Compound of glycosaminoglycan and its fabrication method as well as application
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Publication Number
US-11229665-B2
Publication Date
2022-01-25
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 covalent conjugates of a glycosaminoglycan with active anticancer compounds for targeted drug delivery. A preferred glycosaminoglycan is hyaluronic acid, and the conjugates are designed to exploit CD44 receptor targeting for site-selective drug delivery.
The disclosure addresses the need for therapeutic approaches that provide improved efficacy at the target site while reducing systemic side effects. The HA-CD44 interactions are used as a mechanism to increase local drug concentration and promote accumulation and cellular entry in CD44-rich environments.
The specification describes conjugates in which anticancer agents are covalently coupled to hyaluronic acid. Exemplary active anticancer compounds include gemcitabine and COX-2 antagonists such as nimesulide and celecoxib, and the disclosed conjugation is based on a carboxyl-functional group of hyaluronic acid coupling to the active compound, optionally using linkers or spacers.
The document further provides experimental evidence and reported outcomes supporting CD44-dependent accumulation and cellular entry using HA-dye or HA-fluorescent constructs in CD44-rich versus CD44-low colon cancer cell lines, and reports in vitro cytotoxicity and in vivo tumor suppression improvements for HA-drug conjugates compared to free drugs or controls.
Claims Coverage
One independent inventive feature is explicitly supported: a hyaluronic acid–gemcitabine conjugate defined by direct NH2-to-carboxyl conjugation and an HA average molecular weight range of 350–700 kDa.
Hyaluronic acid–gemcitabine conjugate with direct NH2-to-carboxyl conjugation at defined HA molecular weight
A compound consisting of a conjugate from a hyaluronic acid and gemcitabine, wherein the gemcitabine has an —NH2 group in direct conjugation with a carboxylic group of the hyaluronic acid, its derivative, or a salt thereof wherein the hyaluronic acid has an average molecular weight comprised in the range from 350 kDa to 700 kDa.
Liver cancer treatment using the HA–gemcitabine conjugate
A compound according to claim 1 for use in treating liver cancer.
Hepatocellular carcinoma treatment using the HA–gemcitabine conjugate
The compound according to claim 2 for treating liver cancer, wherein the liver cancer is hepatocellular carcinoma.
Pharmaceutical composition containing the HA–gemcitabine conjugate
A pharmaceutical composition comprising at least one compound according to claim 1 together with at least one excipient and/or diluent.
Therapeutic administration of the HA–gemcitabine conjugate for liver cancer
A method for treating cancer by administering a therapeutically effective amount of a compound according to claim 1 to a subject, wherein the cancer is liver cancer.
Preparation method using carbodiimide coupling and dialysis
A method for preparing a compound comprising forming an aqueous hyaluronic acid solution with N-(3-dimethylamino propyl)-N-ethyl carbodiimide hydrochloride and N-hydroxysuccinimde, forming an organic-solvent solution of gemcitabine, mixing and stirring the two solutions at room temperature for at least 10 hours, and then dialyzing the mixed solution for several days.
The claim coverage centers on a specific HA-gemcitabine covalent conjugate defined by direct —NH2 to HA carboxyl conjugation and an HA average molecular weight range of 350–700 kDa. Dependent coverage further specifies liver cancer, including hepatocellular carcinoma, a pharmaceutical composition with excipients/diluents, therapeutic administration to a subject, and a preparation workflow including carbodiimide coupling and dialysis.
Stated Advantages
Increases local drug concentration at the target site via HA-CD44 interactions.
Improves therapeutic efficacy of HA-drug conjugates compared to free drugs or controls.
Reduces systemic side effects.
Promotes CD44-dependent accumulation and cellular entry in CD44-rich versus CD44-low colon cancer cell lines.
Improves in vivo tumor suppression compared to free drugs or controls.
Documented Applications
Site-selective drug delivery based on CD44 receptor targeting using covalent HA-drug conjugates.
Treatment use for liver cancer, including hepatocellular carcinoma.
Treatment method by administering a therapeutically effective amount of the HA–gemcitabine conjugate to a subject with liver cancer.
Preparation of HA–gemcitabine conjugates using carbodiimide coupling and dialysis [procedural detail omitted for safety].
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