Polymers for functional particles

• US 8,367,113 B2
• Filed: 05/15/2007
• Issued: 02/05/2013
• Est. Priority Date: 05/15/2006
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Inventors: Gu, Frank X., Teply, Benjamin A., Langer, Robert S., Farokhzad, Omid C.
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Shomer, Isaac
• Application Number:
  US11/803,843
• Publication Number:
  US 20080081074A1
• Time in Patent Office: 2,093 Days
• Field of Search: None
• US Class Current: 424/489
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61K 51/1244 microparticles or nanoparticles, e.g. polymeric nanoparticles
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 63/912 derived from hydroxycarboxylic acids
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

The present invention generally relates to polymers and macromolecules, in particular, to block polymers useful in particles such as nanoparticles. One aspect of the invention is directed to a method of developing nanoparticles with desired properties. In one set of embodiments, the method includes producing libraries of nanoparticles having highly controlled properties, which can be formed by mixing together two or more macromolecules in different ratios. One or more of the macromolecules may be a polymeric conjugate of a moiety to a biocompatible polymer. In some cases, the nanoparticle may contain a drug. The moiety, in some embodiments, may have a molecular weight greater than about 1000 Da; for example, the moiety may include a polypeptide or a polynucleotide, such as an aptamer. The moiety may also be a targeting moiety, an imaging moiety, a chelating moiety, a charged moiety, or a therapeutic moiety. Another aspect of the invention is directed to systems and methods of producing such polymeric conjugates. In some embodiments, a solution containing a polymer is contacted with a liquid, such as an immiscible liquid, to form nanoparticles containing the polymeric conjugate. Other aspects of the invention are directed to methods using such libraries, methods of using or administering such polymeric conjugates, methods of promoting the use of such polymeric conjugates, kits involving such polymeric conjugates, or the like.

Claims

1. A nanoparticulate composition comprising a particle having an average characteristic dimension of less than about 1 micrometer,

the particle formed of an amphiphilic macromolecule comprising

(a) a first hydrophobic portion,

(b) a second hydrophilic portion;

and

(c) a third portion comprising a moiety selected from the group consisting of a targeting moiety, an imaging moiety, a chelating moiety, a moiety having multiple charge groups, and a therapeutic moiety,

wherein the first, second or both portions comprise a biocompatible polymer, and

wherein the particles are formed by self-assembling the macromolecule into nanoparticles having a greater concentration of the third portion moiety on the surface of the nanoparticle and a detectable amount of the third portion moiety in the interior of the nanoparticle.

2. The composition of claim 1, wherein the moiety has a molecular weight of at least about 1000 Da.

3. The composition of claim 1, wherein the moiety has a molecular weight of no more than about 1000 Da.

4. The composition of claim 1, wherein the amphiphilic macromolecule is a block copolymer.

5. The composition of claim 1, wherein at least a portion of the macromolecule is biodegradable.

6. The composition of claim 5, wherein at least a portion of the macromolecule is hydrolyzable.

7. The composition of claim 1, wherein the biocompatible polymer comprises a polymer selected from the group consisting of poly(lactide-co-glycolide), poly(lactide), poly(glycolide), poly(orthoesters), poly(caprolactones), polylysine, poly(ethylene imine), poly(acrylic acid), poly(urethanes), poly(anhydrides), poly(esters), poly(trimethylene carbonate), poly(ethyleneimine), poly(beta amino esters), and copolymers thereof.

8. The composition of claim 1, comprising a targeting moiety comprising a molecule selected from the group consisting of a polypeptide, a nucleic acid, a fatty acid, a carbohydrate, a peptidoglycan, and a glycopeptide.

9. The composition of claim 8, wherein the targeting moiety comprises an aptamer.

10. The composition of claim 1, wherein the targeting moiety specifically binds prostate specific membrane antigen.

11. The composition of claim 1, wherein the targeting moiety comprises an antibody or an antibody fragment.

12. The composition of claim 1, wherein the targeting moiety is able to specifically bind to a molecule on the surface of a cell.

13. The composition of claim 1, wherein the targeting moiety is able to specifically bind to a biological entity selected from the group consisting of bacterial membrane proteins, cytokines, chemokines, growth factors, insulin, erythropoietin, tumor necrosis factor, glycoproteins, adhesion molecules, fibronectins, laminin, and antigens.

14. The composition of claim 1, wherein the nanoparticle further comprises a second macromolecule.

15. The composition of claim 1, wherein the nanoparticle further comprises a therapeutic, prophylactic or diagnostic agent.

16. The composition of claim 15, wherein the agent is hydrophobic, the amphiphilic macromolecule comprises a polymer having a hydrophobic portion, and the agent associates with the hydrophobic portion of the polymer in the nanoparticle.

17. The composition of claim 1, wherein the nanoparticle comprises a therapeutic agent selected from the group consisting of antimicrobial agents, analgesics, antiinflammatory agents, counterirritants, coagulation modifying agents, diuretics, sympathomimetics, anorexics, gastrointestinal agents;

antiparasitics, antihypertensives, anticholinergics, antihormones, central and respiratory stimulants, drug antagonists, lipid-regulating agents, uricosurics, cardiac glycosides, electrolytes, ergot and derivatives thereof, expectorants;

hypnotics;

sedatives, antiinfectives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, para-sympathomimetics, anticonvulsants, purgatives, antiarrhythmics, tranquilizers, vasodilators, antiviral agents, antiasthmatic agents, anticonvulsants, antidepressants, antidiuretic agents, antidiarreals, antihistamines, antimigraine preparations, antinauseants, antiparkinsonism drugs, antipsychotics, antispasmodics, anticholinergics, calcium channel blockers, beta-blockers, vasodilators, decongestants, hormones, steroids, hypnotics, immunosuppressives, parasympatholytics, psychostimulants, tranquilizers, and antineoplastic, cytostatic agents or other agents with anticancer properties, or a combination thereof.

18. The composition of claim 1, wherein the nanoparticle comprises a peptide or a protein, nucleic acid, fatty acid, carbohydrate, peptidoglycan, or glycopeptide.

19. The composition of claim 1, wherein the nanoparticle comprises docetaxel.

20. The composition of claim 1, wherein the nanoparticle comprises an enzyme.

21. The composition of claim 1, wherein the nanoparticle has an average characteristic dimension of less than about 150 nm.

22. The composition of claim 4, wherein the block copolymer comprises poly(alkylene glycol).

23. The composition of claim 22, wherein the poly(alkylene glycol) comprises poly(ethylene glycol).

24. The composition of claim 1, wherein the nanoparticle is made by a process comprising providing a solution comprising the macromolecule;

and contacting the solution with a polymer nonsolvent wherein the macromolecules self-assemble to produce the nanoparticle particle having a greater concentration of the second portion on the outside and a greater concentration of the first portion on the inside.

25. The composition of claim 24, wherein the solution comprising the macromolecule is an organic solution and the polymer nonsolvent is an aqueous solution.

26. The composition of claim 1, comprising a nanoparticle formed of first macromolecules and second macromolecules;

wherein the first macromolecules are block copolymers comprising a first biocompatible polymer, a poly(alkylene glycol), and a moiety selected from the group consisting of a targeting moiety, an imaging moiety, a chelating moiety, a moiety having multiple charge groups, and a therapeutic moiety; and

wherein the second macromolecules are block copolymers comprising a poly(alkylene glycol).

27. The nanoparticulate composition of claim 14, wherein the nanoparticle is made by a process comprising providing a solution comprising the macromolecules and contacting the solution with a polymer nonsolvent wherein the macromolecules self-assemble to produce the nanoparticle.

28. The composition of claim 1, the particle further comprising at least one other polymer.

29. The composition of claim 28 wherein the molecular weights, charges, or ratios of the polymers are selected to control surface charge, surface density of the moiety or the size of the particle.