Core-shell particle formulation for delivering multiple therapeutic agents

1. A core-shell particle formulation for delivering multiple therapeutic agents comprising:

one or more polymers forming a core, wherein the one or more polymers forming the core comprise poly vinyl alcohol; and

one or more proteins forming a shell encapsulating the core to form a particle formulation, wherein the one or more proteins forming the shell comprise protamine;

wherein the core and the shell each comprise one or more therapeutic agents, wherein the one or more therapeutic agents of the core comprise doxorubicin and the one or more therapeutic agents of the shell comprise sorafenib;

wherein the particle formulation is configured to independently release the therapeutic agents from the core and the shell; and

wherein the therapeutic agents are configured to be delivered by active targeting, wherein the active targeting is done by conjugating the core-shell formulation with transferrin ligand.

2. The formulation of claim 1 , wherein the core is of average size ≦500 nm.

3. The formulation of claim 1 , wherein the shell is of average thickness ≦200 nm.

4. The formulation of claim 1 , wherein the therapeutic agents of the core and shell further comprise one or more small molecule kinase inhibitors or chemotherapeutic drugs.

5. The formulation of claim 1 , wherein the shell comprises one or both of hydrophilic and hydrophobic therapeutic agents.

6. The formulation of claim 1 , wherein the one or more polymers forming the core further comprise poly glycolic acid, poly(lactic-co-glycolic acid), glycolide/trimethylene carbonate copolymers, poly-lactides, poly-L lactide, poly-DL-lactide, L-lactide/DL-lactide copolymers, lactide/tetramethyl-glycolide copolymers, poly-caprolactone, poly-valerolacton, poly-hydroxy butyrate, poly-hydroxyvalerate, polyvinylpyrrolidone, or polyethyleneimine and lactide/trimethylene carbonate copolymers.

7. The formulation of claim 1 , wherein the one or more proteins forming the shell further comprise human serum albumin, bovine serum albumin, protamine, transferrin, lactoferrin, fibrinogen, or gelatin.

8. The formulation of claim 4 , wherein the small molecule kinase inhibitor is chosen from the group consisting of inhibitors of tyrosine kinase, epidermal growth factor receptor inhibitors, vascular endothelial growth factor receptor inhibitors, platelet derived growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, Rous sarcoma oncogene/Breakpoint cluster region/Abl inhibitors, insulin-like growth factor 1 receptor inhibitors, FLT-3 inhibitors, HER-2 inhibitors, c-Kit inhibitors, c-Met inhibitors, ALK inhibitors, ETA receptor inhibitors, HIF inhibitors, Syk inhibitors, Tie2 kinase inhibitors, vascular disrupting agents, cell cycle/check point inhibitors, polo-like kinase inhibitors, cyclin dependent kinase inhibitors, topoisomerase inhibitors, microtubule inhibitors, antimetabolites, telomerase inhibitors, DNA replication inhibitors, RNA replication inhibitors, dihydrofolate reductase inhibitors, HDAC inhibitors, Bcl-2 inhibitors, TNF-a inhibitors, p53 inhibitors, PARP inhibitors, MAPK inhibitors, PI3K/Akt/mTOR inhibitors, integrase inhibitors, protease inhibitors, Wnt/Hedgehog/Notch inhibitors, Jak/STAT inhibitors, PKC inhibitors, TGF-P inhibitors, antioxidant inhibitors, and combinations thereof.

9. The formulation of claim 4 , wherein the chemotherapeutic drug is chosen from the group consisting of aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, dasatinib, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, vinorelbine and combinations thereof.

10. The formulation of claim 1 , wherein the therapeutic agents are configured to be delivered from the shell and core sequentially.

11. The formulation of claim 1 , wherein the therapeutic agents are configured to be delivered from the shell and core simultaneously.