Nanoparticle drug conjugates
Described herein are nanoparticle drug conjugates (NDCs), which, in certain embodiments, comprise a non-toxic, multi-modality, clinically proven silica-based nanoparticle platform with covalently attached drug molecules/moieties. The nanoparticle drug conjugates (NDCs) demonstrate imaging capability and targeting ligands which efficiently clear through the kidneys. Furthermore, the conjugates incorporate therapeutic agents for cancer detection, prevention, and/or treatment.
1. A nanoparticle drug conjugate (NDC) comprising:
a non-mesoporous nanoparticle;
an enzyme sensitive linker moiety; and
a drug moiety,
wherein the non-mesoporous nanoparticle comprises a silica-based core and a silica shell surrounding a least a portion of the core,
wherein the NDC has a diameter less than 10 nm,
wherein the non-mesoporous nanoparticle is coated with an organic polymer, and
wherein the drug moiety and enzyme sensitive linker moiety form a cleavable linker-drug construct that is covalently linked to the non-mesoporous nanoparticle and that facilitates enzyme catalyzed drug release.
2. The NDC of claim 1 , wherein the enzyme sensitive linker moiety comprises one or more amino acids.
3. The NDC of claim 1 , wherein the enzyme sensitive linker moiety comprises
(Amino-(spacer) x ) y -peptide or (spacer) z -peptide,
wherein the spacer has from 2 to 50 atoms,
wherein x is an integer from 1 to 5,
wherein y is an integer from 1 to 5,
wherein z is an integer from 5 to 15, and
wherein the enzyme sensitive linker moiety comprises a degradable moiety between the enzyme sensitive linker moiety and the drug moiety.
4. The NDC of claim 1 , wherein the enzyme sensitive linker moiety comprises a spacer between a peptide and the drug moiety.
5. The NDC of claim 4 , comprising a fluorescent compound.
6. The NDC of claim 1 , further comprising a radiolabel.
7. The NDC of claim 1 , wherein the enzyme sensitive linker moiety is capable of undergoing hydrolysis at a C-terminal end upon protease binding, thereby releasing the drug moiety from the non-mesoporous nanoparticle.
8. The NDC of claim 1 , wherein the drug moiety comprises a receptor tyrosine kinase (RTK) inhibitor.
9. The NDC of claim 1 , further comprising from 1 to 20targeting moieties, wherein the targeting moieties bind to receptors on tumor cells.
10. The NDC of claim 9 , wherein the NDC is a theranostic.
11. The NDC of claim 5 , wherein the fluorescent compound is Cy5.5.
12. The NDC of claim 6 , wherein the drug moiety is attached to the radiolabel.
13. The NDC of claim 3 , wherein
the one or more amino acids include a peptide or polypeptide, and include 1 to 10 amino acids,
the (Amino-(spacer) x ) y -peptide or (spacer) z -peptide is a dipeptide, the dipeptide being one of phenylalanine-arginine (Phe-Arg) or phenylalanine-lysine (Phe-Lys),
the spacer is PEG, and
the degradable moiety is an amide bond, the degradable moiety allowing cleavage the drug moiety in the presence of a protease.
14. The NDC of claim 5 , wherein
the spacer comprises a member selected from the group consisting of polyethylene glycol (PEG), PEG 2 , and para-aminobenzyloxy carbamate (PABC), and
the fluorescent compound is associated with the non-mesoporous nanoparticle or within the core of the non-mesoporous nanoparticle.
15. The NDC of claim 7 , wherein the protease is serine protease including trypsin, or cysteine protease including cathepsin B.
16. The NDC of claim 8 , wherein the receptor tyrosine kinase (RTK) inhibitor is dasatinib or gefitinib, including analogs thereof, or pharmaceutical or therapeutic equivalents thereof, modified to provide attachment to the enzyme sensitive linker moiety without perturbing underlying chemical structure of an active binding site of the drug moiety.
17. The NDC of claim 9 , wherein the targeting moieties include cyclic arginylglycylaspartic acid (cRGD).
18. A nanoparticle drug conjugate (NDC) comprising:
a non-mesoporous nanoparticle;
an enzyme sensitive linker moiety; and
a drug moiety,
wherein the NDC has a diameter less than 10 nm,
wherein the non-mesoporous nanoparticle is coated with an organic polymer, and
wherein the drug moiety and enzyme sensitive linker moiety form a cleavable linker-drug construct that is covalently linked to the non-mesoporous nanoparticle and that facilitates enzyme catalyzed drug release, and
wherein: (i) the drug moiety includes a member selected from the group consisting of dasatinib, gefitinib, an analog of dasatinib, and an analog of gefitinib, (ii) the organic polymer comprises at least one bifunctionalized maleimide silyl-polyethylene glycol group attached to at least one enzyme cleavable linker-drug construct, (iii) the cleavable linker-drug construct is formed via a protease, the enzyme cleavable linker-drug construct being linked to the non-mesoporous nanoparticle via the enzyme sensitive linker moiety, and (iv) the average drug moiety to non-mesoporous nanoparticle ratio ranges from 1 to 20.
19. The NDC of claim 18 , wherein the enzyme sensitive linker moiety comprises one or more amino acids.
20. The NDC of claim 18 , wherein the enzyme sensitive linker moiety comprises (Amino-(spacer) x ) y -peptide or (spacer) z -peptide,
wherein the spacer has from 2 to 50 atoms,
wherein x is an integer from 1 to5,
wherein y is an integer from 1 to 5,
wherein z is an integer from 5 to 15, and
wherein the enzyme sensitive linker moiety comprises a degradable moiety between the enzyme sensitive linker moiety and the drug moiety.
21. The NDC of claim 18 , wherein the enzyme sensitive linker moiety comprises a spacer between a peptide and the drug moiety.
22. The NDC of claim 21 , comprising a fluorescent compound.
23. The NDC of claim 18 , further comprising a radiolabel.
24. The NDC of claim 18 , wherein the enzyme sensitive linker moiety is capable of undergoing hydrolysis at a C-terminal end upon protease binding, thereby releasing the drug moiety from the non-mesoporous nanoparticle.
25. The NDC of claim 18 , wherein the drug moiety comprises a receptor tyrosine kinase (RTK) inhibitor.
26. The NDC of claim 18 , further comprising from 1 to 20 targeting moieties, wherein the targeting moieties bind to receptors on tumor cells.
27. The NDC of claim 26 , wherein the NDC is a theranostic.
28. The NDC of claim 22 , wherein the fluorescent compound is Cy5.5.
29. The NDC of claim 23 , wherein the drug moiety is attached to the radiolabel.
30. The NDC of claim 20 , wherein
the one or more amino acids include a peptide or polypeptide, and include 1 to 10 amino acids,
the (Amino-(spacer) x ) y -peptide or (spacer) z -peptide is a dipeptide, the dipeptide being one of phenylalanine-arginine (Phe-Arg) or phenylalanine-lysine (Phe-Lys),
the spacer is PEG, and
the degradable moiety is an amide bond, the degradable moiety allowing cleavage the drug moiety in the presence of a protease.
31. The NDC of claim 22 , wherein
the spacer comprises a member selected from the group consisting of polyethylene glycol (PEG), PEG 2 , and para-aminobenzyloxy carbamate (PABC), and
the fluorescent compound is associated with the non-mesoporous nanoparticle or within the core of the non-mesoporous nanoparticle.
32. The NDC of claim 24 , wherein the protease is serine protease including trypsin, or cysteine protease including cathepsin B.
33. The NDC of claim 25 , wherein the receptor tyrosine kinase (RTK) inhibitor is dasatinib or gefitinib, including analogs thereof, or pharmaceutical or therapeutic equivalents thereof, modified to provide attachment to the enzyme sensitive linker moiety without perturbing underlying chemical structure of an active binding site of the drug moiety.
34. The NDC of claim 26 , wherein the targeting moieties include cyclic arginylglycylaspartic acid (cRGD).