COMPOUNDS AND COMPOSITIONS FOR TARGETING MACROPHAGES AND OTHER MANNOSE-BINDING C-TYPE LECTIN RECEPTOR HIGH EXPRESSING CELLS AND METHODS OF TREATING AND DIAGNOSIS USING SAME
Provided are compounds and compositions for targeting macrophages and other mannose-binding c-type lectin receptor high expressing cells and methods of treatment and diagnosis using such compounds and compositions.
1 . A compound comprising a dextran backbone having one or more CD206 targeting moieties and one or more therapeutic agents attached thereto.
2 . A compound according to claim 1 , wherein the compound is a compound of Formula (II):
wherein
each X is independently H, L 1 -A, or L 2 -R;
each L 1 and L 2 are independently linkers;
each A independently comprises a therapeutic agent or a detection label or H;
each R independently comprises a CD206 targeting moiety or H; and
n is an integer greater than zero; and
wherein at least one A comprises a CD206 targeting moiety and at least one A comprises a therapeutic agent.
3 . A compound comprising a dextran backbone having one or more mannose-binding C-type lectin receptor targeting moieties and one or more therapeutic agents attached thereto.
4 . A compound according to claim 3 , wherein the compound is a compound of Formula (II):
wherein
each X is independently H, L 1 -A, or L 2 -R;
each L 1 and L 2 are independently linkers;
each A independently comprises a therapeutic agent or a detection label 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 and at least one A comprises a therapeutic agent.
5 . A compound according to any of the previous claims, wherein at least one R is selected from the group consisting of mannose, fucose, and n-acetylglucosamine.
6 . A compound according to any of the previous claims, wherein at least one A is selected from the group consisting of chemotherapeutic agents; antibiotics; immunological adjuvants; steroids; nucleotides; antigens; peptides; proteins; microRNA; siRNA; and antivirals.
7 . A compound according to any of the previous claims, wherein at least one A is selected from the group consisting of doxorubicin.
8 . A compound according to any of the previous claims, wherein at least one A is a metal.
9 . A compound according to any of the previous claims, wherein at least one A is selected from the group consisting of gadolinium, gallium, silver, and a silver antibiotic.
10 . A compound according to any of the previous claims wherein at least one L 1 is a C 2-12 hydrocarbon chain optionally interrupted by up to three heteroatoms selected from the group consisting of O, S and N.
11 . A compound according to any of the previous claims wherein at least one L 1 comprises —(CH 2 ) p S(CH 2 )—NH—, wherein p and q are integers from 0 to 5.
12 . A compound according to any of the previous claims wherein at least one L 2 is a C 2-12 hydrocarbon chain optionally interrupted by up to three heteroatoms selected from the group consisting of O, S and N.
13 . A compound according to any of the previous claims wherein at least one L 2 comprises —(CH 2 ) p S(CH 2 )—NH—, wherein p and q independently are integers from 0 to 5.
14 . A method of diagnosing and treating a disease comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 - 13 ; and detecting the detection label at a predetermined location in the subject; wherein the disease is selected from AIDS, HIV infection and Leishmaniasis.
15 . A method of treating a disease comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 - 13 ; wherein the disease is selected from AIDS, HIV infection and Leishmaniasis.
16 . A method of treating a disease comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 - 13 , wherein the disease is an autoimmune disease, an inflammatory disease, or cancer.
17 . A method of targeting tumor-associated macrophages comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 - 13 .
18 . A method according to any one of claims 14 - 17 wherein the compound contains has at least one therapeutic agent and at least one detection label.
19 . A method according to any one of claims 14 - 18 wherein a linker is used to attach the one or more CD206 targeting moieties, one or more mannose-binding C-type lectin receptor targeting moieties one or more therapeutic agents, and/or the one or more detection labels.
20 . A method according to any one of claims 14 - 19 wherein at least one L 1 comprises a degradable linker.
21 . A method according to any one of claims 14 - 20 wherein at least one L 1 comprises a hydrolysable linker.
22 . A method according to any one of claims 14 - 21 wherein at least one L 1 comprises an acid-sensitive linker.
23 . A method according to any one of claims 16 and 18 - 22 , wherein the disease is rheumatoid arthritis.
24 . A method according to any one of claims 16 and 18 - 22 , wherein the disorder is cancer.
25 . A method according to claim 24 , wherein the cancer is a sarcoma, lymphoma, leukemia, carcinoma, blastoma, melanoma, or germ cell tumor.
26 . A method according to claim 25 , wherein the cancer is Kaposi's sarcoma.
27 . A method according to any one of claims 14 - 26 , wherein at least one A is a detection label and the detection label is a fluorophore.
28 . A method according to any one of claims 14 - 27 , wherein at least one L 1 -A comprises a chelator.