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, wherein the non-mesoporous nanoparticle comprises a silica-based core and a silica shell surrounding a least a portion of the core;
an enzyme sensitive linker moiety; and
a drug moiety,
wherein the non-mesoporous nanoparticle comprises silica,
wherein the NDC has a diameter less than 25 nm, and
wherein the drug moiety and enzyme sensitive linker moiety form a cleavable linker-drug construct 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 1 , comprising an imaging agent.
6. The NDC of claim 5 , wherein the imaging agent comprises 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 20 targeting 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 1 , wherein the non-mesoporous nanoparticle is coated with an organic polymer, wherein the cleavable linker-drug construct is covalently linked to the polymer-coated non-mesoporous nanoparticle.
12. The NDC of claim 5 , wherein the imaging agent comprises a fluorescent compound.
13. The NDC of claim 12 , wherein the fluorescent compound is Cy5.5.
14. The NDC of claim 6 , wherein the drug moiety is attached to the radiolabel.
15. The NDC of claim 3 , wherein the enzyme sensitive linker moiety comprises one or more amino acids, 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.
16. The NDC of claim 4 , wherein
the spacer comprises a member selected from the group consisting of polyethylene glycol (PEG), PEG 2 , and para-aminobenzyloxy carbamate (PABC).
17. The NDC of claim 7 , wherein the protease is serine protease including trypsin, or cysteine protease including cathepsin B.
18. 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.
19. The NDC of claim 9 , wherein the targeting moieties include cyclic arginylglycylaspartic acid (cRGD).
20. The NDC of claim 11 , wherein
the drug moiety includes a dasatinib or gefitinib, and analogs thereof,
the organic polymer comprises at least one bifunctionalized maleimide silyl-polyethylene glycol group attached to at least one linker-drug construct,
the cleavable linker-drug construct is formed via a protease, the linker-drug construct being linked to the non-mesoporous nanoparticle via the linker moiety, and
the average drug moiety to non-mesoporous nanoparticle ratio ranges from 1 to 20.
21. The NDC of claim 5 , wherein the non-mesoporous nanoparticle comprises a metal and wherein the imaging agent comprises the metal.
22. The NDC of claim 21 , wherein the metal comprises gold.
23. The NDC of claim 21 , wherein the metal comprises a transition metal complex.
24. The NDC of claim 21 , wherein the non-mesoporous nanoparticle has a core comprising the metal.