Polymer-based therapeutics for inductive browning of fat

A technology of polymers and therapeutic agents, applied in the direction of drug combinations, organic active ingredients, animal/human peptides, etc., can solve the problem of limited number of adults

Pending Publication Date: 2018-08-21
PURDUE RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Classical BAT is abundant in neonates but decrease

Method used

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  • Polymer-based therapeutics for inductive browning of fat
  • Polymer-based therapeutics for inductive browning of fat
  • Polymer-based therapeutics for inductive browning of fat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1: Inhibition of Notch signaling promotes browning of white adipocytes:

[0113] The Notch signaling pathway is important for cell-cell communication and cell fate decisions during development and is required for adult tissue homeostasis. Notch target gene Hairy / enhancer-of-split 1 (Hes1) directly binds to PR domain-containing 16 (Prdm16), peroxisome proliferator-activated receptor gamma (Pparγ), and Pparγ coactivator 1α (Ppargc1a) promoters to repress their transcription. This results in reduced mitochondrial biogenesis and reduced Ucp1 levels.

[0114] Pharmacological inhibition of Notch signaling induces browning of white adipocytes during in vitro culture. In cultured white adipocytes with the γ-secretase inhibitor DAPT (N-[N-(3,5-difluorophenylacetyl)-1-alanyl]-S-phenylglycine tert-butyl ester) Inhibits Notch signaling. DAPT inhibited Notch signaling and upregulated the expression of brown fat-specific genes Ucp1, Cidea, Prdm16 and Ppargc1a (Fig. 2A-2C)...

Embodiment 2

[0118] Example 2: PLGA microsphere-based DBZ delivery system promotes browning of WAT for treatment of obesity:

[0119] In this example, a DBZ delivery system based on PLGA microspheres is disclosed to promote the browning of WAT for the treatment of obesity ( Figure 4 ). PLGA with a 50:50 ratio of lactide to glycolide was used because this particular polymer has a relatively fast degradation rate in the PLGA family, which favors the induction of browning. We formulated DBZ-loaded PLGA microspheres using emulsion / solvent evaporation techniques and characterized the morphology and release profile of those microspheres. Furthermore, we demonstrate that DBZ-loaded PLGA microspheres inhibit Notch and thus promote browning in vitro and in vivo. To our knowledge, this is the first time an effective bioengineered system has been developed to deliver a therapeutic agent to convert white fat cells into beige fat cells. This study not only contributes to our understanding of the me...

Embodiment 3

[0165] Example 3: PPHOS Prodrug System Enabling Gradual Release of γ-Secretase Inhibitors:

[0166]PPHOS is a high molecular weight polymer with a backbone of alternating phosphorus and nitrogen atoms. Each phosphorus atom bears two organic substituents, with a variety of side groups available for performance optimization. The type of side group attached to the PPHOS backbone has profound effects on the physicochemical and biological properties of the polymer. For example, chlorine substitution of poly(dichlorophospazene) with hydrolytically labile groups such as amino acid esters, imidazolyl, glucosyl, glyceryl, and glycolate or lactate, depending on the specific molecular structure of the polymer The atoms sensitize the polymer to break down at physiological temperatures within hours, days, months or years. On the other hand, hydrophobic side groups such as aryloxy, fluoroalkoxy and higher alkoxy units protect the polymer backbone from hydrolysis. PPHOS has been studied t...

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Abstract

The invention discloses methods and compositions involving development of novel polymer-based therapeutics that induce browning of white adipocytes for the treatment of obesity and its associated metabolic diseases. The therapeutic effects are largely attributed to the promotion of brown and/or beige adipocyte development and function by leveraging adipocyte plasticity and polymer-based drug delivery systems. Both brown and beige adipocytes are densely packed with mitochondria which highly express uncoupling protein-1 (UCP1), a thermogenic protein mediating non-shivering thermogenesis.

Description

[0001] cross reference [0002] This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 62 / 247,192, filed October 27, 2015, the contents of which are incorporated herein in their entirety. field of invention [0003] The present disclosure relates generally to the treatment of obesity and diabetes, and in particular to novel polymer-based systems that allow for the controlled generation of brown / beige adipose tissue. Background of the invention [0004] This section introduces aspects that may contribute to a better understanding of the disclosure. Accordingly, these statements should be read in this light and should not be construed as an admission of what is or is not prior art. [0005] The obesity epidemic has caused major public health concerns in modern society due to its association with a range of metabolic diseases, including type 2 diabetes (T2D), heart disease, hyperglycemia and various cancers. Obesity is morphologically c...

Claims

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Application Information

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IPC IPC(8): C07K14/47A61K31/137
CPCA61K31/137C07K14/47A61K31/4439A61K47/593A61K47/605A61P5/48A61K31/426A61K47/58
Inventor 邓萌姜春辉邝良菊匡世焕
Owner PURDUE RES FOUND INC
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