CD206 targeted drug delivery vehicles carrying novel bisphosphonate drug payloads via a degradable linker
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.
1. A compound comprising:
a polymeric carbohydrate backbone;
one or more mannose-binding C-type lectin receptor targeting moieties; and
a nitrogenous bisphosphonate compound coupled to the polymeric carbohydrate backbone via a thiol-maleimide conjugation.
2. The compound of claim 1 , wherein the compound comprises a subunit as shown in Formula (I):
wherein
each X is independently H, L 1 —A—Z, or L 2 —R, wherein each X is bound to an OH group;
each of L 1 and L 2 are independently amine terminated leashes;
each A independently comprises a substituted or unsubstituted maleimide moiety;
each Z independently comprises a bisphosphonate compound modified with a hydrazone moiety or is absent;
each R independently comprises the mannose-binding C-type lectin receptor targeting moiety or H; and
n is an integer greater than zero, wherein each unit of n may be the same or different; and
wherein at least one A is the substituted maleimide moiety and wherein the thiol-maleimide conjugation is between A and Z.
3. The compound of claim 2 , wherein at least one X is L 1 —A—Z, wherein at least one X is L 2 —R, and wherein R comprises the mannose-binding C-type lectin receptor targeting moiety.
4. The compound of claim 1 , wherein the polymeric carbohydrate backbone has a molecular weight between about 1 kD to about 50 kD.
5. The compound of claim 1 , wherein the mannose-binding C-type lectin receptor targeting moiety comprises a mannosyl coupling aglycon moiety, mannose, high-mannose glycans or mannose oligosaccharides, fucose, N-acetylglucosamine, peptides, galactose, or a combination thereof.
6. The compound of claim 2 , wherein at least one L 1 comprises —(CH 2 ) p S(CH 2 )q—NH—, wherein p and q are integers from 0 to 5.
7. The compound of claim 2 , wherein at least one L 2 comprises —(CH 2 ) p S(CH 2 )q—NH—, wherein p and q are integers from 0 to 5.
8. The compound of claim 2 , wherein the bisphosphonate compound is substituted with a carbonyl functional group prior to being modified to a hydrazone moiety.
9. The compound of claim 2 , wherein the hydrazone moiety comprises an acyl hydrazone.
10. The compound of claim 9 , wherein the hydrazone moiety has the following structure:
11. The compound of claim 10 , wherein R 2 comprises —R 4 —SH, wherein R 4 is a substituted or unsubstituted, linear or branched C 1 -C 12 alkyl, alkenyl, alkynyl, or aromatic group.
12. The compound of claim 11 , wherein R 2 comprises —(CH 2 ) 2 SH.
13. A pharmaceutical composition comprising:
the compound according to claim 1 ; and
a pharmaceutically acceptable carrier.
14. The composition of claim 13 , wherein the compound comprises a subunit as shown in Formula (I):
wherein each X is independently H, L 1 —A—Z, or L 2 —R, wherein each X is bound to an OH group;
each of L 1 and L 2 are independently amine terminated leashes;
each A independently comprises a substituted or unsubstituted maleimide moiety;
each Z independently comprises a bisphosphonate compound modified with a hydrazone moiety or is absent;
each R independently comprises the mannose-binding C-type lectin receptor targeting moiety or H; and
n is an integer greater than zero, wherein each unit of n may be the same or different; and
wherein at least one A is the substituted maleimide moiety and wherein the thiol-maleimide conjugation is between A and Z.
15. A method of making the compound according to claim 1 , comprising:
(a) synthesizing a polymeric carbohydrate backbone having one or more amine terminated leashes attached thereto;
(b) synthesizing a nitrogenous bisphosphonate compound comprising a carbonyl functional group;
(c) reacting the carbonyl functional group with an acylhydrazide to form the nitrogenous bisphosphonate compound modified with a hydrazone moiety;
(d) modifying one or more amine terminated leashes with a maleimide moiety; and
(e) substituting one or more maleimide moieties from step (d) with the bisphosphonate compound modified with the hydrazone moiety from step (c) through a thiol-maleimide conjugation.
16. The method of claim 15 , wherein step (d) may occur before step (b), after step (b), before step (c), or after step (c).
17. The method of claim 15 , wherein in Formula (I), at least one Xis L 1 —A—Z, wherein at least one X is L 2 —R, and wherein R comprises the mannose-binding C-type lectin receptor targeting moiety.
18. The method of claim 15 , wherein the polymeric carbohydrate backbone has a molecular weight between about 1 kD to about 50 kD.
19. The method of claim 15 , wherein the mannose-binding C-type lectin receptor targeting moiety comprises a mannosyl coupling aglycon moiety, mannose, high-mannose glycans or mannose oligosaccharides, fucose, N-acetylglucosamine, peptides, galactose, or a combination thereof.
20. The method of claim 15 , wherein in Formula (I), at least one L 1 comprises —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5.
21. The method of claim 15 , wherein in Formula (I), at least one L 2 comprises —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5.
22. The method of claim 15 , wherein the hydrazone moiety has the following structure:
23. The method of claim 22 , wherein R 2 comprises —R 4 —SH, wherein R 4 is a substituted or unsubstituted, linear or branched C 1 -C 12 alkyl, alkenyl, alkynyl, or aromatic group.
24. The method of claim 23 , wherein R 2 comprises —(CH 2 ) 2 SH.
25. A method of repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype, comprising:
administering to a subject in need thereof an effective dose of a compound comprising a polymeric carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties, and a nitrogenous bisphosphonate compound coupled to the polymeric carbohydrate backbone via a thiol-maleimide conjugation.
26. The method of 25 , wherein the compound comprises a subunit as shown in Formula (I):
wherein
each X is independently H, L 1 -A-Z, or L 2 -R, wherein each X is bound to an OH group;
each of L 1 and L 2 are independently amine terminated leashes;
each A independently comprises a substituted or unsubstituted maleimide moiety;
each Z independently comprises a bisphosphonate compound modified with a hydrazone moiety or is absent;
each R independently comprises the mannose-binding C-type lectin receptor targeting moiety or H; and
n is an integer greater than zero, wherein each unit of n may be the same or different; and
wherein at least one A is the substituted maleimide moiety and wherein the thiol-maleimide conjugation is between A and Z.
27. The method of claim 25 , wherein the compound is administered in conjunction with at least one other therapy or treatment and, wherein the at least one other treatment or therapy is a chemotherapy, radiation therapy, or immunotherapy.
28. The method of claim 25 , wherein the bisphosphonate compound is released from the polymeric carbohydrate backbone at a pH of below about 5.5.
29. A method of treating a disease, comprising:
administering to a subject in need thereof an effective amount of a compound according to claim 1 ,
wherein the disease is cancer, an autoimmune disease, or an inflammatory disorder.
30. The method of claim 29 , wherein the compound is administered in conjunction with at least one other therapy or treatment and, wherein the at least one other treatment or therapy is a chemotherapy, radiation therapy, or immunotherapy.
31. The method of claim 29 , wherein the disease is cancer.