Formulated and/or co-formulated liposome compositions containing toll-like receptor (“TLR”) agonist prodrugs useful in the treatment of cancer and methods thereof
Formulated and/or co-formulated liposomes comprising TLR prodrugs and/or TLR Lipid Moieties and methods of making the liposomes are disclosed herein. The TLR prodrug compositions comprise a drug moiety, a lipid moiety, and linkage unit that inhibit Toll-Like Receptor (e.g., TLR1/2, TLR4, and/or TLR7). The TLR prodrugs can be formulated and/or co-formulated into a liposome to provide a method of treating cancer, immunological disorders, and other disease by utilizing a targeted drug delivery vehicle.
1. A Toll-like receptor (TLR) prodrug composition comprising,
(i) a drug moiety;
(ii) a lipid moiety; and
(iii) a linkage unit (“LU”),
whereby the drug moiety comprises a TLR agonist and whereby the LU conjugates the drug moiety with the lipid moiety and wherein the TLR prodrug has the following chemical structure:
2. The TLR prodrug of claim 1 , wherein the lipid moiety comprises a lipid selected from the group consisting of cholesterol, the sodium salt of 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol), the sodium salt of 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol), 1-decanoyl-2-hydroxy-sn-glycero-3-phosphocholine, the sodium salt of 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), soy L-α-lysophosphatidylcholine, the sodium salt of 1,2-dilauroyl-sn-glycero-3-phospho-(1′rac-glycerol), the ammonium salt of 1,2-dipalmitoyl-sn-glycero-3-phospho((ethyl-1′,2′, 3′-triazole)triethyleneglycolmannose, N-palmitoyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)2000]} and monophosphoryl Lipid A.
3. The TLR prodrug of claim 1 , wherein the lipid moiety comprises Stearic Acid.
4. A nanocarrier comprising, a TLR prodrug whereby the nanocarrier releases an active TLR inhibitor after cleavage of the LU.
5. The nanocarrier of claim 4 , further comprising a helper lipid, whereby the helper lipid is selected from the group consisting of the chloride salt of 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-dioleyloxy-3-dimethylaminopropane, 1,2-dilinoleyloxy-3-dimethylaminopropane, 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane, 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, cholesterol, N-[(methoxy poly(ethylene glycol)2000)carbamyI]-1,2-dimyristyloxlpropyl-3-amine, cholesteryl hemisuccinate, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1 2-distearoyl- sn-glycero-3-phosphocholine and 4-(2-aminoethyl)-morpholino-cholesterolhemisuccinate.
6. The nanocarrier of claim 4 , wherein the TLR prodrug comprises TR5.
7. The nanocarrier of claim 4 , whereby the nanocarrier is further co-formulated with an iNKT (i-natural kill T cell) activator.
8. The nanocarrier of claim 7 , wherein the iNKT activator is Alpha-galactosylceramide (α-GalCer).
9. The nanocarrier of claim 4 , whereby the nanocarrier is further co-formulated with an immune modulating agent, wherein the immune modulating agent is selected from the group consisting of other TLR agonists and/or prodrugs, immunogenic-cell death inducing chemotherapeutics, IDO (indoleamine 2,3-dioxygenase) antagonists, STING (stimulator of interferon genes) agonists, CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitors, PD-1/PD-L1 (programmed cell death 1/programmed cell death ligan 1) inhibitors and/or prodrugs thereof.
10. The nanocarrier of claim 4 , whereby the nanocarrier is further co-formulated with an ICD (immunogenic cell death)-inducing chemotherapeutic, wherein the ICD-inducing chemotherapeutic is selected from the group consisting of doxorubicin, mitoxantrone, oxaliplatin, cyclophosphamide, Bortezomib, Carfilzimib, or Paclitaxel.
11. The nanocarrier of claim 4 , further comprising doxorubicin (DOX).
12. The nanocarrier of claim 4 , wherein the nanocarrier comprises a liposome.
13. The liposome of claim 12 , wherein the liposome comprises the TLR prodrug of claim 3 .
14. The nanocarrier of claim 4 , wherein the nanocarrier comprises a solid-lipid nanoparticle (SLNP).
15. The SLNP of claim 14 , wherein the SLNP comprises the TLR prodrug of claim 3 .
16. A Toll-like receptor (TLR) prodrug composition comprising,
(i) a drug moiety;
(ii) a lipid moiety; and
(iii) a linkage unit (“LU”),
whereby the drug moiety comprises a TLR agonist and whereby the LU conjugates the drug moiety with the lipid moiety and wherein the TLR prodrug has the following chemical structure: