Materials, Methods, and Systems for Cavitation-mediated Ultrasonic Drug Delivery in vivo
First Claim
1. A method suitable for the controlled intracellular and extracellular delivery of one or more therapeutic compounds to a region of a patient, the method comprising the acts (steps) of(a) administering to the patient one or more therapeutics;
- (b) administering to the patient one or more contrast agents;
wherein said contrast agents may be the same as or different from one another;
where steps (a) and (b) are performed(i) in any order, or(ii) simultaneously;
(c) alteration of the permeability or structural integrity of said region of said patient comprising(i) administering to the patient acoustic energy at one or more frequencies, inducing acoustic cavitation at said region of said patient;
(ii) measuring the level of acoustic cavitation at said region of said patient by measuring acoustic emissions either (1) alone;
(2) possibly in combination with one or more additional properties directly or indirectly related to the level of acoustic cavitation at said region of said patient; and
(3) possibly in combination with one or more properties of said acoustic energy;
at the time of or subsequent to the initial application of said acoustic energy;
(d) utilizing the measurement(s) obtained in act (step) (c) to modify continued or subsequent application of acoustic energy to said region of said patient, and possibly administering to said patient one or more additional contrast agents, therapeutics, and other compounds;
wherein said contrast agents, therapeutics, or other compounds may be the same as or different from one another;
where said acoustic energy is applied at a level below the threshold level for lethal sonolysis or cytotoxicity;
(e) allowing said therapeutic compounds to traverse said disrupted cellular membranes and/or other internal structures of said patient, in said region; and
(f) possibly repeating acts (steps) (a) through (e), in whole or in part, either independently or in any combination, one or more times.
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Abstract
Materials, methods, and systems for targeted and non-targeted therapeutic delivery in vivo utilizing cavitation-mediated ultrasonic drug delivery are described. Noninvasive sonic energy being applied to the patient in a controlled fashion at the treatment area results in controlled acoustic cavitation at said region, and cell and tissue specific drug delivery. Microbubbles, both in the form of contrast agents, and/or other active agents infused into the patient, and/or bubbles formed from previous ultrasound exposure, allow for predictable cavitation thresholds, requiring much lower incident ultrasound intensities for permeating tissue. Further, methods and systems are provided that result in more spatially regular areas of controlled tissue permeability upon treatment, limiting cytotoxicity and sonolysis, and maximizing intracellular drug delivery. Moreover, by using pulsed cavitation-mediated ultrasonic drug delivery as described by the present teachings, a large number of parameters are created, which provided the appropriate monitoring and feedback mechanisms are present, allow the use of a diversity of parameter optimizations and control systems for customizing the methods and systems for a given application. Preferred therapeutics for use with the present invention include nucleic acids, proteins, peptides, and other therapeutic macromolecules.
162 Citations
55 Claims
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1. A method suitable for the controlled intracellular and extracellular delivery of one or more therapeutic compounds to a region of a patient, the method comprising the acts (steps) of
(a) administering to the patient one or more therapeutics; -
(b) administering to the patient one or more contrast agents;
wherein said contrast agents may be the same as or different from one another;
where steps (a) and (b) are performed(i) in any order, or (ii) simultaneously; (c) alteration of the permeability or structural integrity of said region of said patient comprising (i) administering to the patient acoustic energy at one or more frequencies, inducing acoustic cavitation at said region of said patient; (ii) measuring the level of acoustic cavitation at said region of said patient by measuring acoustic emissions either (1) alone;
(2) possibly in combination with one or more additional properties directly or indirectly related to the level of acoustic cavitation at said region of said patient; and
(3) possibly in combination with one or more properties of said acoustic energy;
at the time of or subsequent to the initial application of said acoustic energy;(d) utilizing the measurement(s) obtained in act (step) (c) to modify continued or subsequent application of acoustic energy to said region of said patient, and possibly administering to said patient one or more additional contrast agents, therapeutics, and other compounds;
wherein said contrast agents, therapeutics, or other compounds may be the same as or different from one another;
where said acoustic energy is applied at a level below the threshold level for lethal sonolysis or cytotoxicity;(e) allowing said therapeutic compounds to traverse said disrupted cellular membranes and/or other internal structures of said patient, in said region; and (f) possibly repeating acts (steps) (a) through (e), in whole or in part, either independently or in any combination, one or more times. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)
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55. The targeting moiety according to claim 55, wherein said targeting moiety is comprised of at least one component useful in magnetically targeting said vesicle.
Specification