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Targeted synthetic nanocarriers with ph sensitive release of immunomodulatory agents

a technology of immunomodulatory agents and synthetic nanocarriers, which is applied in the field of synthetic nanocarriers, can solve the problems of off-target immunostimulatory effects and deleterious effects, and achieve the effect of inducing or enhancing an immune respons

Inactive Publication Date: 2011-01-27
SELECTA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0393]The results shown in FIG. 6 demonstrate that R848 adjuvant (a TLR 7 / 8 agonist) contained in the NC augments humoral immune response against NC-associated antigen (groups 2-5>>group 1). Furthermore, neither fast (group 2), nor slow (group 5) release of R848 was elevated an immune response to the same level as NC releasing R848 at intermediate rate (group 3≈group 4>group 2≈group 5).

Problems solved by technology

However, systemic administration of stabilized CpG oligonucleotides can result in off-target immunostimulatory effects, such as general inflammation, non-specific activation of lymphocytes, and flu-like symptoms.
When immunomodulatory agents are injected in free form, or when they are released from a synthetic nanoparticle outside the APCs, only a small portion of that immunomodulatory agent finds its way to the APCs, while the rest diffuses through the body, where the immune stimulation would be less and may result in deleterious effects.

Method used

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  • Targeted synthetic nanocarriers with ph sensitive release of immunomodulatory agents
  • Targeted synthetic nanocarriers with ph sensitive release of immunomodulatory agents
  • Targeted synthetic nanocarriers with ph sensitive release of immunomodulatory agents

Examples

Experimental program
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Effect test

example 1

Preparation of Activated Polymer

[0160]PLA (dl-polylactide) (Resomer R202H from Boehringer-Ingelheim, KOH equivalent acid number of 0.21 mmol / g, intrinsic viscosity (iv): 0.21 dl / g) (10 g, 2.1 mmol, 1.0 eq) was dissolved in dichloromethane (DCM) (35 mL). EDC (2.0 g, 10.5 mmol, 5 eq) and NHS (1.2 g, 10.5 mmol, 5 eq) were added. The solids were dissolved with the aid of sonication. The resulting solution was stirred at room temperature for 6 days. The solution was concentrated to remove most of DCM and the residue was added to a solution of 250 mL of diethyl ether and 5 mL of MeOH to precipitate out the activated PLA-NHS ester. The solvents were removed and the polymer was washed twice with ether (2×200 mL) and dried under vacuum to give PLA-NHS activated ester as a white foamy solid (˜8 g recovered, H NMR was used to confirm the presence of NHS ester). The PLA-NHS ester was stored under argon in a below −10 C freezer before use.

[0161]Alternatively, the reaction can be performed in DMF...

example 2

Preparation of Activated Polymer

[0163]PLA (R202H, acid number of 0.21 mmol / g) (2.0 g, 0.42 mmol, 1.0 eq) was dissolved in 10 mL of dry acetonitrile. N,N′-disuccinimidyl carbonate (DSC) (215 mg, 1.26 mmol, 3.0 eq) and catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP) were added. The resulting mixture was stirred under argon for 1 day. The resulting solution was concentrated to almost dryness. The residue was then added to 40 mL of ether to precipitate out the polymer which was washed twice with ether (2×30 mL) and dried under vacuum to give PLA-NHS activated ester (1H NMR showed the amount of NHS ester at about 80%).

example 3

Preparation of Activated Polymer

[0164]PLA (R202H) (5.0 g, 1.05 mmol) was dissolved in 25 mL of anhydrous DCM and 2.5 mL of anhydrous DMF. DCC (650 mg, 3.15 mmol, 5.0 eq) and pentafluorophenol (PFP) (580 mg, 3.15 mmol, 5.0 eq) were added. The resulting solution was stirred at room temperature for 6 days and then concentrated to remove DCM. The resulting residue was added to 250 mL of ether to precipitate out the activated PLA polymer which was washed with ether (2×100 mL) and dried under vacuum to give PLA-PFP activated ester as a white foamy solid (4.0 g).

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Abstract

This invention relates to compositions, and related methods, of synthetic nanocarriers that target sites of action in cells, such as antigen presenting cells (APCs), and comprise immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner. Also disclosed are compositions and methods relating to synthetic nanocarriers that encapsulate labile immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner.

Description

RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119 of U.S. provisional applications 61 / 217,129, 61 / 217,117, 61 / 217,124, and 61 / 217,116, each filed May 27, 2009, the contents of each of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]This invention relates to compositions, and related methods, of synthetic nanocarriers that target sites of action in cells, such as antigen presenting cells (APCs), and comprise immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner. The invention additionally relates to protection of labile immunomodulatory agents by means of their encapsulation in synthetic nanocarriers.BACKGROUND[0003]Immunomodulatory agents are used to produce immune responses in subjects. Stimulation of the immune system, which includes stimulation of either or both innate immunity and adaptive immunity, is a complex phenomenon that can result in either protective or a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/385C07D471/04C07D473/34C07H21/00A61P37/02
CPCA61K9/5138C08G64/42A61K47/48176A61K47/48192A61K47/482A61K47/48215A61K47/48246A61K47/48869A61K47/48907A61K47/48915A61K2039/55511A61K2039/55544A61K2039/55555A61K2039/55561A61K2039/6093B82Y5/00A61K47/48238A61K39/385A61K39/39A61K2039/62A61K47/48207C08G63/08C08G63/912A61K39/0013A61K31/437A61K31/52A61K39/0005C07D471/04C07D473/34C08G63/06C08J3/24A61K2039/627A61K39/00C08J2367/04A61K2300/00A61K47/60A61K47/58A61K47/59A61K47/593A61K47/64A61K47/6925A61K47/6935A61K47/6937A61P25/28A61P25/30A61P25/34A61P29/00A61P3/00A61P31/00A61P35/00A61P37/02A61P37/04A61P43/00A61K31/525C07D473/32
Inventor ZEPP, CHARLESGAO, YUNKEEGAN, MARK J.BALDWIN, SAMFU, FEN-NIJOHNSTON, LLOYDLIPFORD, GRAYSON B.
Owner SELECTA BIOSCI
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