COMPOSITIONS AND METHODS FOR ALTERING MACROPHAGE PHENOTYPE
Disclosed are methods and compositions for repolarizing a tumor associated macrophage (TAM) from M2 to M1 comprising administering to a subject in need thereof an effective dose of a compound comprising a dextran backbone and one or more CD206 targeting moieties conjugated thereto. In certain aspects, the compound further comprises a therapeutic agent selected from: paclitaxel, gemcitabine, lapatinib, and doxorubicin. In further aspect, the therapeutic agent comprises a chelator and at least one metal ion. In certain implementations, the at least one metal ion comprises at least one Cu(II) ions.
1 . A method for 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 carbohydrate backbone, one or more C-type lectin receptor targeting moieties comprising mannose, fucose, or n-acetylglucosamine conjugated thereto, and a therapeutic agent comprising at least one metal ion.
2 . The method of claim 1 , wherein the therapeutic agent is attached to the carbohydrate backbone via an amino-terminated leash comprising the formula —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5.
3 . The method of claim 2 , wherein the therapeutic agent further comprises at least one chelator.
4 . The method of claim 3 , wherein the at least one metal ion is bound to the at least one chelator, and wherein the at least one chelator is bound to the amino-terminated leash.
5 . The method of claim 3 , wherein the at least one chelator comprises DTPA, DOTA, TETA, NETA, NOTA, or a combination thereof.
6 . The method of claim 1 , wherein the at least one metal ion comprises copper, arsenic, antimony, silver, cadmium, gallium, gadolinium, or a combination thereof.
7 . The method of claim 3 , wherein the at least one metal ion comprises at least one Cu(II) ion, and wherein the at least one Cu(II) ion is between about 1 Cu(II) ion and a number of Cu(II) ions equal to the number of chelators.
8 . The method of claim 2 , wherein the at least one metal ion is attached to the amino-terminated leash via a biodegradable linker.
9 . The method of claim 8 , wherein the biodegradable linker comprises a hydrazone linker.
10 . The method of claim 1 , 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.
11 . The method of claim 10 , wherein the at least one other treatment or therapy is anti-CTLA4 immunotherapy.
12 . The method of claim 10 , wherein the combined administration of the compound and the at least one treatment or therapy is synergistically effective relative to administration of either alone.
13 . The method of claim 1 , wherein the one or more C-type lectin receptor targeting moieties is attached to the carbohydrate backbone via an amino-terminated leash having the formula —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5.
14 . The method of claim 1 , wherein administration of the composition to the subject has reduced toxicity relative to an equivalent dose of the therapeutic agent not conjugated to the composition.
15 . The method of claim 1 , wherein the compound comprises a compound of Formula (I):
wherein
each X is independently H, L1-A, or L2-R;
each L1 and L2 are independently amino-terminated leashes;
each A independently comprises a therapeutic agent or H bound to the amino-terminated leash, wherein the amino-terminated leash has the formula —(CH 2 ) p S(CH 2 ) q —NH— with an optional attachment with amide, amidine, and/or hydrazone group, wherein p and q are integers from 0 to 5, and wherein the therapeutic agent comprises one or more metal ions;
each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H;
and n is an integer greater than zero; and
wherein at least one R comprises the mannose-binding C-type lectin receptor targeting moiety and at least one A comprises the therapeutic agent.
16 . The method of claim 15 , wherein the therapeutic agent further comprises at least one chelator.
17 . The method of claim 15 , wherein the at least one metal ion comprises copper, arsenic, antimony, silver, cadmium, gallium, gadolinium, or a combination thereof.
18 . A compound for repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype comprising a compound of Formula (I):
wherein
each X is independently H, L1-A, or L2-R;
each L1 and L2 are independently amino-terminated leashes;
each A independently comprises a therapeutic agent or H;
each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H;
and n is an integer greater than zero; and
wherein at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine and at least one A comprises a therapeutic agent.
19 . The compound of claim 18 , wherein the amino-terminated leashes comprise the formula —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5.
20 . The compound of claim 18 , wherein the therapeutic agent comprises paclitaxel, gemcitabine, lapatinib, doxorubicin, a bisphosphonate, at least one metal ion, or at least one metal ion and at least one chelator.