Active targeting of cells by monosized protocells
In one aspect, the disclosure provides mesoporous silica nanoparticles (MSNPs), monodisperse populations of MSNPs and related protocells which exhibit cell binding specificity. For example, MSNPs and protocells of the disclosure may be used to target specific delivery of therapeutic agents to CD19 or EGFR expressing cancer cells, or target specific delivery of therapeutic agents to other cell types. Related protocells, pharmaceutical compositions and therapeutic and diagnostic methods are also provided.
1. A population of protocells comprising a cargo and a lipid bi- or multi-layer coating monodisperse mesoporous silica nanoparticles (MSNPs), wherein the lipid bi- or multi-layer comprises a plurality of lipid molecules comprising polyethylene glycol (PEG) and a CD 19 targeting ligand or an EGFR targeting ligand and a plurality of lipid molecules covalently attached to nanocapsules comprising a proteolytic enzyme that degrades extracellular matrix, wherein the MSNPs have a diameter ranging from about 1 nm to about 300 nm.
2. The population of claim I wherei :he targeting ligand is an antibody, an antibody fragment or a scFv.
3. The population of claim 1 wherein the lipid bi- or multi-layer is PEGylated.
4. The population of claim 1 wherein the cargo comprises peptides, proteins, antibodies, nucleic acids, or drugs.
5. The population of claim 4 wherein the drug comprises vincristine, daunorubicin, doxorubicin, cytarabine, L-asparaginase, PEG-L-asparaginase, etoposide, teniposide, 6-mercaptopurine, methotrexate, cyclophosphamide, predisone, dexamethasone, imatinib, dasatinib, nilotinib, ponatinib, nelarabine, rituximab, blinatumumab, or inotuzumab.
6. The population of claim 1 wherein the lipid bi- or multi-layer comprises DSPC, cholesterol, PEG-DSPC, or a combination thereof.
7. The population of claim 6 wherein the amount of DSPC is about 45 mol % to about 80 mol % or about 50 mol % to about 78 mol %.
8. The population of claim 6 wherein the amount of cholesterol is about 10 mol % to about 50 mol % or about 17 mol % to about 25 mol %.
9. The population of claim 8 wherein the amount of PEG-DSPC is about 1 mol % to about 3 mol % or about 2 mol % to about 2.7 mol %.
10. The population of claim 1 wherein said MSNPs have an average diameter of less than about 200 nm or greater than about 20 nm.
11. The population of claim 1 wherein the CD19 targeting ligand comprises blinatumomab or a portion thereof, coltuxmiabravtasine or a portion thereof, MOR208 or a portion thereof, MEDI-551 or a portion thereof, denintuzumabmafodotin or a portion thereof, B4 or a portion thereof, DI-B4 or a portion thereof, taplitumomapaptox or a portion thereof, XmAb 5871 or a portion thereof, MDX-1342 or a portion thereof, or AFM 11 or a portion thereof.
12. The population of claim 1 wherein the EGFR targeting ligand comprises cetuximab, panitumumab, IMC-225, CR62, ABX-EGF, necitumumab, EMD72000, matuzumab, zalutumumab, or nemotuzmumab, a fragment thereof, or a scFv thereof.
13. A pharmaceutical composition comprising the population of claim 1 , in combination with a pharmaceutically acceptable carrier, additive and/or excipient.
14. A population of protocells comprising MSNPs, and a lipid bi-layer comprising lipid molecules comprising PEG and an EGFR targeting ligand and lipid molecules comprising covalently linked nanocapsules comprising an enzyme that degrades extracellular matrix, wherein the MSNPs have a diameter ranging from about 1 nm to about 300 nm, and wherein the protocells optionally comprise a chemotherapeutic drug.
15. A method of treating cancer, comprising administering to a subject in need thereof the pharmaceutical composition of claim 13 which comprises a CD19 targeting ligand or an EGFR targeting ligand.
16. The method of claim 15 wherein the composition is systemically administered.
17. The method of claim 15 wherein the subject has ALL.
18. The method of claim 15 wherein the targeting ligand is an antibody, an antibody fragment or a scFv.
19. The method of claim 15 wherein the cargo comprises peptides, proteins, antibodies, nucleic acids, or a drug.
20. The method of claim 15 wherein the CD19 targeting ligand comprises blinatumomab or a portion thereof, coltuxmiabravtasine or a portion thereof, MOR208 or a portion thereof, MEDI-551 or a portion thereof, denintuzumabmafodotin or a portion thereof, B4 or a portion thereof, DI-B4 or a portion thereof, taplitumomapaptox or a portion thereof, XmAb 5871 or a portion thereof, MDX-1342 or a portion thereof, or AFM 11 or a portion thereof or wherein the EGFR targeting ligand comprises cetuximab, panitumumab, IMC-225, CR62, ABX-EGF, necitumumab, EMD72000, matuzumab, zalutumumab, or nemotuzmumab, a fragment htereof, or a scFv thereof.