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Controlled release of immunosuppressants from synthetic nanocarriers

a technology of synthetic nanocarriers and immunosuppressants, which is applied in the direction of liposome delivery, peptide/protein ingredients, powder delivery, etc., can solve the problems of insufficient information regarding the optimal release of agents from delivery vehicles, the risk of severe side effects, tumors, etc., and achieve the effect of reducing the undesired immune respons

Inactive Publication Date: 2012-11-29
SELECTA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present disclosure provides a composition that includes synthetic nanocarriers, an APC presentable antigen, and an immunosuppressant. The synthetic nanocarriers are adapted to release the immunosuppressant in a controlled manner. The composition can also include other synthetic nanocarriers, such as liposomes, metallic nanoparticles, or polymers. The immunosuppressant can include statins, mTOR inhibitors, TGF-β signaling agents, corticosteroids, inhibitors of mitochondrial function, P38 inhibitors, NF-κβ inhibitors, adenosine receptor agonists, prostaglandin E2 agonists, phosphodiesterase 4 inhibitors, HDAC inhibitors, or proteasome inhibitors. The composition can generate a tolerogenic immune response to the APC presentable antigen, which can be useful in the treatment of autoimmune diseases, inflammatory diseases, allergies, or graft-versus-host diseases.

Problems solved by technology

However, in order to maintain immunosuppression, immunosuppressive drug therapy is generally a life-long proposition, and the use of broad-acting immunosuppressants are associated with a risk of severe side effects, such as tumors, infections, nephrotoxicity and metabolic disorders.
While it is at times advantageous to couple agents to delivery vehicles, information regarding what kind of release provides for optimal effects and how the release of agents from delivery vehicles can be controlled is lacking.

Method used

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  • Controlled release of immunosuppressants from synthetic nanocarriers
  • Controlled release of immunosuppressants from synthetic nanocarriers
  • Controlled release of immunosuppressants from synthetic nanocarriers

Examples

Experimental program
Comparison scheme
Effect test

example 1

Mesoporous Silica Nanoparticles with Coupled Ibuprofen (Prophetic)

[0244]Mesoporous SiO2 nanoparticle cores are created through a sol-gel process. Hexadecyltrimethyl-ammonium bromide (CTAB) (0.5 g) is dissolved in deionized water (500 mL), and then 2 M aqueous NaOH solution (3.5 mL) is added to the CTAB solution. The solution is stirred for 30 min, and then Tetraethoxysilane (TEOS) (2.5 mL) is added to the solution. The resulting gel is stirred for 3 h at a temperature of 80° C. The white precipitate which forms is captured by filtration, followed by washing with deionized water and drying at room temperature. The remaining surfactant is then extracted from the particles by suspension in an ethanolic solution of HCl overnight. The particles are washed with ethanol, centrifuged, and redispersed under ultrasonication. This wash procedure is repeated two additional times.

[0245]The SiO2 nanoparticles are then functionalized with amino groups using (3-aminopropyl)-triethoxysilane (APTMS)....

example 2

Liposomes Containing Cyclosporine A (Prophetic)

[0248]The liposomes are formed using thin film hydration. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (32 μmol), cholesterol (32 μmol), and cyclosporin A (6.4 μmol) are dissolved in pure chloroform (3 mL). This lipid solution is added to a 50 mL round-bottom flask, and the solvent is evaporated on a rotary evaporator at a temperature of 60° C. The flask is then flushed with nitrogen gas to remove remaining solvent. Phosphate buffered saline (2 mL) and five glass beads are added to the flask, and the lipid film is hydrated by shaking at 60° C. for 1 h to form a suspension. The suspension is transferred to a small pressure tube and sonicated at 60° C. for four cycles of 30s pulses with a 30 s delay between each pulse. The suspension is then left undisturbed at room temperature for 2 h to allow for complete hydration. The liposomes are washed by centrifugation followed by resuspension in fresh phosphate buffered saline.

example 3

Polymeric Nanocarrier Containing Polymer-Rapamycin Conjugate

(Prophetic)

[0249]Preparation of PLGA-Rapamycin Conjugate

[0250]PLGA polymer with acid end group (7525 DLG1A, acid number 0.46 mmol / g, Lakeshore Biomaterials; 5 g, 2.3 mmol, 1.0 eq) is dissolved in 30 mL of dichloromethane (DCM). N,N-Dicyclohexylcarbodimide (1.2 eq, 2.8 mmol, 0.57 g) is added followed by rapamycin (1.0 eq, 2.3 mmol, 2.1 g) and 4-dimethylaminopyridine (DMAP) (2.0 eq, 4.6 mmol, 0.56 g). The mixture is stirred at rt for 2 days. The mixture is then filtered to remove insoluble dicyclohexylurea. The filtrate is concentrated to ca. 10 mL in volume and added to 100 mL of isopropyl alcohol (IPA) to precipitate out the PLGA-rapamycin conjugate. The IPA layer is removed and the polymer is then washed with 50 mL of IPA and 50 mL of methyl t-butyl ether (MTBE). The polymer is then dried under vacuum at 35 C for 2 days to give PLGA-rapamycin as a white solid (ca. 6.5 g).

[0251]Preparation of nanocarrier containing PLGA-rap...

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Abstract

Disclosed are synthetic nanocarrier compositions that provide controlled release of immunosuppressants as well as related methods. The synthetic nanocarrier compositions may also include antigen in some embodiments.

Description

RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119 of U.S. provisional application 61 / 480,946, filed Apr. 29, 2011, 61 / 513,514, filed Jul. 29, 2011, 61 / 531,147, filed Sep. 6, 2011, 61 / 531,153, filed Sep. 6, 2011, 61 / 531,164, filed Sep. 6, 2011, 61 / 531,168, filed Sep. 6, 2011, 61 / 531,175, filed Sep. 6, 2011, 61 / 531,180, filed Sep. 6, 2011, 61 / 531,194, filed Sep. 6, 2011, 61 / 531,204, filed Sep. 6, 2011, 61 / 531,209, filed Sep. 6, 2011, 61 / 531,215, filed Sep. 6, 2011, the entire contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to synthetic nanocarrier compositions, and related methods, where the compositions comprise an immunosuppressant coupled to the synthetic nanocarriers and an APC presentable antigen. The immunosuppressants dissociate from the synthetic nanocarriers in a time-dependent manner at a pH that ranges from 4.5 to 6.5. The nanocarriers allow for the targeting of sites of actio...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A61P37/04A61P37/06A61K39/35A61K39/385
CPCA61K39/00C12N5/0637A61K39/0005A61K9/127A61K47/48861A61K47/48884A61K47/48915A61K9/51A61K2039/577A61K2039/6093B82Y5/00A61K2039/55511A61K39/36A61K2300/00A61K39/385A61K9/14A61K9/5115A61K9/5146A61K9/5153A61K31/192A61K38/13A61K38/1816A61K38/38A61K39/0008A61K39/001A61K39/35A61K47/50A61K47/52A61K47/544A61K47/593A61K47/643A61K47/69A61K47/6923A61K47/6929A61K47/6937G01N33/505G01N33/56972A61K2039/5154A61K2039/55555B82Y40/00G01N2333/7051G01N2333/70514G01N2333/70517A61K31/436A61K45/06A61K31/366A61P1/16A61P11/02A61P11/06A61P15/00A61P17/00A61P29/00A61P35/00A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P41/00A61P43/00A61P7/06Y02A50/30
Inventor ALTREUTER, DAVID H.GRISET, AARON P.MALDONADO, ROBERTO A.
Owner SELECTA BIOSCI
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