Conducting polymer nanotube actuators for precisely controlled release of medicine and bioactive molecules

• US 20080097280A1
• Filed: 08/24/2007
• Published: 04/24/2008
• Est. Priority Date: 08/25/2006
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Martin, David, Abidian, Mohammad
• Granted Patent: US 8,936,794 B2
• Time in Patent Office: Days
• US Class Current: 604/21
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• 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 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Abstract

Drug delivery devices, their manufacture, and their use comprising electrocontractile nanotubes that can be used for precise controlled bioactive substance release for example, medical, veterinary, pharmaceutical compounds and growth factors. The conducting polymer nanotubes significantly decrease the impedance and increase the charge capacity of recording electrode sites on microfabricated electrode devices. Bioactive substances released from the nanotubes can be controlled in a desired fashion by controlled electrical stimulation of the nanotubes.

Claims

1. A drug delivery device comprising:

a first and second electrically conductive substrate;

a plurality of electrocontractile nanotubes coated on at least a portion of said first conductive substrate, said nanotube comprising at least one opening and walls of conductive polymer defining a lumen therein, said lumen containing at least one bioactive substance;

a power source operably connected to said first and said second conductive substrate; and

wherein upon electrical actuation of at least a portion of said nanotubes, a release of said at least one bioactive substance from said electrically actuated nanotubes through said one or more openings.

2. The drug delivery device according to claim 1, wherein said first and said second electrically conductive substrate comprises a metal, a carbon composite, silicon, a metal oxide, conductive polymer or combinations thereof.

3. The drug delivery device according to claim 1, wherein said nanotubes comprise poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), polyanilines, polyacetylenes, polythiophenes, or polymer blends thereof.

4. The drug delivery device according to claim 1, wherein said nanotubes comprise poly(3,4-ethylenedioxythiophene) (PEDOT).

5. The drug delivery device according to claim 1, further comprising a dopant selected from the group consisting of poly(styrene sulfonate), LiClO₄, phosphate-buffered saline (PBS), Hank'"'"'s Balanced Salt Solution (HBSS), collagen, poly-D-lysine (PDL), poly-L-lysine, poly-ornithine, poly acrylic acid, serum, dodecylbenzene sulfonic acid (DBSA), p-toluenesulfonic acid (p-TSA), and combinations thereof.

6. The drug delivery device according to claim 1, wherein said bioactive substance is selected from the group consisting of a pharmaceutical active, a growth factor, a polypeptide, a lipid, a nucleic acid, a amino acid, a receptor, a steroid, a carbohydrate, a glycoprotein, a glycolipid, a neurotransmitter, an antineoplastic agent, an antiproliferative agent, an antithrombogenic agent, an anticoagulant, an antiplatelet agent, an antibiotic, an anti-inflammatory agent, a gene therapy agent, a therapeutic substance, and combinations thereof.

7. The drug delivery device according to claim 1, wherein said nanotubes comprise a diameter ranging from about 10 nm to about 1000 nm.

8. The drug delivery device according to claim 1, wherein said nanotubes comprise a wall thickness ranging from about 1 nm to about 500 nm.

9. A biocompatible electrode comprising:

a first and second electrically conductive substrate; and

a plurality of electrocontractile nanotubes comprising walls of conductive polymer defining a lumen therein containing at least one bioactive substance, said nanotubes coated on at least at a portion of said first conductive substrate,

wherein upon electrical actuation of said nanotubes induces contraction of said nanotube walls causing the release of said bioactive substance from said nanotube lumens.

10. The biocompatible electrode according to claim 9, wherein the conductive polymer is selected from the group consisting of poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), polyanilines, polyacetylenes, polythiophenes, or polymer blends thereof

11. The biocompatible electrode according to claim 9, wherein the bioactive substance is selected from the group consisting of pharmaceutical active, a growth factor, a polypeptide, a lipid, a nucleic acid, an amino acid, a receptor, an enzyme, a steroid, a carbohydrate, a glycoprotein, a glycolipid, or a neurotransmitter.

12. A sensor device comprising:

(1) a substrate having one or more sealed microchannels and at least one reaction chamber forming a microfluidic assembly;

(2) a power source capable of providing a voltage to said microfluidic assembly; and

(3) a data recorder for recording changes in electronic signals provided by said microfluidic assembly;

the microfluidic assembly comprises;

(i) a reaction chamber having a first and a second conductive substrate, said first conductive substrate is in electrical communication with a plurality of electrocontractile nanotubes,

wherein said nanotubes contain a lumen with a bioactive substance, said bioactive substance capable of being released from said nanotubes upon electrical actuation of said nanotube with said power source, enabling binding of said bioactive substance with a test analyte thereby producing a change in electronic signal capable of being transduced by said microfluidic assembly to said data recorder.

13. The sensor device according to claim 12, wherein the target analyte is selected from the group consisting of glucose, troponin I, troponin T, myoglobin, prostate serum antigen, CA, 19-9, CEA, EGFr, p53, p27, and amyloid-beta peptide.

14. A method for controlled release of a bioactive substance, comprising the steps:

(i) providing a drug delivery device comprising;

(A) a first and second electrically conductive substrate;

(B) a plurality of electrocontractile nanotubes formed on at least a portion of said first conductive substrate, the nanotube comprising walls of conductive polymer defining a lumen therein, the lumen containing at least one bioactive substance; and

(C) a power source operably connected to said first and second conductive substrate;

(ii) placing said device in contact with a biological tissue, and

(iii) applying a voltage to at least one of said first and said second electrically conductive substrate of said device so as to supply a voltage to said conductive polymer walls of said nanotubes, thereby causing a contraction of said nanotubes and concomitant release of said at least one bioactive substance.

15. The method according to claim 14, wherein the bioactive substance is released from said nanotubes after applying to said at least one of said first and said second electrically conductive substrate with a voltage ranging from about ±

0.1 V to about ±

5 V with a scan rate of between 0.01 to 1 V/sec for a period of 0.1 seconds to 6 hours.

16. The method according to claim 14, wherein said nanotube wall comprises poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), polyanilines, polyacetylenes, polythiophenes, or polymer blends thereof.

17. The method according to claim 14, wherein said plurality of nanotubes are formed on at least a portion of said first electrically conductive substrate comprising the steps:

(i) electrospinning a solution comprising a biodegradable polymer and at least one bioactive substance onto at least a portion of a surface of said first electrically conductive substrate thereby forming a mesh of nanofibers in contact with said first electrically conductive substrate;

(ii) electrochemically depositing conductive polymers around said nanofibers forming a plurality of nanotubes; and

(iii) degrading said biodegradable polymer of said nanofibers with a solvent, thereby leaving said at least one bioactive substance inside said lumen of said plurality of nanotubes.

18. The method according to claim 17, wherein the concentration ratio of biodegradable polymer to bioactive substance ranges from 1:

99 to 99;

1.

19. The method according to claim 17, wherein the conductive polymers comprise poly(3,4-ethylenedioxythiophene) (PEDOT), poly(pyrrole), or polymer blends thereof.

20. The method according to claim 17, wherein the nanofibers is selected from the group consisting of poly(D-lactic acid) (PDLA), poly(L-lactic acid) (PLLA), poly(lactide-co-glycolide) (PLGA) poly(glycolic acid) (PGA), and their derivatives, poly(epsilon caprolactone) (PCL), chitosan, nylon, PEOxide, alginates, poly vinyl alcohol and combinations thereof.

21. A method for treating a disease in a patient, comprising the steps:

(i) providing an electrically mediated drug delivery device, said device comprising;

(A) a first and second electrically conductive substrate;

(B) a plurality of electrically contractile nanotubes in contact with at least a portion of said first electrically conductive substrate, a plurality of said nanotubes having at least one opening and a lumens containing at least one bioactive substance that is effective in treating the disease; and

(C) a power source operably connected to said first and said second electrically conductive substrate;

(ii) placing said device in contact or near a treatment site in said patient,

(iii) applying a voltage to at least one of said first and said second electrically conductive substrate of said device so as to supply current to said electrically conductive nanotubes, thereby causing contraction of said nanotubes and concomitant release of said at least one bioactive substance from said nantotube opening at or near the treatment site.

22. The method according to claim 21, wherein the disease is selected from the group consisting of neurological disease, cardiac disease, cardiovascular disease, muscular disease, endocrinology disease, immunological disease, circulatory disease and combinations thereof.

23. The method according to claim 21, wherein the disease to be treated is any one or more of Parkinson'"'"'s disease, muscular dystrophy, Alzheimer'"'"'s disease, epilepsy, diabetes, and coronary artery disease.