Compound of glycosaminoglycan and its fabrication method as well as application
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Publication Number
US-10342878-B2
Publication Date
2019-07-09
Expiration Date
Abstract
The present invention is related to a compound conjugating a drug with a glycosaminoglycan, such as hyaluronic acid (HA), where the drug is useful for the treatment of diseases such as inflammation, auto-immune disease, allergy, infection and preferably cancer. The conjugated compound of the present invention can increase the concentration of drug at the specific site of disease by an interaction of the glycosaminoglycan used as target drug delivery carrier and the CD44 cell surface receptor, then enhancing the therapeutic efficacy and reducing the systemic side effect of the site-delivered drug.
Core Innovation
The invention relates to hyaluronic acid (HA) drug-conjugate compounds for targeted delivery to cells that interact with HA, including CD44. The described compounds include an active compound covalently conjugated to HA, where the active compound is conjugated by means of a functional group to a carboxylic group of the hyaluronic acid, or a salt thereof, to form a covalent conjugate.
The covalent conjugate is formed by direct conjugation by means of an amide bond. The active compound is selected from Lenalidomide, Nimesulide and Celecoxib, and the biological rationale presented is that HA-CD44 interactions increase local drug concentration and reduce systemic side effects.
The document supports the concept with biological experiments, including cell uptake and fluorescence comparisons between CD44-rich versus low CD44 lines, cytotoxicity comparisons between HA-drug conjugates and free drugs, and in vivo xenograft tumor suppression showing improved tumor inhibition for an HA-NiNH2 conjugate compared with Nimesulide and control, with no significant body-weight loss reported.
Claims Coverage
The independent claim provides treatment coverage for cancer by administering a therapeutically effective amount of a covalently bound HA-active compound conjugate, with direct amide-bond conjugation, active compound limited to Lenalidomide, Nimesulide, or Celecoxib, and cancer limited to colon cancer or glioblastoma. A dependent refinement specifies an HA molecular-weight range of 10 kDa to 2000 kDa.
HA-active compound covalent conjugate for cancer treatment
A method for treatment of cancer comprising administering to a subject a therapeutically effective amount of a compound consisting of a conjugate from hyaluronic acid and an active compound.
Direct functional-group conjugation to HA carboxylic group via amide bond
The active compound is conjugated by means of a functional group to a carboxylic group of the hyaluronic acid, or a salt thereof, to form a covalent conjugate, and the covalent conjugate is formed by direct conjugation by means of an amide bond.
Active compound selection limited to Lenalidomide, Nimesulide, and Celecoxib
The active compound is selected from the group consisting of Lenalidomide, Nimesulide and Celecoxib.
Cancer limited to colon cancer or glioblastoma
The cancer is colon cancer or glioblastoma.
HA average molecular weight range
The hyaluronic acid has an average molecular weight between 10 kDa and 2000 kDa.
Overall, the claim coverage is limited to administering direct amide-bond HA covalent conjugates with active compounds selected from Lenalidomide, Nimesulide, or Celecoxib for treating colon cancer or glioblastoma, with an additional dependent constraint specifying an HA average molecular weight of 10 kDa to 2000 kDa.
Stated Advantages
Increased local drug concentration via HA-CD44 interactions.
Reduced systemic side effects.
Improved tumor inhibition in vivo for the HA-NiNH2 conjugate compared with Nimesulide and control.
No significant body-weight loss reported in vivo.
Documented Applications
Treatment of cancer, specifically colon cancer and glioblastoma.
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