Amphiphilic polymers and methods of use thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C08G-063/06
C08G-063/12
C08G-069/08
C08G-075/00
C08G-063/00
C08G-067/00
C08G-069/00
A61K-047/30
출원번호
US-0405012
(2006-04-17)
등록번호
US-8349991
(2013-01-08)
발명자
/ 주소
Colton, Clark K.
Watterson, Arthur
Kumar, Rajesh
Parmar, Virinder S.
Fisher, Robert
Kumar, Jayant
출원인 / 주소
Massachusetts Institute of Technology
대리인 / 주소
Fish & Richardson P.C.
인용정보
피인용 횟수 :
2인용 특허 :
26
초록
The present invention relates to amphiphilic polymers, and micelles and compositions comprising the same, and their use in a variety of biological settings, including imaging, targeting drugs, or a combination thereof for diagnostic and therapeutic purposes.
대표청구항▼
1. An amphiphilic polymer, characterized by the structure of the general formula I: wherein R is a hydroxyl, O-alkyl, O-Acyl, O-Activating group, SH, S-alkyl, an acid activating group comprising halogen, O-vinyl, O-allyl, O-aryl, OCOalkyl, OCOaryl, OCH2CF3, or NH2;R′ is OH, NH2, or SH;each R1 group
1. An amphiphilic polymer, characterized by the structure of the general formula I: wherein R is a hydroxyl, O-alkyl, O-Acyl, O-Activating group, SH, S-alkyl, an acid activating group comprising halogen, O-vinyl, O-allyl, O-aryl, OCOalkyl, OCOaryl, OCH2CF3, or NH2;R′ is OH, NH2, or SH;each R1 group is, independently, a perfluorocarbon, a perfluorocarbon-R4, a perfluorocarbon-OR4, or each R2 group is, independently, perfluorocarbon, a perfluorocarbon-R4, a perfluorocarbon-OR4, or each R3 group is, independently, a drug, a labeling agent, or a targeting moiety; orOR3 is a fluorinated ether group;each R4 group is, independently, an alkyl group, an alkylene group, a carboxylate group, a carboxylic acid group, an amino group, an ammonium group, an alkoxyl group, a hydroxyl group, or another nitrogen, oxygen, or sulfur-containing group;each A group is, independently, O, NH, S, an acyl group, an aryl group, a linear or branched alkenyl group, or a linear or branched alkyl group, t,n, m, p, p′ and x are integers, such that the weight of a fraction of the polymer ranges between 0-5% or 6-99% or 50-100% of the weight of said polymer, wherein said fraction is represented by the structure: andq is an integer between 0-10;wherein comprises a molecular weight of from 60 to 10,000 Daltons; andwherein:x is greater than 0 and the R1 or R2 group consists of a perfluorocarbon, a perfluorocarbon-R4 or a perfluorocarbon-OR4, wherein any of said perfluorocarbons is further selected from the group consisting of (CF2)zCF3 wherein z is an integer, CH2OCH2(CF2)8CF3, CH2OCH2(CF2)6CF3, CH2OCH2(CF2)4CF3, and CH2OCH2CH2(CF2)11CF3; orm is greater than 0 and the OR3 group consists of a fluorinated ether group, wherein said fluorinated ether group is further selected from the group consisting of CH2OCH2(CF2)8CF3, CH2OCH2(CF2)6CF3, CH2OCH2(CF2)4CF3, and CH2OCH2CH2(CF2)11CF3, or the R2 group consists of a perfluorocarbon, a perfluorocarbon-R4 or a perfluorocarbon-OR4 wherein any of said perfluorocarbons is further selected from the group consisting of (CF2)zCF3 wherein z is an integer, CH2OCH2(CF2)8CF3, CH2OCH2(CF2)6CF3, CH2OCH2(CF2)4CF3, and CH2OCH2CH2(CF2)11 CF3 ; orboth x and m are greater than 0 and the R1 or R2 group consists of a perfluorocarbon, a perfluorocarbon-R4 or a perfluorocarbon-OR4 wherein any of said perfluorocarbons is further selected from the group consisting of (CF2)zCF3 wherein z is an integer, CH2OCH2(CF2)8CF3, CH2OCH2(CF2)6CF3, CH2OCH2(CF2)4CF3, and CH2OCH2CH2(CF2)11CF3, the OR3 group consists of a fluorinated ether group, wherein said fluorinated ether group is further selected from the group consisting of CH2OCH2(CF2)8CF3, CH2OCH2(CF2)6CF3, CH2OCH2(CF2)4CF3, and CH2OCH2CH2(CF2)11CF3. 2. The polymer of claim 1, wherein any of said perfluorocarbons is (CF2)zCF3, wherein z is an integer. 3. The polymer of claim 2, wherein any of said perfluorocarbons is (CF2)8CF3, (CF2)6CF3, or (CF2)3CF3. 4. The polymer of claim 1, wherein any of said perfluorocarbon-OR4— groups is CH2OCH2(CF2)8CF3, CH2OCH2(CF2)6CF3, CH2OCH2(CF2)4CF3 or CH2OCH2CH2(CF2)11CF3. 5. The polymer of claim 1, wherein if m is 0, then R1 is and R2 is a perfluorocarbon, a perfluorocarbon-OR4, or a derivative thereof. 6. The polymer of claim 1, wherein any of said targeting moieties is a peptide, an antibody, an antibody fragment, a receptor, Protein A, Protein G, biotin, avidin, streptavidin, a metal ion chelate, an enzyme cofactor, a nucleic acid or a ligand. 7. The polymer of claim 6, wherein said peptide binds to an underglycosylated mucin-1. 8. The polymer of claim 7, wherein said peptide is an EPPT1 peptide (SEQ ID NO: 1). 9. The amphiphilic polymer of claim 1 wherein m is 0 and x is greater than 0. 10. The amphiphilic polymer of claim 1 wherein x is 0 and m is greater than 0. 11. The amphiphilic polymer of claim 1, wherein the polymer comprises a drug. 12. The amphiphilic polymer of claim 1, wherein the polymer comprises a targeting moiety. 13. The amphiphilic polymer of claim 1, wherein the polymer comprises a labeling agent. 14. The amphiphilic polymer of claim 1, wherein the polymer comprises two or more of a drug, a targeting moiety, and a labeling agent. 15. The amphiphilic polymer of claim 1, wherein the polymer comprises a drug, a targeting moiety, and a labeling agent. 16. The polymer of claim 1, wherein said polymer is characterized by the structure of the general formula II: wherein R′═OH, NH2, or SH;R═OH, O-Alkyl, O-aryl, O-acyl, or O-activating group;R1 is, independently, a perfluorocarbon, a perfluorocarbon-R4, a perfluorocarbon-OR4, or each R3 group is, independently, a drug, a labeling agent or a targeting moiety; orOR3 is a fluorinated ether group; whereineach R2 is, independently, a perfluorocarbon, a perfluorocarbon-R4, a perfluorocarbon-OR4, or andA=O, NH, or S. 17. The polymer of claim 16, wherein the weight of a fraction of said polymer ranges between 6-99% of the weight of said polymer, said fraction represented by the structure: 18. The polymer of claim 16, wherein the weight of a fraction of said polymer ranges between 1-94% of the weight of said polymer, said fraction represented by the structure: 19. The amphiphilic polymer of claim 16, wherein the polymer comprises a drug. 20. The amphiphilic polymer of claim 16, wherein the polymer comprises a targeting moiety. 21. The amphiphilic polymer of claim 16, wherein the polymer comprises a labeling agent. 22. The amphiphilic polymer of claim 16, wherein the polymer comprises two or more of a drug, a targeting moiety, and a labeling agent. 23. The amphiphilic polymer of claim 16, wherein the polymer comprises a drug, a targeting moiety, and a labeling agent. 24. A composition comprising the polymer of claim 1. 25. A micelle comprising the polymer of claim 1. 26. The micelle of claim 25, wherein a fluorochrome, an indole-containing compound, an antibody or antibody fragment, a peptide, an oligonucleotide, a labeling agent, a drug, an enzyme, a chemomimetic functional group, a glycolipid, a metal ion chelate, an enzyme cofactor, a cytotoxic compound, a growth factor, a hormone, a cytokine, a toxin, a prodrug, an antimetabolite, a microtubule inhibitor, a radioactive material, a perfluorocarbon, or a combination thereof, is encapsulated within said micelle. 27. A process for producing an amphiphilic polymer of claim 1 comprising perfluorocarbons, the process comprising the steps of: i. contacting a dialkyl 5-hydroxy-isophthalate, a dialkyl 5-alkoxy-isophthalate, a dialkyl 5-amino-isophthalate, any derivative thereof or any combination thereof with a polyethylene glycol to form an amphiphilic copolymer; andii. linking a perfluorocarbon to said amphiphilic copolymer, thereby being a process for producing amphiphilic polymers comprising perfluorocarbons. 28. The process of claim 27, wherein said process is performed in the presence of an enzyme. 29. The process of claim 28, wherein said enzyme is a lipase. 30. The process of claim 27, wherein said linking a perfluorocarbon to said amphiphilic copolymer comprises the step of alkylating the hydroxy group of said isophthalate to produce —(CH2)qCO-R2. 31. The process of claim 27, further comprising the step of dissolving said product in water. 32. The process of claim 31, wherein micelles comprising polymeric units of said product self-assemble. 33. A method of imaging a cell, the method comprising the steps of contacting a cell with the amphiphilic polymer of claim 1, wherein the polymer comprises a labeling agent, and imaging said cell, whereby said polymer enables the imaging of said cell. 34. The method of claim 33, wherein said imaging is accomplished with computed tomography, computed radiography, magnetic resonance imaging, fluorescence microscopy, angiography, arteriography, nuclear imaging or a combination thereof. 35. A method of imaging a cell, the method comprising the steps of contacting a cell with the amphiphilic polymer of claim 16, wherein the polymer comprises a labeling agent, and imaging said cell, whereby said polymer enables the imaging of said cell. 36. A method of targeted delivery of at least one agent in a subject comprising the steps of administering to said subject the amphiphilic polymer of claim 1, wherein said polymer comprises said agent and a targeting moiety. 37. The method of claim 36, wherein the agent is a drug. 38. The method of claim 36, wherein the polymer comprises at least two agents, wherein a first agent is a drug and a second agent is a labeling agent. 39. A method of targeted delivery of at least one agent in a subject comprising the steps of administering to said subject the amphiphilic polymer of claim 16, wherein said polymer comprises said agent and a targeting moiety. 40. The method of claim 39, wherein the agent is a drug. 41. The method of claim 39, wherein the polymer comprises at least two agents, wherein a first agent is a drug and a second agent is a labeling agent.
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