Particle formulations of all-trans retinoic acid and transforming growth factor beta for the treatment of type 1 diabetes mellitus
Inventors
Giannoukakis, Nick • Trucco, Massimo M. • Meng, Wilson S.
Assignees
University of Pittsburgh • Duquesne University of the Holy Spirit
Publication Number
US-10105334-B2
Publication Date
2018-10-23
Expiration Date
2035-01-16
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Abstract
Particle formulations are disclosed that include polymeric particles containing a small molecule drug and a high molecular weight therapeutic protein. Methods of making and using the particle formulations also are disclosed. These particle formulations are of use to treat an autoimmune disease, such as diabetes, or an inflammatory disease.
Core Innovation
The invention provides particle formulations comprising polymeric particles that contain a small molecule drug, all-trans retinoic acid (ATRA), encapsulated within a polymeric matrix, and a high molecular weight therapeutic protein, transforming growth factor beta (TGFβ), adsorbed on the surface. Methods for making and using these particle formulations are also disclosed, including approaches to encapsulate ATRA to protect it from degradation and to load TGFβ onto the particle surface after particle formation, preserving its biological activity.
This particle-based delivery system enables the coadministration of both ATRA and TGFβ, providing gradual, sustained release of each under physiological conditions. The polymeric matrix may include poly-(d, l-lactic-co-glycolic) acid (PLGA), and optional incorporation of metal-chelating compounds (such as nickel-chelating lipids) facilitates the stable adsorption of histidine-tagged or biotinylated TGFβ through specific biochemical interactions. The system allows for the controlled release kinetics of both agents, which may be tuned by altering the characteristics of the polymer or the choice of metal chelation.
The problem addressed by this invention is the inadequate and declining efficacy of existing diabetes treatments, which primarily focus on insulin supplementation without addressing the underlying autoimmunity and loss of beta-cell function characteristic of type 1 diabetes. Conventional therapies, despite glucose management, do not prevent or reverse disease progression, leading to gradual health deterioration in affected individuals. The disclosed particle formulations are intended to provide an additional therapeutic strategy by targeting the underlying immune mechanisms in autoimmune and inflammatory diseases such as type 1 diabetes.
Claims Coverage
The independent claim defines one main inventive feature regarding the method for treating autoimmune disorders using a specific particle formulation. Additional dependent claims further detail components, methods, and patient populations.
Method for treating autoimmune disorder with a particle formulation comprising ATRA and surface-adsorbed TGFβ
A method is provided for treating a subject with an autoimmune disorder by: - Selecting a subject with the autoimmune disorder. - Administering a therapeutically effective amount of a particle formulation comprising: - A particle with all-trans retinoic acid (ATRA) encapsulated within a polymeric matrix. - Transforming growth factor beta (TGFβ) adsorbed on the surface of the particle. This treatment is claimed as effective for treating autoimmune disorders in the selected subject.
The inventive feature is centered on a defined method of treating autoimmune disorders using a dual-agent polymeric particle system, specifically encapsulating ATRA and surface-adsorbed TGFβ.
Stated Advantages
Provides coadministration and gradual, sustained release of both ATRA and TGFβ, allowing controlled dosing over time.
Circumvents ATRA’s poor water solubility and protects it from chemical degradation by encapsulation within the polymeric matrix.
Prevents denaturation of therapeutic proteins like TGFβ by loading them after particle formation.
Enables the rate of release of ATRA and TGFβ to be adjusted by varying the polymer characteristics or the coordinating metal, offering customizable therapy.
Allows for targeted treatment of autoimmune and inflammatory diseases, potentially addressing underlying immune mechanisms rather than just symptoms.
Documented Applications
Treatment of autoimmune diseases, including but not limited to type 1 diabetes mellitus.
Treatment of inflammatory diseases such as inflammatory bowel disease.
Treatment of pre-diabetes.
Treatment of autoimmune diseases such as rheumatoid arthritis and Hashimoto's thyroiditis.
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