Bone fracture repair by targeting of agents that promote bone healing
Inventors
Low, Stewart Andrew • Low, Philip S. • Galliford, Christopher • Kopecek, Jindrich • Yang, Jiyan
Assignees
Purdue Research Foundation • University of Utah
Publication Number
US-11623009-B2
Publication Date
2023-04-11
Expiration Date
2036-05-29
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Abstract
Aspects of the present disclosure generally relate to compounds for targeting and healing bone fractures. Some of these compounds include a negatively charged oligopeptide comprising an acidic oligopeptide, a linker, which may be hydrolyzable or may be a substrate for the protease cathepsin K, and at least one molecule that promotes bone healing. In some compounds the molecule that promotes bone healing is an anabolic compound that inhibits GSK3β, in some compounds the molecule that promotes the healing of bone fracture is a pro-inflammatory agent such as PGE1. Other embodiments include methods of treating a bone fracture comprising administering a therapeutic amount of any one of the compounds disclosed herein.
Core Innovation
The invention provides compounds for targeting and healing bone fractures. These compounds typically consist of three structural components: a negatively charged oligopeptide, a hydrolysable linker, and a molecule that promotes bone healing, which may be an anabolic compound such as a GSK3β inhibitor (e.g., 6-bromoindirubin-3′-oxime) or a pro-inflammatory agent such as prostaglandin E1 (PGE1). The oligopeptide, often composed of aspartic acid residues, is designed to direct the compound specifically to fracture sites by targeting exposed hydroxyapatite, while the linker facilitates controlled release of the therapeutic agent at or near the bone fracture.
The background identifies a key problem: current clinical treatments for bone fractures seldom employ site-specific anabolic drugs, with systemic administration being unsuitable due to lack of targeting and possible side effects. Available drugs like BMP-2 and BMP-7 are used only in limited open fracture cases, and widespread use of bisphosphonates, which inhibit bone turnover, complicates fracture healing. There is a clear clinical need for a drug that can be administered systemically but targets and acts locally at the fracture site.
The invention addresses this by providing drug delivery systems, including micelles and polymers, in which the bone-targeting oligopeptide confers specificity to fracture sites. The hydrolysable linker enables controlled release of the therapeutic agent in the microenvironment of the bone fracture. The invention further provides methods and compositions, including unimers, branched and linear micelles, and HPMA copolymers, that carry bone anabolic or pro-inflammatory agents and demonstrate targeted accumulation and promotive effects on bone healing in animal models.
Claims Coverage
The patent contains one independent claim covering several inventive features related to the method of treating bone fractures using a specifically structured compound.
Use of negatively charged oligopeptide for targeting
The claimed method requires administering a compound containing at least one negatively charged oligopeptide. This oligopeptide serves as a targeting moiety, and in dependent claims may be specifically an acidic oligopeptide or comprise amino acids such as D-aspartic acid, L-aspartic acid, D-glutamic acid, or L-glutamic acid.
Inclusion of a defined peptide-based linker
The compound includes a linker defined by the formula -Gly-Gly-Pro-Xle-, where Gly is glycine, Pro is proline, and Xle is chosen from a group consisting of norleucine, leucine, isoleucine, a hydrophobic amino acid, or an amphipathic amino acid.
Therapeutic agent selected from prostaglandin E1 or prostaglandin E2
The active compound (D in the formula) is specifically defined as prostaglandin E1 or prostaglandin E2, which promote the healing of bone fractures as part of the administered composition.
HPMA polymer backbone supporting multiple functional components
The compound contains a backbone structure (MA) that is N-(2-Hydroxypropyl) methacrylamide, enabling multiple copies (n is 1 to 1000) and supporting linkages to both the spacer (B) and the linker (C). Variations include the possibility for additional linked groups such as 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(3-(3-methacrylamidopropyl)thioureido)benzoic acid.
Administration as a method for treating bone fractures
The inventive method comprises administering a therapeutic amount of the described compound to a patient suffering from a bone fracture, thereby providing treatment that targets and promotes bone repair.
In summary, the claim coverage encompasses a method of treating bone fractures by administering a composition with a defined negatively charged oligopeptide for targeting, a specific peptide linker, a prostaglandin therapeutic payload, and a polymeric backbone structure, providing targeted delivery and controlled release at fracture sites.
Stated Advantages
The invention enables systemic administration of bone fracture treatment agents that specifically migrate to and accumulate at the fracture site, improving targeting compared to direct application.
The compositions allow for controlled release of the therapeutic compound at or near the bone fracture, reducing off-target effects and increasing local drug availability.
The bone-targeting oligopeptides, particularly those containing D-aspartic acid, have low toxicity and enhanced stability against proteolytic degradation.
Micelle and polymer designs enable delivery of hydrophobic drugs in a soluble and stable form, improving biodistribution and reducing accumulation in non-target organs compared to free drug.
Treatment with the targeted compounds increases bone density and fracture callus volume in animal models, indicating enhanced healing efficacy.
Documented Applications
Systemic treatment of bone fractures in patients by administration (oral or intravenous) of compounds to promote targeted healing at fracture sites.
Use in animal models (mice and rats) for accelerated healing of long bone fractures, improving bone density and callus formation.
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