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 method of treating a subject having or diagnosed with having cancer comprising,
(i) administering to a human subject in need of such treatment an effective amount of a nanocarrier, wherein the nanocarrier is a liposome, lipid nanoparticle (LNP), or a solid-lipid nanoparticle (SLNP), and wherein the nanocarrier comprises a Toll-Like Receptor (TIR) prodrug, wherein the TLR prodrug comprises TR6 having the following chemical structure:
and/or TR6(A) having the following chemical structure:
and wherein the lipid moiety comprises cholesterol hemisuccinate (CHEMS).
2 . The method of claim 1 , wherein the nanocarrier comprises TR6 and/or TR6(A) further co-formulated with an immunogenic cell death (ICD)-inducing chemotherapeutic.
3 . The method of claim 2 , wherein the immunogenic cell death (ICD)-inducing chemotherapeutic is selected from the group consisting of doxorubicin (DOX), mitoxantrone (MTO), oxaliplatin (OXA), cyclophosphamide (CP), Bortezomib, Carfilzimib, or Paclitaxel.
4 . The method of claim 1 , wherein the nanocarrier comprises TR6 and/or TR6(A) further co-formulated with an immune modulating agent.
5 . The method 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 antagonists, STING agonists, CTLA-4 inhibitors, PD-1/PD-L1 inhibitors and/or prodrugs thereof.
6 . The method of claim 1 , wherein the nanocarrier comprises TR6 and/or TR6(A) further co-formulated with an invariant natural killer T cell (iNTK) activator.
7 . The method of claim 6 , wherein the iNTK activator is Alpha-galactosylceramide (α-GalCer).
8 . The method of claim 1 , wherein the nanocarrier is a lipid nanoparticle and the TLR prodrug is TR6 and the lipid nanoparticle is denoted LNP-TR6.
9 . The method of claim 1 , wherein the nanocarrier is a solid-lipid nanoparticle and the TLR prodrug is TR6 and the solid-lipid nanoparticle is denoted SLNP-TR6.
10 . The method of claim 1 , wherein the cancer is breast cancer.
11 . The method of claim 1 , wherein the cancer is melanoma.
12 . The method of claim 1 , wherein the cancer is colorectal cancer.
13 . The method of claim 1 , wherein the nanocarrier is administered with doxorubicin in liposomal form.
14 . The method of claim 1 , wherein the nanocarrier is administered with α-Galactosyl Ceramide in liposomal form.
15 . The method of claim 1 , wherein the nanocarrier is administered with Mitoxantrone in liposomal form.