CD206 targeted drug delivery vehicles carrying novel bisphosphonate drug payloads via a degradable linker
Inventors
Ralph, David A. • Arnold, Jeffrey Scott
Assignees
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Publication Number
US-12297222-B2
Publication Date
2025-05-13
Expiration Date
Abstract
Provided are novel compounds containing a polymeric carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties, and a nitrogenous bisphosphonate compound coupled to the backbone via a thiol-maleimide conjugation, in addition to pharmaceutical compositions, methods of synthesizing, and methods of use. The thiol-maleimide conjugation of a bisphosphonate to a polymeric carbohydrate backbone provides for methods of using the compounds and compositions thereof for releasing the therapeutic payload when internalized into a mannose-binding C-type lectin receptor-expressing cell, such as tumor associated macrophages (TAMs) for the treatment of various diseases, including, cancer, autoimmune diseases, and inflammatory disorders.
Core Innovation
The disclosure describes CD206 targeted mannosylated amine dextran drug delivery constructs that carry nitrogenous bisphosphonate payloads. The constructs use thiol-maleimide conjugation to an intermediate hydrazone linker that is pH-sensitive and endosome-cleavable.
The disclosure frames a therapeutic effect as tumor-associated macrophage repolarization from M2-like immunosuppressive toward M1-like proinflammatory phenotypes using the mannosylated amine dextran delivery constructs bearing nitrogenous bisphosphonate payloads. The targeting and payload release are tied to CD206 recognition and the pH-sensitive hydrazone linker.
Structurally, the carrier subunit is described as a dextran backbone with mannose ligand types and percentages and amine-terminated leashes, together enabling thiol-maleimide conjugation. The bisphosphonate payloads are described as nitrogenous bisphosphonate variants defined by general bisphosphonate structures including Formulas (I) to (VI), where nitrogenous bisphosphonates are modified with a hydrazone moiety using an acylhydrazide and carbonyl combination.
Claims Coverage
The independent claim coverage centers on one bisphosphonate scaffold defined by Formula (II), with multiple explicit inventive structural options in R1, X1, Y, and W, and a defining condition for when the bisphosphonate is modified with a hydrazone moiety. Dependent claims narrow the scaffold by specifying the carbonyl-acylhydrazide combination, the NH2-NH-C(O)-R2 motif, and the terminal thiol-containing group.
Hydrazone-modified bisphosphonate scaffold defined by Formula (II)
A bisphosphonate compound defined by Formula (II) in which Y is NH or absent and W is an imidazole or a thiazole substituted with a C1-alkyl and further substituted with a carbonyl group that is either a ketone group or, when combined with an acylhydrazide, forms a bisphosphonate compound modified with a hydrazone moiety.
Variable substituent pattern R1 and X1 within Formula (II)
In the bisphosphonate compound of Formula (II), R1 are each independently H, a positively-charged counter ion, a substituted or unsubstituted linear or branched C1-C6 alkyl group, or an acyloxyalkyl group, and X1 is H or a C1 alkyl group.
Carbonyl-acylhydrazide combination to form the hydrazone moiety
A bisphosphonate compound modified with a hydrazone moiety is defined by combining a carbonyl group with an acylhydrazide.
Acylhydrazide motif specified as NH2-NH-C(O)-R2
The acylhydrazide moiety is specified by the structural form NH2-NH-C(O)-R2.
Terminal thiol-containing R2 substituent defined via R4
R2 contains a -R4-SH group, where R4 is a substituted or unsubstituted linear or branched C1-C12 alkyl, alkenyl, alkynyl, or aromatic group.
Example R2 substituent as -(CH2)2SH
R2 is specifically defined to include a -(CH2)2SH group.
Overall claim coverage centers on a Formula (II) bisphosphonate scaffold where a hydrazone moiety is defined by a carbonyl and an acylhydrazide, with dependent claims specifying the NH2-NH-C(O)-R2 motif and constraining the terminal thiol-containing R2 substituent, including an explicit -(CH2)2SH example, while varying R1 and X1.
Stated Advantages
pH-dependent payload release from the MAD-BIS constructs triggered by endosomal acidified pH
Macrophage phenotype modulation, including reduced CD206/CD163/SIRP- and increased CD80/CD86
Documented Applications
Use in MAD constructs for payload release associated with endosomal pH, with activity discussed in the context of CD206-mediated intracellular delivery
Macrophage phenotype modulation in connection with markers including CD206, CD163, SIRP-, CD80, and CD86
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