Biodegradable Triblock Copolymers for Use in Acoustically Mediated Intracellular Drug Delivery in vivo

• US 20080243049A1
• Filed: 06/05/2008
• Published: 10/02/2008
• Est. Priority Date: 06/06/2007
• Status: Abandoned Application

• Current Assignee: Biovaluation & Analysis Incorporated
• Original Assignee: Biovaluation & Analysis Incorporated
• Inventors: Hardy, Charles Thomas
• Application Number:
  US12/133,631
• Publication Number:
  US 20080243049A1
• Time in Patent Office: Days
• US Class Current: 604/22
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Targeted therapeutic delivery systems comprising specially designed nanocarriers for intracellular therapeutic delivery, mediated by acoustic energy, for use either in vivo or in vitro, are described. Nanocarriers comprised of substantially biodegradable triblock copolymers, and mixtures thereof, are used to treat a variety of diseases in humans and other species, such as cancer, opthalmological, pulmonary, urinary or other pathologies. Methods for preparing the targeted therapeutic delivery systems are also embodied, which comprise processing a solution comprised of biopolymers or other species and components, with or without targeting moieties, adding said biopolymers and other compounds to a solution containing one or more therapeutic agents, stabilizing or not stabilizing said nanocarriers, adding one or more contrast agents, and resulting in a targeted therapeutic delivery system. Preferred therapeutics for use with the present invention include nucleic acids, proteins, peptides, and other therapeutic macromolecules.

Claims

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 said patient a therapeutic delivery system comprising a nanocarrier, in combination with one or more therapeutic compounds, wherein said nanocarrier is comprised of a biodegradable triblock copolymers or mixtures thereof, wherein said biodegradable triblock copolymers may be the same as or different from one another;

(b) administering to said 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) applying therapeutic ultrasound to said region to induce rupturing of said nanocarrier, and disruption of cellular membranes and other structures of said patient, in said region, wherein said therapeutic compounds are encapsulated or embedded in said nanocarrier, thereby releasing one or more therapeutic compounds in said region, where said therapeutic ultrasound is applied at a level below the threshold level for lethal sonolysis or cytotoxicity; and

(d) allowing said therapeutic compounds to traverse said disrupted cellular membranes and/or other internal structures of said patient, in said region; and

(e) possibly repeating steps (a) through (d), in whole or in part, either independently or in any combination, one or more times.

2. The method as defined in claim 1, wherein at least one targeting moiety is associated with said nanocarrier.

3. The method as defined in claim 1, wherein at least one targeting moiety is associated with at least one of said contrast agents.

4. The method as defined in claim 1, wherein said nanocarrier is comprised substantially of a stabilized biodegradable triblock copolymers or mixtures thereof, wherein said stabilized biodegradable triblock copolymers may be the same as or different from one another.

5. The nanocarrier according to claim 1, further comprising at least one lipid, phospholipid, steroid, cholesterol, single-chain alcohol, polymer, copolymer, or surfactant.

6. A nanocarrier according to claim 1 wherein said triblock copolymer has an A-B-A structure

wherein each A end block is water-soluble, hydrophilic, and non-toxic;

and wherein the B middle block of said triblock copolymer is a polycarbonate with the same as or different repeating units with the following structure

7. A nanocarrier according to claim 6 wherein said A end blocks of said triblock copolymer are poly(alkylene oxides) having the structure

8. A nanocarrier according to claim 6 wherein the end blocks of said triblock copolymer have the structure

9. A nanocarrier according to claim 6 wherein Z of said triblock copolymer is about 10.

10. A nanocarrier according to claim 6 wherein R₁ and R₂, of said triblock copolymer contain an ether linkage.

11. A nanocarrier according to claim 6 wherein R₁ of said triblock copolymer is —

CH₂—

CH₂—

.

12. A nanocarrier according to claim 6 wherein R₂ of said triblock copolymer is selected from the group consisting of ethyl, butyl, hexyl, octyl, decyl, dodecyl, and benzyl groups.

13. A nanocarrier according to claim 1 wherein said triblock copolymer has an A-B-A structure

wherein each A end block is water-soluble, hydrophilic, and non-toxic;

and wherein each B middle block is hydrophobic with the same as or different repeating units having the following structure

14. A nanocarrier according to claim 13 wherein the end groups of said triblock copolymer are poly(alkylene oxides) having the structure

15. A nanocarrier according to claim 13, wherein the A end blocks of said triblock copolymer have the structure

16. A nanocarrier according to claim 13 wherein Z of said triblock copolymer is about 10.

17. A nanocarrier according to claim 13 wherein one or more of R, R₁, and R₂, of said triblock copolymer contains an ether linkage.

18. A nanocarrier according to claim 13 wherein R₁ of said triblock copolymer is —

CH₂—

CH₂—

.

19. A nanocarrier according to claim 13 wherein R of said triblock copolymer contains up to 12 carbon atoms.

20. A nanocarrier according to claim 19, wherein R of said triblock copolymer is selected from the group consisting of:

—

CH₂—

CH₂—

C(═

O)—

, —

CH═

CH—

, —

CH₂—

CH(—

OH)—

, —

CH₂-—

C(═

O)— and

(—

CH₂—

)_z, wherein z is between 0 and 12, inclusive.

21. A nanocarrier according to claim 13, wherein R₂ of said triblock copolymer is selected from the group consisting of ethyl, butyl, hexyl, octyl, and benzyl groups.

22. The method as defined in claim 1, wherein said therapeutic compound is genetic material.

23. The therapeutic compound according to claim 22, wherein said genetic material comprises a nucleic acid, RNA or DNA of either natural or synthetic origin, comprising recombinant RNA and DNA, antisense RNA, RNA interference (RNAi), small interfering RNA (siRNA), or any combination thereof.

24. The nanocarrier according to claim 1, wherein said nanocarrier, which may be the same or different from one another, is embedded or dispersed in a drug delivery polymer matrix such as a hydrogel.

25. The method as defined in claim 1, wherein said method is for delivering one or more of said therapeutic compounds to the anterior or posterior portion of the eye.

26. The method as defined in claim 1, where previous to being administered to said patient, said therapeutic is embedded in a polymer, gel, or other matrix, allowing extended intracellular therapeutic release.

27. The method as defined in claim 1, wherein said therapeutic ultrasound comprises continuous wave ultrasound.

28. The method as defined in claim 1, wherein said therapeutic ultrasound is selected from the group consisting of amplitude and frequency modulated pulses.

29. The method as defined in claim 1, wherein said therapeutic ultrasound is applied externally to said patient.

30. The method as defined in claim 1, wherein said therapeutic ultrasound is applied endoscopically to said patient.

31. The method as defined in claim 1, wherein said nanocarrier is administered intravenously to said patient.