Biodegradable poly(β-amino esters) and uses thereof

Inactive Publication Date: 2012-08-28
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0038]“Biodegradable”: As used herein, “biodegradable” compounds are those that, when introduced into cells, are broken down by the cellular machinery or by hydrolysis into components that the cells can either reuse or dispose of without significant toxic effect on the cells (i.e., fewer than about 20% of the cells are killed when the components are added to cells in vitro). The components preferably do not induce inflammation or other adverse effects in vivo. In certain preferred embodiments, the chemical reactions relied upon to break down the biodegradable compounds are uncatalyzed.

Problems solved by technology

Preferred polymers are biodegradable and biocompatible.

Method used

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  • Biodegradable poly(β-amino esters) and uses thereof
  • Biodegradable poly(β-amino esters) and uses thereof
  • Biodegradable poly(β-amino esters) and uses thereof

Examples

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example 1

Degradable Poly(β-Amino Esters): Synthesis, Characterization, and Self-Assembly with Plasmid DNA

Experimental Section

[0167]General Considerations. All manipulations involving live cells or sterile materials were performed in a laminar flow using standard sterile technique. 1H NMR (300.100 MHz) and 13C NMR (75.467 MHz) spectra were recorded on a Varian Mercury spectrometer. All chemical shift values are given in ppm and are referenced with respect to residual proton or carbon signal from solvent. Organic phase gel permeation chromatography (GPC) was performed using a Hewlett Packard 1100 Series isocratic pump, a Rheodyneu Model 7125 injector with a 100-μL injection loop, and two PL-Gel mixed-D columns in series (5 μm, 300×7.5 mm, Polymer Laboratories, Amherst, Mass.). THF / 0.1 M piperidine was used as the eluent at a flow rate of 1.0 mL / min. Data was collected using an Optilab DSP interferometric refractometer (Wyatt Technology, Santa Barbara, Calif.) and processed using the TriSEC GPC...

example 2

Rapid, pH-Triggered Release from Biodegradable Poly(β-Amino Ester) Microspheres Within the Ranger of Intracellular pH

Experimental Section

[0203]Fabrication of microspheres. The optimized procedure for the fabrication of microspheres was conducted in the following general manner: An aqueous solution of rhodamine-conjugated dextran (200 μL of a 10 μg / μL solution, Mn≈70 kD) was suspended in a solution of poly-1 in CH2Cl2 (200 mg of poly-1 in 4 mL CH2Cl2, Mn≈10 kD), and the mixture was sonicated for 10 seconds to form a primary emulsion. The cloudy pink emulsion was added directly to a rapidly homogenized (5,000 rpm) solution of poly(vinyl alcohol) [50 mL, 1% PVA (w / w)] to form the secondary emulsion. The secondary emulsion was homogenized for 30 seconds before adding it to a second aqueous PVA solution [100 mL, 0.5% PVA (w / w)]. Direct analysis of the microsphere suspension using a Coulter microparticle analyzer revealed a mean particle size of approximately 5 micrometers. The secondary ...

example 3

Accelerated Discovery of Synthetic Transfection Vectors: Parallel Synthesis and Screening of a Degradable Polymer Library

Introduction

[0215]The safe and efficient delivery of therapeutic DNA to cells represents a fundamental obstacle to the clinical success of gene therapy (Luo et al. Nat. Biotechnol. 18:33-37, 2000; Anderson Nature 392 Suppl.:25-30, 1996; each of which is incorporated herein by reference). The challenges facing synthetic delivery vectors are particularly clear, as both cationic polymers and liposomes are less effective at mediating gene transfer than viral vectors. The incorporation of new design criteria has led to recent advances toward functional delivery systems (Lim et al. J. Am. Chem. Soc. 123:2460-2461, 2001; Lim et al. J. Am. Chem. Soc. 122:6524-6525, 2000; Hwang et al. Bioconjugate Chem. 12:280-290, 2001; Putnam et al. Proc. Natl. Acad. Sci. USA 98:1200-1205, 2001; Benns et al. Bioconjugate Chem. 11:637-645, 2000; Midoux et al. Bioconjugate Chem. 10:406-411...

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Abstract

Poly(β-amino esters) prepared from the conjugate addition of bis(secondary amines) or primary amines to a bis(acrylate ester) are described. Methods of preparing these polymers from commercially available starting materials are also provided. These tertiary amine-containing polymers are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems. Given the poly(amine) nature of these polymers, they are particularly suited for the delivery of polynucleotides. Nanoparticles containing polymer/polynucleotide complexes have been prepared. The inventive polymers may also be used to encapsulate other agents to be delivered. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings. A system for preparing and screening polymers in parallel using semi-automated robotic fluid delivery systems is also provided.

Description

RELATED APPLICATIONS[0001]More than one reissue application has been filed for the reissue of U.S. Pat. No. 7,427,394. The reissue applications are U.S. patent applications, U.S. Ser. No. 12 / 568,481 (the present application), filed Sep. 28, 2009, and U.S. Ser. No. 12 / 833,749, filed Jul. 9, 2010, which is a divisional of U.S. Ser. No. 12 / 568,481.[0002]The present application, U.S. patent application, U.S. Ser. No. 12 / 568,481, filed Sep. 28, 2009, is a reissue application of and claims priority under 35 U.S.C. §120 to U.S. patent application, U.S. Ser. No. 10 / 446,444, filed May 28, 2003, issued as U.S. Pat. No. 7,427,394, which claims priority under 35 U.S.C. §120 to and is a continuation-in-part of application U.S. Ser. No. 09 / 969,431, filed Oct. 2, 2001, now U.S. Pat. No. 6,998,115 entitled “Biodegradable Poly(beta-amino esters) and Uses Thereof,” which claims priority to provisional applications, U.S. Ser. No. 60 / 305,337, filed Jul. 13, 2001, and U.S. Ser. No. 60 / 239,330, filed Oct...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/765C08G69/44C08G63/44C07C327/00
CPCA61K47/48192A61K47/482A61K47/48907B82Y5/00C08G73/02A61K9/5146C08G73/0611C08G73/0616C12N15/88C08G73/0627A61K9/1641C08G73/06A61K47/59A61K47/593A61K47/6935
Inventor ANDERSON, DANIEL GRIFFITHLYNN, DAVID M.AKINC, AKINLANGER, ROBERT S.
Owner MASSACHUSETTS INST OF TECH
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