Peptide-Bone Targeting Conjugates for Osteoporosis Treatment
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Solution Overview
Problem
Current treatments for conditions causing bone loss, such as osteoporosis, often result in side effects due to short half-lives of therapeutic peptides like hPTH (1-34) and IGF-1, which limit their clinical application and efficiency in preventing bone fractures.
Innovation Solution
Development of compositions where parathyroid hormone or insulin is covalently bonded with a bone-targeting moiety, such as a polyether group, to increase molecular weight, stability, and half-life, and reduce immunogenicity, allowing for enhanced targeting and retention at bone sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If therapeutic peptides like hPTH (1-34) and IGF-1 are administered to treat bone loss conditions, then bone formation is stimulated, but the short half-life of these peptides limits their clinical application and requires frequent dosing
Solution Approach 1:
The patent conjugates therapeutic peptides (hPTH (1-34) or IGF-1) with bone-targeting moieties (bisphosphonates or RANKL ligands) to create composite molecules. This composite structure combines the bone-forming activity of the peptide with the bone-targeting and retention properties of the moiety, thereby extending the effective half-life and reducing dosing frequency while maintaining therapeutic efficacy.
2Reliability
If high doses of hPTH (1-34)/PTH are administered to achieve therapeutic effect, then bone resorption occurs, but low doses are needed to promote bone formation
Solution Approach 1:
The bone-targeting moiety confers localized binding affinity to bone surfaces, particularly to hydroxyapatite in bone mineral. This local targeting ensures that the peptide is concentrated at the bone site where it is needed, allowing lower systemic doses to achieve effective local concentrations for bone formation without triggering unwanted bone resorption effects that occur with high systemic doses.
Solution Approach 2:
The bone-targeting moiety acts as an intermediary that mediates the interaction between the therapeutic peptide and bone tissue. It facilitates selective binding to bone surfaces through mechanisms such as hydroxyapatite interaction (for bisphosphonates) or RANKL-RANK binding (for RANKL ligands), thereby controlling peptide delivery and reducing the need for precise high-dose administration.
3Reliability
If current treatments are administered to prevent bone loss, then bone mass is maintained, but various side effects occur including cancers, bone necrosis, and osteonecrosis
Solution Approach 1:
By confining the therapeutic action to bone surfaces through targeted binding, the invention limits the exposure of other tissues to the therapeutic peptide and its potential side effects. The bone-targeting moiety ensures that hPTH (1-34) or IGF-1 acts primarily at the intended site (bone), reducing systemic exposure and associated harmful effects such as cancers and bone necrosis observed with conventional non-targeted treatments.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified peptides demonstrate improved bone-targeting and retention, potentially reducing side effects and enhancing the ability to prevent bone loss and fractures by increasing bioavailability and stability, as shown in ovariectomized rat models.
Implementation Method 1
parathyroid hormone or insulin that includes at least one bone targeting moiety, wherein the bone targeting moiety is covalently bonded to the peptide
Implementation Method 2
enhanced targeting and retention at bone sites
Data Source
AI summary
Described herein is insulin, an insulin-like growth factor, parathyroid hormone, a fragment of parathyroid hormone, or a parathyroid hormone related protein that includes at least one bone targeting moiety, wherein the bone targeting moiety is covalently bonded to the peptide. Also described herein are the methods of making these compositions that prevent or treat conditions associated with bone loss and preventing bone fractures, and/or the inability to initiate de novo bone turnover and stimulate bone fracture repair.