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Charge reversible polymers

a charge-reversible polymer and polymer technology, applied in the field of charge-reversible polymers, can solve the problems of severe serum inhibition, inability to reach the targeted tissues other than the liver or intracellular compartment, and limited in vivo applications of positively charged macromolecules or colloidal particles, etc., to achieve rapid hydrolysis, low toxicity, and easy hydrolysis.

Inactive Publication Date: 2009-06-04
UNIVERSITY OF WYOMING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The present invention relates to charge reversible polymers, peptides and their resulting colloidal particles. Their primary and secondary amines are protected as easily hydrolysable amides. The amides are relatively stable at neutral pH but quickly hydrolyze at low pH. These polymers, peptides or particles are thus charge-reversible: at neutral pH they are negatively charged but become positively charged at acidic pH. One of the applications of these charge-reversible polymers, peptides or particles is as carriers for drug delivery to solid tumors and lysosomes, where the pH can be as low as 6, and 4-5, respectively. The present invention discloses a technique that can preserve the amine groups as negatively charged groups that have no or low interactions with cells and low toxicity. These groups are stable at neutral pH but rapidly decompose and convert back to amine groups at pH less than 7. This technique has many applications including their development as drug or gene delivery carriers.

Problems solved by technology

The in vivo applications of those positively charged macromolecules or colloidal particles, however, is very limited because cationic charges can cause severe serum inhibition and rapid clearance from the plasma compartment, and sequestered to mainly in the liver.
Such a fast plasma clearance makes them impossible to reach their targeted tissues other than the liver or intracellular compartment.
Positively charged polymers or colloidal particles can cause severe serum inhibition and are rapidly cleared from the plasma compartment, and thus cannot be used in vivo.

Method used

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Examples

Experimental program
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example 1

Polymer Synthesis (Scheme 3—FIG. 3)

[0031]Synthesis of poly(ε-caprolactone) (PCL) (a): ε-Caprolactone (ε-CL) (12.5 mL, 113 mmol) and octanoic acid (1.75 mL, 11 mmol) were charged into a flask. The flask was sealed with a rubber septum and degassed. It was heated at 225° C. for 3.5 h with magnetic stirring. The solid was cooled to about 60° C. and dissolved in THF. The solution was poured into 10-fold cold methanol to remove the unreacted monomer. The solid was isolated and purified by reprecipitation. It then was dried under high vacuum at 60° C. PCL with a terminal carboxylic acid (PCL-COOH) (11.8 g, yield 47%) was obtained. 1H-NMR (400 MHz, CDCl3): δ (ppm): 4.08 (t), 2.32 (t), 1.71-1.57 (m), 1.42-1.34 (m), 0.88 (t). Its molecular weight was 3.8 KDa determined by NMR, and 3.2 KDa determined by gel permeation chromatography with polydispersity index of 1.15.

[0032]Synthesis of PCL-COO—NHS (b): PCL-COOH (2.45 g, 0.64 mmol), N-hydroxysuccinimide (NHS, 0.38 g, 3.3 mmol) and 1,3-dicyclohe...

example 2

[0037]Model compound synthesis and hydrolytic kinetics measurement (Scheme 4—FIG. 4): Briefly, N,N-diethylamine (415 μL, 4 mmol) and 1,2-cis-cyclohexanedicarboxylic anhydride (617 mg, 4 mmol) were dissolved in 10 mL dichloride methane. The reaction was kept at room temperature for 2 h with stirring. The solvent was then removed by rotary evaporation to obtain the raw product. The raw product was purified by recrystallizing from benzene to get 2-[(diethylamino)carbonyl]cyclohexanecarboxylic acid. 1H NMR (400 MHz, CDCl3): δ (ppm): 3.60-3.22 (m), 2.77 (m), 2.51-2.45 (m), 1.87-1.66 (m), 1.58-1.46 (m), 1.49-1.39 (m), 1.28 (q), 1.17 (t). Similarly, 2-[(isopropylamino)carbonyl]cyclohexanecarboxylic acid was synthesized. 1H NMR (400 MHz, CDCl3): δ (ppm): 3.83 (q), 2.73 (q), 2.64 (q), 1.87 (m), 1.79 (m), 1.64 (m), 1.45 (m), 1.33 (m), 1.01 (d).

[0038]The hydrolysis of the model compounds was monitored by 1H-NMR. Briefly, 2-[(isopropylamino)carbonyl]cyclohexanecarboxylic acid (10 mg) was dissol...

example 3

[0039]The amide hydrolysis kinetics of TCRNs: The hydrolysis of the amides in the TCRNs was monitored by 1H-NMR. The TCRNs in DI water were prepared as described above. The nanoparticle solution was adjusted to pH of 5.0, 6.0 or 7.4, respectively, at a concentration of 1 mg / mL. DMF (1 μl) was added to the solution as the internal standard. These solutions were immersed in a 37° C. water bath. At predesigned time intervals, the TCRN solution (0.5 ml) was sampled and filtered using Centricon centrifugal filter devices (YM-3, 3,000 MWCO, Millipore Corp., Bedford, Mass.). The percentage of hydrolyzed amides was calculated from the integrations of the reference peak at 3.0-2.7 ppm (DMF signal) and the peak at 1.7-1.0 ppm of free 1,2-cis-cyclohexanedicarboxylic acid hydrolyzed from the amides.

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Abstract

Described are charge reversible polymers, peptides and their resulting colloidal particles, comprising polymers and peptides having primary and secondary amines that are protected as easily hydrolysable amides. The amides are charge-reversible such that at neutral pH they are negatively charged but become positively charged at pH less than 6 and thus are relatively stable at neutral pH but quickly hydrolyze at pH below 6. Incorporating a drug in a micelle or a polymer comprised of the charge-reversible polymers or peptides provides a drug carrier for delivering the drug preferentially to the solid tumor or other targeted cells.

Description

[0001]This application claims priority to Patent Cooperation Treaty Application PCT / US2007 / 008146, which claims priority to U.S. Patent Application Ser. No. 60 / 787,789, filed Mar. 30, 2006, which is incorporated herein by this reference. This application also claims priority to Patent Cooperation Treaty Application PCT / US2007 / 015447, which claims priority to U.S. Patent Application Ser. No. 60 / 818,882, filed Jul. 6, 2006, which is incorporated herein by this reference.[0002]The United States Government has rights in this invention under the National Science Foundation (BES-0401982) and the American Cancer Society (RSG-06-11821-CDD).BACKGROUND OF THE INVENTION[0003]The invention relates generally to charge reversible polymers, peptides and their resulting colloidal particles and, more specifically, to easily hydrolysable amides that are relatively stable at neutral pH but quickly hydrolyze at low pH.[0004]Cationization is a potent approach to enhance cellular uptake by electrostatica...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/30A61P35/00A61K47/42A61K47/48
CPCA61K9/0019A61K9/1075A61K31/785A61K47/488A61K47/48192A61K47/482A61K47/48315A61K47/48107A61K47/551A61K47/59A61K47/593A61K47/645A61K47/6907A61P35/00C08G73/0206C08G73/00C08G69/02A61K47/30
Inventor SHEN, YOUQINGXU, PEISHENG
Owner UNIVERSITY OF WYOMING
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