RF energy is pulsed for durations between 5 microseconds to 100 milliseconds.
11. A system as in claim 8 , wherein the electric pulse is produced by a DC power source.
12. A system as in claim 8 , wherein the electric pulse is produced by an AC power source.
13. A system as in claim 1 , wherein the energy applicator is adapted to apply ultrasonic energy to the targeted region.
14. A system as in claim 13 , wherein the energy applicator is adapted to apply focused ultrasound to the targeted region.
15. A system as in claim 1 , wherein the energy applicator is adapted to apply an x-ray beam to the targeted region.
16. A system as in claim 1 , wherein the energy applicator is adapted to apply microwaves to the targeted region.
17. A system as in claim 1 , wherein the catheter comprises a needle for delivering the toxin.
18. A system as in claim 1 , wherein the catheter comprises a port for aerosolizing the toxin.
19. A system as in claim 1 , wherein the catheter comprises a balloon for deflecting one or more ports against target tissue.
20. A system as in claim 19 , wherein the balloon comprises the one or more ports.
21. A system as in claim 1 , wherein the energy applicator is on the catheter.
22. A system as in claim 21 , wherein the energy applicator applies acoustic energy from a transducer on the catheter.
23. A system as in claim 21 , wherein the energy applicator applies electrical energy from an electrode on the catheter.
24. A system as in claim 1 , wherein the applicator applies energy from a source external to the patient.
25. A system as in claim 24 , wherein the source is an acoustic energy transducer.
26. A system as in claim 25 , wherein the acoustic energy transducer is focused ultrasound transducer.
27. A system for delivering toxins to target cells in a mammalian target, said system comprising:
a toxin delivery structure adapted to introduce a toxin to a region adjacent the target cells;
an acoustic energy delivery element configured for applying acoustic energy to the target cells under conditions which causes poration of the cell membranes to enhance delivery of the toxin; and
a toxin delivered by the catheter, the toxin consisting of a light chain of a neurotoxin fragment, wherein the delivery element is configured to deliver acoustic energy at a level sufficient to result in poration of the cell membranes to allow the toxin to pass into the target cells.
28. A system as in claim 27 , wherein the acoustic energy delivery element comprises an ultrasound transducer.
29. A system as in claim 27 , wherein the acoustic energy delivery element is adapted to selectively apply the acoustic energy to the target cells within the region where toxin has been introduced.
30. A system as in claim 27 , wherein the toxin is an active toxin fragment.
31. A system as in claim 30 , wherein the active fragment is selected from the group consisting of botulinum toxin fragments, ricin fragments, exotoxin A fragments, diphtheria toxin fragments, cholera toxin fragments, and tetanus toxin fragments.
32. A system as in claim 30 , wherein the active fragment consists of the botulinum light chain (BoNT-LC).
33. A system as in claim 32 , wherein the light chain fragment is derived from at least one of botulinum toxins A, B, C, D, E, F, and G.
34. A system as in claim 27 , wherein the acoustic energy delivery element is adapted to apply focused ultrasound to the targeted region.
35. A system as in claim 27 , wherein the toxin delivery structure comprises a needle for delivering the toxin.
36. A system as in claim 27 , wherein the toxin delivery structure comprises a port for aerosolizing the toxin.
37. A system as in claim 27 , wherein the toxin delivery structure comprises a balloon for deflecting one or more ports against target tissue.
38. A system as in claim 37 , wherein the balloon comprises the one or more ports.