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Publication Number
US-12285441-B2
Publication Date
2025-04-29
Expiration Date
Abstract
The present disclosure is related to a conjugate of an active drug and a glycosaminoglycan, such as hyaluronic acid (HA). For example, the active drug can be lenalidomide, nimesulide, or gemcitabine. The conjugate of the present disclosure is useful in the treatment of certain cancers.
Core Innovation
The invention relates to glycosaminoglycan drug conjugates for cancer treatment, preferably conjugates of hyaluronic acid (HA) with an active compound. The conjugates are designed for targeting CD44-overexpressing cells, which are described as being present in inflamed or injured tissues and in cancer cells with HA uptake. The approach uses covalent conjugation of the active compound to HA.
In particular, the conjugates are configured as HA-active compound constructs, including HA conjugated with lenalidomide, COX-2 antagonists such as nimesulide and celecoxib, and gemcitabine. The conjugation is described as forming an amide bond by linking the drug to HA carboxyl groups, either directly or via linkers. The disclosure specifically includes modification of nimesulide so that it provides an amino group suitable for amide coupling to HA.
The disclosed rationale is that HA adhesion to injured or inflamed tissues and interaction with CD44-rich cancer cells enables cell uptake and improved anti-cancer effect. The disclosure reports improved in vitro cytotoxicity trends with HA-based conjugates, including enhanced effects for HA-lenalidomide relative to comparison cells, and enhanced cytotoxicity trends for HA conjugates of nimesulide forms. The disclosure further reports in vivo tumor suppression with a HA conjugate form in a xenograft model without notable body-weight loss.
Claims Coverage
The partial content provides one independent claim. It contains three main inventive aspects: a method for treating breast cancer by administering an HA-active compound conjugate, a structural requirement that the active compound is nimesulide modified to have an amino group, and a direct conjugation to HA carboxylic groups with an HA molecular weight range.
Treating breast cancer by administering a therapeutically effective HA conjugate
A method for treating breast cancer by administering to a subject in need thereof a therapeutically effective amount of a conjugate of a hyaluronic acid and an active compound.
Nimesulide modified to have an amino group
The active compound is nimesulide modified to have an amino group, having the structure such that the amino group is part of the modified nimesulide.
Direct amino-to-HA carboxyl conjugation and HA molecular weight range
The amino group is conjugated directly to a carboxylic group of the hyaluronic acid or a salt thereof, and the hyaluronic acid has an average molecular weight comprised in the range from 350 kDa to 700 kDa.
Overall, the claim coverage centers on administering an HA-drug conjugate for breast cancer, where the active compound is nimesulide modified to introduce an amino group that is directly conjugated to HA carboxyl groups, with HA having an average molecular weight of 350 kDa to 700 kDa.
Stated Advantages
Improved in vitro cytotoxicity trends of HA-based conjugates compared with relevant comparisons
Enhanced tumor suppression in vivo with a HA conjugate form in a xenograft model
No notable body-weight loss in the reported in vivo context
Documented Applications
Breast cancer treatment by administering a therapeutically effective amount of a conjugate of hyaluronic acid and an active compound
Targeting CD44-overexpressing cells for cancer treatment
In vitro cytotoxicity testing using HT29 cells versus CD44-low HCT15 cells and additional reported cell contexts
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