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, wherein the compound is Formula (I);
wherein
each X is independently H, L1-A, or L2-R;
each L1 and L2 are independently an amino-terminated leash;
each A independently is H or a therapeutic agent bound to the amine-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, wherein the therapeutic agent is selected from the group consisting of paclitaxel, gemcitabine, lapitinib, doxorubicin, and a bisphophonate;
each R indepedently is mannose, fucose, n-acetylglucosamine, or H;
and n is an integer greater than zero,
wherein at least one A is the therapeutic agent, and at least one R is mannose.
2. The method of claim 1 , wherein the therapeutic agent is selected from: the paclitaxel, gemcitabine, lapatinib, and doxorubicin.
3. The method of claim 2 , wherein the therapeutic agent is the doxorubicin.
4. The method of claim 2 , wherein administration of the compound to the subject has reduced toxicity relative to an equivalent dose of the therapeutic agent not conjugated to the compound.
5. The method of claim 1 , wherein the therapeutic agent is the bisphosphonate.
6. The method of claim 5 , wherein the bisphosphonate is zoledronic acid.
7. 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.
8. The method of claim 7 , wherein the at least one other treatment or therapy is anti-CTLA4 immunotherapy.
9. The method of claim 7 , wherein the combined administration of the compound and the at least one treatment or therapy provides greater efficacy or is synergistically effective relative to administration of either alone.