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Polyglutamate-amino acid conjugates and methods

a technology of polyglutamate and amino acid, applied in the field of biocompatible watersoluble polymers, can solve the problems of/or drug, poor bioavailability of the relative hydrophobic imaging agent, and poor so as to achieve the effect of effective solubility of the imaging agent and/or drug, increasing functionality and/or bioavailability

Inactive Publication Date: 2007-06-07
NITTO DENKO CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] The inventors have discovered a series of novel polyglutamate-amino acids that are capable of conjugating to a number of agents, such as imaging agents and / or drugs. In certain embodiments, the polymers and the resulting conjugates preferentially accumulate in certain tissues (e.g., tumor tissues), and thus are useful for delivering drugs (e.g., anticancer drugs) and / or imaging agents to specific parts of the body (e.g., tumors). In certain embodiments, the polymers and the resulting polymer conjugates form nanoparticles that effectively solubilize the imaging agent and / or drug in aqueous systems by dispersing it at a molecular level, thereby increasing functionality and / or bioavailability.

Problems solved by technology

Relatively hydrophobic imaging agents and drugs (such as certain hydrophobic anti-cancer drugs, therapeutic proteins and polypeptides) often suffer from poor bioavailability.
It is believed that this problem is due at least in part to the poor solubility of these imaging agents and drugs in aqueous systems.
Certain enzymatically degradable drugs also suffer from poor bioavailability because they are degraded relatively rapidly in the circulatory system, resulting in rapid elimination from the body.

Method used

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  • Polyglutamate-amino acid conjugates and methods
  • Polyglutamate-amino acid conjugates and methods

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0167] A poly-(γ-L-aspartyl-glutamine) was prepared according to the general scheme illustrated in FIG. 1 as follows:

[0168] Polyglutamic acid (0.75 g), average molecular weight of 49,000 daltons based on the Heleos system with MALS detector, was partially added into 100 mL dichloromethane (DCM). DCC (8.7 mL, 1 M in DCM) was added and stirred for 20 minutes. DCM was then removed by rotary evaporation, and the residue was dissolved with DMF (80 mL). H-asp(OtBu)-(OtBu) (2.44 g), pyridine (4 mL), and DMAP (0.1 g) were added and the reaction mixture was stirred at room temperature for 15-24 hours. The reaction mixture was filtered into an acidic water solution (500 mL, pH1H-NMR by the presence of the peak for the O-tBu group at 1.4 ppm.

[0169] The intermediate polymer was treated with 95% trifluoroacetic acid (TFA) in DCM for 5-8 hours. DCM was then added until a precipitate formed. The solvent was removed, and the residue was washed with more DCM. The residue was placed under vacuum to...

example 2

[0170] A poly-(γ-L-aspartyl-glutamine)-poly-L-glutamic acid was prepared according to the general scheme illustrated in FIG. 2 as follows:

[0171] Polyglutamic acid with an average molecular weight of 49,000 daltons based on the Heleos system with MALS detector (0.075 g) was partially dissolved in DMF (3 mL). DCC (130 mg), H-asp(OtBu)-(OtBu) (0.11 g), pyridine (200 μL), and DMAP (0.010 g) were then added. The reaction was carried out using a microwave method at 120° C. for 30 minutes. The reaction was then cooled to room temperature. Completion of reaction was followed by monitoring the complete disappearance of H-asp(OtBu)-(OtBu) using thin-layer-column (TLC, Rf in ethylacetate=0.4). Upon completion, the reaction mixture was filtered into an acidic water solution (150 mL, pH1H-NMR by the presence of a peak for the O-tBu group at 1.4 ppm.

[0172] The intermediate polymer was then treated with 95% trifluoroacetic acid (TFA) in DCM for 5 hours. DCM was added until a precipitate formed. ...

example 3

[0173] A poly-(γ-L-aspartyl-glutamine) was prepared according to the general scheme illustrated in FIG. 3 as follows:

[0174] Polyglutamate sodium salt (10.0 g) with an average molecular weight of 49,000 daltons based on the Heleos system with MALS detector, EDC (33.8 g), HOBt (15.9 g), and H-asp(OtBu)-(OtBu)-HCl (32.0 g) were mixed in DMF (700 mL). The reaction mixture was stirred at room temperature for 15-24 hours, and then poured into a water solution (3 L). A white precipitate formed, and was filtered and washed with water. The intermediate polymer was then freeze-dried. The structure of the intermediate polymer was confirmed via 1H-NMR by the presence of a peak for the O-tBu group at 1.4 ppm.

[0175] The intermediate polymer was treated with TFA (200 mL) for 5 hours. Then, the TFA was partially removed by rotary evaporation. Water was added to the residue and the residue was dialyzed using semi-membrane cellulose (molecular weight cut-off 10,000 daltons) in reverse-osmosis water...

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Abstract

Various biodegradable polyglutamate-amino acids comprising recurring units of the general formulae (I) and (II) are prepared. Such polymers are useful for variety of drug, biomolecule and imaging agent delivery applications.

Description

[0001] This application claims priority to U.S. Provisional Application No. 60 / 742,291, entitled “POLYGLUTAMATE-AMINO ACID AND METHODS,” filed on Dec. 5, 2005; U.S. Provisional Application No. 60 / 757,917, entitled “POLYGLUTAMATE-ASPARTATE-TAXANES,” filed on Jan. 10, 2006; and U.S. Provisional Application No. 60 / 790,735, entitled “POLYGLUTAMATE-ASPARATATE-MRI CHELATES,” filed on Apr. 10, 2006; all of which are incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates generally to biocompatible water-soluble polymers with pendant functional groups and methods for making them, and particularly to polyglutamate amino acid conjugates useful for a variety of drug, biomolecule and imaging agent delivery applications. [0004] 2. Description of the Related Art [0005] A variety of systems have been used for the delivery of drugs, biomolecules, and imaging agents. For example, such systems include capsules, li...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/10A61K49/00A61K31/785
CPCA61K47/48238A61K47/48315A61K49/146C08G69/10C08G69/48A61K47/645A61K47/62A61K31/337A61K31/4745A61K31/704A61P35/00A61K47/56A61K47/64A61K47/42A61K49/0041A61K49/0056
Inventor YU, LEIZHAO, GANGVAN, SANGDAS, SANJIB KUMARFENG, ZHONGLINGFU, XIAOLIWANG, XINGHEJIN, YICHEN, FU
Owner NITTO DENKO CORP
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