Bioorthogonal compositions

Abstract

The present disclosure provides bioorthogonal compositions for delivering agents in a subject. The disclosure also provides methods of producing the compositions, as well as methods of using the same.

What is claimed is: 
     
         1 . A support composition comprising:
 a support, wherein the support comprises a hydrogel support or a support particle;   a first binding agent attached to the support and comprising a first bioorthogonal functional group that is a member of a first complementary binding pair;   a second binding agent attached to the support and comprising a second bioorthogonal functional group that is a member of a second complementary binding pair different from the first complementary binding pair; and   wherein if the support comprises the support particle, then the support composition further comprises a targeting agent attached to the support particle.   
     
     
         2 . The support composition of any of  claims 1  to  3 , wherein the support comprises a hydrogel support. 
     
     
         3 . The support composition of any of  claims 1  to  3 , wherein the support is a support particle and the support composition comprises the targeting agent attached to the support particle. 
     
     
         4 . The support composition of any of  claims 1  to  3 , further comprising a first linker covalently linking the first binding agent to the support. 
     
     
         5 . The support composition of any of  claims 1  to  3 , further comprising a second linker covalently linking the second binding agent to the support. 
     
     
         6 . The support composition of any of  claims 1  to  3 , wherein the first bioorthogonal functional group and the second bioorthogonal functional group are a trans-cyclooctene and an azide. 
     
     
         7 . The support composition of any of  claims 1  to  3 , wherein the first bioorthogonal functional group and the second bioorthogonal functional group are a trans-cyclooctene and an alkyne. 
     
     
         8 . The support composition of any of  claims 1  to  3 , wherein the first bioorthogonal functional group and the second bioorthogonal functional group are a tetrazine and an azide. 
     
     
         9 . The support composition of any of  claims 1  to  3 , wherein the first bioorthogonal functional group and the second bioorthogonal functional group are a tetrazine and an alkyne. 
     
     
         10 . The support composition of any of  claims 1  to  3 , wherein the first binding agent is covalently bound to a first functionalized payload. 
     
     
         11 . The support composition of any of  claims 1  to  3 , wherein the first functionalized payload comprises a first complementary binding agent that selectively binds to the first binding agent, a first payload, and a linker covalently linking the first complementary binding agent to the first payload. 
     
     
         12 . The support composition of  claim 11 , wherein the first payload comprises a therapeutic agent, a diagnostic agent or a targeting agent. 
     
     
         13 . The support composition of  claim 11 , wherein the linker comprises a releasable linker. 
     
     
         14 . The support composition of any of  claims 1  to  3 , wherein the second binding agent is covalently bound to a second functionalized payload. 
     
     
         15 . The support composition of  claim 14 , wherein the second functionalized payload comprises a second complementary binding agent that selectively binds to the second binding agent, a second payload, and a linker covalently linking the second complementary binding agent to the second payload. 
     
     
         16 . The support composition of  claim 15 , wherein the second payload comprises a therapeutic agent, a diagnostic agent or a targeting agent. 
     
     
         17 . The support composition of  claim 15 , wherein the linker comprises a releasable linker. 
     
     
         18 . The support composition of any of  claims 1  to  3 , wherein the support particle is a nanoparticle or a microparticle. 
     
     
         19 . A method for delivering an effective amount of a payload to a target location in a subject, the method comprising:
 administering to the subject a support composition comprising:
 a support, wherein the support comprises a hydrogel support or a support particle; 
 a first binding agent attached to the support and comprising a first bioorthogonal functional group that is a member of a first complementary binding pair; 
 a second binding agent attached to the support and comprising a second bioorthogonal functional group that is a member of a second complementary binding pair different from the first complementary binding pair; and 
 wherein if the support comprises the support particle, then the support composition further comprises a targeting agent attached to the support particle; and 
   administering to the subject a first functionalized payload comprising a first complementary binding agent that selectively binds to the first binding agent, a first payload, and a linker covalently linking the first complementary binding agent to the first payload, such that the first functionalized payload binds to the support composition.   
     
     
         20 . The method of  claim 19 , wherein the linker comprises a releasable linker, and the method further comprises releasing the first payload, thereby delivering the first payload to the target location in the subject. 
     
     
         21 . The method of  claim 19 , further comprising administering to the subject a second functionalized payload comprising a second complementary binding agent that selectively binds to the second binding agent, a second payload, and a linker covalently linking the second complementary binding agent to the second payload, such that the second functionalized payload binds to the support composition. 
     
     
         22 . The method of  claim 21 , wherein the linker comprises a releasable linker, and the method further comprises releasing the second payload, thereby delivering the second payload to the target location in the subject. 
     
     
         23 . The method of  claim 19 , further comprising administering to the subject a second support composition, wherein the second support composition comprises:
 a second support;   a second complementary binding agent attached to the second support that selectively binds to the second binding agent; and   a third binding agent attached to the second support and comprising a third bioorthogonal functional group,   such that the second support composition binds to the support composition.   
     
     
         24 . The method of  claim 19 , wherein the first binding agent has a shorter in vivo half life than the second binding agent. 
     
     
         25 . The method of  claim 19 , wherein the first binding agent has a longer in vivo half life than the second binding agent. 
     
     
         26 . A kit comprising:
 a support composition comprising:
 a support, wherein the support comprises a hydrogel support or a support particle; 
 a first binding agent attached to the support and comprising a first bioorthogonal functional group that is a member of a first complementary binding pair; 
 a second binding agent attached to the support and comprising a second bioorthogonal functional group that is a member of a second complementary binding pair different from the first complementary binding pair; and 
 wherein if the support comprises the support particle, then the support composition further comprises a targeting agent attached to the support particle; and 
   a packaging containing the support composition.   
     
     
         27 . The kit of  claim 26 , further comprising a first functionalized payload. 
     
     
         28 . The kit of  claim 27 , wherein the first functionalized payload comprises a first complementary binding agent that selectively binds to the first binding agent, a first payload, and a linker covalently linking the first complementary binding agent to the first payload. 
     
     
         29 . The kit of  claim 26 , further comprising a second functionalized payload. 
     
     
         30 . The kit of  claim 29 , wherein the second functionalized payload comprises a second complementary binding agent that selectively binds to the second binding agent, a second payload, and a linker covalently linking the second complementary binding agent to the second payload. 
     
     
         31 . A functionalized payload of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         D is a payload; 
         L is a linker; 
         R 1 , at each occurrence, is independently selected from the group consisting of halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 1a , —NR 1b R 1c , —SR 1d , —SO 2 R 1e , —S(O)R 1f , and —P(O)OR 1g R 1h ; 
         R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , and R 1h , are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl; and 
         n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; 
         wherein said alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, at each occurrence, are independently substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkyl sulfonyl, aryl sulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl. 
       
     
     
         32 . The functionalized payload of  claim 31 , wherein D is an antibiotic agent, antifungal agent, antiviral agent, anticancer agent, cardiovascular agent, CNS agent, anti-inflammatory/anti-arthritic agent, anti-TB/anti-leprosy agent, anti-histaminic/respiratory disorder agent, corticosteroid agent, immunosuppressant agent, or anti-ulcer agent. 
     
     
         33 . The functionalized payload of  claim 31  or  claim 32 , wherein D is selected from at least one of paclitaxel, doxorubicin, daunorubicin, etoposide, irinotecan, SN-38, docetaxel, gemcitabine, podophyllotoxin, carmustine, ixabepilone, patupilone, cyclosporin A, rapamycin, amphotericin, vancomycin, daptomycin, doxycycline, ceftriaxone, trimethoprim, sulfamethoxazole, acyclovir, nystatin, amphotericin B, flucytosine, emtricitabine, gentamicin, colistin, L-dopa, oseltamivir, cefalexin, 5-aminolevulinic acid, cysteine, celecoxib, and nimodipine. 
     
     
         34 . The functionalized payload of any one of  claims 31 - 33 , wherein D comprises a radionuclide. 
     
     
         35 . The functionalized payload of any one of  claims 31 - 34 , wherein L is an immolative linker. 
     
     
         36 . The functionalized payload of any one of  claims 31 - 34 , wherein L is a pH tunable linker. 
     
     
         37 . The functionalized payload of any one of  claims 31 - 36 , wherein n is 0. 
     
     
         38 . The functionalized payload of any one of  claims 31 - 36 , wherein n is greater than 0, and at least on R 1  is a solubilizing substituent group. 
     
     
         39 . The functionalized payload of any one of  claims 31 - 38 , having formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R 1 , at each occurrence, is independently selected from the group consisting of halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 1a , —NR 1b R 1c , —SR 1d , —SO 2 R 1e , —S(O)R 1f , and —P(O)OR 1g R 1h ; 
         R 2 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 2a , —NR 2b R 1c , —SR 2d , —SO 2 R 2e , —S(O)R 2f , and —P(O)OR 2g R 2h ; 
         R 3 , at each occurrence, is independently selected from the group consisting of halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 3a , —NR 3b R 3c , —SR 3d , —SO 2 R 3e , —S(O)R 3f , and —P(O)OR 3g R 3h ; 
         R 4 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 4a , —NR 4b R 4c , —SR 4d , —SO 2 R 4e , —S(O)R 4f , and —P(O)OR 4g R 4h ; 
         R 5 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 5a , —NR 5b R 5c , —SR 5d , —SO 2 R 5e , —S(O)R 5f , and —P(O)OR 5g R 5h ; 
         R 6 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 6a , —NR 6b R 6c , —SR 6d , —SO 2 R 6e , —S(O)R 6f , and —P(O)OR 6g R 6h ; 
         R 7 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 7a , —NR 7b R 7c , —SR 7d , —SO 2 R 7e , —S(O)R 7f , and —P(O)OR 7g R 7h ; 
         R 8 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 8a , —NR 8b R 8c , —SR 8d , —SO 2 R 8e , —S(O)R 8f , and —P(O)OR 8g R 8h ; 
         R 10 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl; 
         R 11 , at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl; 
         R 12 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, —OR 12a , —NR 12b R 12c , —SR 12d , —SO 2 R 12e , —S(O)R 12f , and —P(O)OR 12g R 12h , 
         R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g , R 8h , R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g , R 12h , are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl 
         Z is selected from the group consisting of O, N(R a ), N(R b ), or S; 
         R a , R b , R c , R d , and R e  are each independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl; 
         L 1  is alkylene; 
         n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; 
         p is 0, 1, 2, 3, or 4; 
         q is 0, 1, 2, 3, 4, or 5; 
         wherein said alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, at each occurrence, are independently substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkyl sulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl. 
       
     
     
         40 . The functionalized payload any one of  claims 31 - 39 , having formula: 
       
         
           
           
               
               
           
         
         wherein Z is O or NR a , wherein R a  is hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl. 
       
     
     
         41 . The functionalized payload of any one of  claims 31 - 39 , having formula, 
       
         
           
           
               
               
           
         
         wherein, 
         G is 
       
       
         
           
           
               
               
           
         
         R 9  at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl, at each occurrence, are independently substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, acylamino, sulfonylamino, sulfinylamino, sulfonyl, alkyl sulfonyl, aryl sulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl; 
         Z is O or NR a ; and 
         R a  and R f  are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; 
       
     
     
         42 . A functionalized payload selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         43 . A therapeutic support composition comprising a tetrazine-containing group of formula 
       
         
           
           
               
               
           
         
         wherein 
         R 20  is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′ R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′ R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S) R′R′″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″; 
         R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl; 
         R′″ at each occurrence is independently selected from aryl and alkyl; 
         R 30  is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy; halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; 
         R a , R 31a  and R 31b  are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and 
         t is 0, 1, 2, 3, or 4. 
       
     
     
         44 . The therapeutic support composition of  claim 43 , wherein the support composition is a particle. 
     
     
         45 . The therapeutic support composition of  claim 44 , wherein the particle is a nanoparticle. 
     
     
         46 . The therapeutic support composition of  claim 43 , wherein the support composition comprises an alginate resin. 
     
     
         47 . The therapeutic support composition of any one of  claims 43 - 46 , comprising an azide-containing group of formula: 
       
         
           
           
               
               
           
         
         wherein L 10  is a linker. 
       
     
     
         48 . The therapeutic support composition of  claim 47 , wherein the linker is a C 1 -Cio-alkylene group. 
     
     
         49 . The therapeutic support composition of any one of  claims 43 - 46 , comprising an alkyne-containing group of formula: 
       
         
           
           
               
               
           
         
         wherein L 11  is a linker. 
       
     
     
         50 . The therapeutic support composition of  claim 49 , wherein the linker is a C 1 -C 10 -alkylene group. 
     
     
         51 . A method of treating or preventing a condition or disorder, comprising administering to a subject in need thereof a functionalized payload and/or therapeutic support composition according to any one of  claims 1 - 50 . 
     
     
         52 . The method of  claim 51 , wherein the condition or disorder is a cancer. 
     
     
         53 . The method of  claim 52 , wherein the cancer is soft tissue sarcoma. 
     
     
         54 . The method of  claim 52 , wherein the cancer is a solid tumor. 
     
     
         55 . The method of  claim 52 , wherein the cancer is as melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), breast cancer (e.g., triple negative breast cancer), glioblastoma, lung cancer (e.g., non-small cell lung cancer), soft tissue carcinoma, fibrosarcoma, osteosarcoma, or pancreatic cancer.