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Cyclodextrin-based polymers for therapeutics delivery

a technology of cyclodextrin and polymer, applied in the direction of extracellular fluid disorder, immunological disorder, metabolism disorder, etc., can solve the problems of toxic side effects, pharmacological profiles, drug delivery of some small molecule therapeutic agents, etc., and achieve the effect of facilitating endocytosis

Inactive Publication Date: 2008-07-24
CERULEAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0097]In certain embodiments as described above, the therapeutic agent is a small molecule. In certain embodiments, the therapeutic agent contains an amino, hydroxyl, or thiol group. In certain embodiments, the therapeutic agent is attached to the self-cyclizing group through the amino, hydroxyl, or thiol group, preferably a hydroxyl group.
[0098]In certain embodiments as described above, the therapeutic agent is etoposide, tubulysin, epothilone, or an analog or derivative thereof. In certain embodiments as disclosed herein, the targeting ligand is a hormone, such a as a hormone that facilitates endocytosis. In certain embodiments, the hormone is lute

Problems solved by technology

Drug delivery of some small molecule therapeutic agents has been problematic due to their poor pharmacological profiles.
These therapeutic agents often have low aqueous solubility, their bioactive forms exist in equilibrium with an inactive form, or high systemic concentrations of the agents lead to toxic side-effects.

Method used

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  • Cyclodextrin-based polymers for therapeutics delivery
  • Cyclodextrin-based polymers for therapeutics delivery
  • Cyclodextrin-based polymers for therapeutics delivery

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of CDP-PEG-GFLG-MEDA-ETOP

[0611]

[0612]Fmoc-PEG-aceticacid (5.7 g, 13 mmol), HBTU (4.9 g, 13 mmol), HOBT (2.0 g, 13 mmol), and DIPEA (3.4 g, 26 mmol) were dissolved in DMF (25 mL). GFLG-MEDA-Z (5.1 g, 8.8 mmol) was dissolved in DMF (13 mL) and DIPEA (3.7 g, 29 mmol) and added to the previous solution prepared. The reaction mixture was stirred for 1.5 h at room temperature. DMF was removed under reduced pressure and the obtained residue was dissolved in 200 mL CH2Cl2, the solution was washed twice with 0.1 N HCl (200 mL) and followed by washing with water (200 mL). It was then dried over MgSO4 and CH2Cl2 was removed under vacuum to yield crude product. It was then purified by flash column chromatography to yield white solid product, FMOC-PEG-GFLG-MEDA-Z (6.2 g, 72%).

[0613]FMOC-PEG-GFLG-MEDA-Z (3.0 g, 3.0 mmol) was dissolved in CH2Cl2 (60 mL) of 0.2 M 2-Bromo-1,3,2-benzodioxaborole (2.4 g, 12 mmol). The reaction mixture was stirred overnight at room temperature. The reaction w...

example 2

Synthesis of CDP-Carbamate-S-S-Etoposide

[0617]

[0618]In a dry 100 mL round bottom flask, etoposide (1.0 g, 1.7 mmol) and TEA (2.5 g, 25 mmol) were dissolved in anhydrous THF (35 mL) under argon. To that solution, 4-nitrophenyl chloroformate (0.39 g, 1.95 mmol) in anhydrous THF (15 mL) was added dropwise over 30 min. The reaction mixture was stirred for additional 2 h at RT. The mixture was filtered and concentrated under reduced pressure to yield yellow solid. The solid was purified by flash column chromatography to yield light yellow solid (0.75 g, 59%).

[0619]In a dry 25 mL round bottom flask, 4-nitrophenyl carbonate ester of etoposide (100 mg, 0.13 mmol), 4-pyridylthiol cysteamine hydrochloride (35 mg, 0.16 mmol), DIPEA (34 mg, 0.27 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature for 15 h. DMF was removed under reduced pressure to yield a light yellow solid. CH2Cl2 (25 mL) was added and it was washed with 0.1 N HCl (10 mL) twice. It was then...

example 4

CDP-PEG-SS-Tubulysin

Synthesis of CDP-PEG-SS-Py

[0623]A mixture of CDP-PEG (2 g, 0.43 mmole), which was synthesized according to a published procedure (Bioconjugate Chem. 2003, 14, 1007), pyridine dithioethylamine hydrochloric salt (384 mg, 1.73 mmole), EDC (333 mg, 1.73 mmole), and NHS (198 mg, 1.73 mmole) was dried overnight in a 200 mL round bottom flask under vacuum. Anhydrous DMF (40 mL) was then added, followed by DIEA (0.3 mL, 1.73 mmole). The reaction mixture was stirred under argon at room temperature for 4 h. Diethyl ether (300 mL) was then added into the mixture to precipitate the polymer. The crude product was dissolved in H2O (400 mL) and the solution was dialyzed using a 25K MWCO membrane (Spectra / Por 7) against water. The dialysis water was changed twice over a period of 24 h, after which the polymer containing solution was filtered through a 0.2 μm filter membrane and lyophilized to yield 1.64 g of CDP-PEG-SS-Py (82% yield) as a white solid.

Synthesis of CDP-PEG-SH

[0624...

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Abstract

The present invention relates to novel compositions comprising polymeric moieties covalently attached to therapeutic agents, wherein the therapeutic agent is attached to the polymeric moiety through a tether. By selecting from a variety of tether groups and targeting ligands the polymers present methods for controlled delivery of the therapeutic agents. The invention also relates to methods of treating subjects with the therapeutic compositions described herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This patent application claims the benefit of U.S. Provisional Application Nos. 60 / 897,096 filed on Jan. 24, 2007, and 61 / 002,752 filed on Nov. 9, 2007. The specifications of these applications are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Drug delivery of some small molecule therapeutic agents has been problematic due to their poor pharmacological profiles. These therapeutic agents often have low aqueous solubility, their bioactive forms exist in equilibrium with an inactive form, or high systemic concentrations of the agents lead to toxic side-effects. Some approaches to circumvent the problem of their delivery have been to conjugate the agent directly to a water-soluble polymer such as hydroxypropyl methacrylate (HPMA), polyethyleneglycol, and poly-L-glutamic acid. In some cases, such conjugates have been successful in solubilizing or stabilizing the bioactive form of the therapeutic agent, or ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K47/30
CPCA61K47/48338A61K47/48923A61K47/4823B82Y5/00A61K47/48969A61K47/65A61K47/6939A61K47/6951A61K47/61A61P1/08A61P11/06A61P11/14A61P17/04A61P19/02A61P19/08A61P21/02A61P25/00A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24A61P29/00A61P3/04A61P31/04A61P31/10A61P31/12A61P35/00A61P37/06A61P43/00A61P5/00A61P7/10A61P9/00A61P9/06A61P9/08A61P9/10A61P9/12
Inventor DAVIS, MARK E.HWANG, JUNGYEONKE, TIANYILIM, CHING-JOUSCHLUEP, THOMAS
Owner CERULEAN PHARMA
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