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 silica nanoparticle;
an enzyme-sensitive linker moiety;
from 1 to 20 targeting moieties; and
a drug moiety,
wherein the NDC has an average diameter from 5 nm to 10 nm,
wherein the enzyme-sensitive linker moiety is capable of undergoing hydrolysis at the C-terminal end upon protease binding, thereby releasing the drug moiety from the nanoparticle,
wherein the silica nanoparticle is coated with an organic polymer, and
wherein the drug moiety and the enzyme-sensitive linker moiety form a cleavable linker-drug construct that is covalently linked to the silica nanoparticle.
2 . The NDC of claim 1 , wherein the linker moiety comprises one or more amino acids.
3 . The NDC of claim 2 , wherein the 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 linker moiety comprises a degradable moiety between the linker moiety and the drug moiety.
4 . The NDC of claim 1 , wherein the linker moiety comprises a spacer between a peptide and the drug moiety.
5 . The NDC of claim 4 , further comprising a fluorescent compound, or further comprising a radiolabel.
6 .- 7 . (canceled)
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 8 , wherein the NDC is a theranostic.
11 . The NDC of claim 4 , wherein the fluorescent compound is Cy5.5.
12 . The NDC of claim 5 , wherein the drug moiety is attached to the radiolabel.
13 . The NDC of claim 1 , wherein the nanoparticle further comprises a silica-based core and a silica shell surrounding a least a portion of the core.
14 . The NDC of claim 1 , 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 nanoparticle via the linker moiety, and
the average drug moiety to nanoparticle ratio ranges from 1 to 20.
15 . 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.
16 . The NDC of claim 5 , wherein
the spacer includes polyethylene glycol (PEG)), PEG 2 , para-aminobenzyloxy carbamate (PABC), and
the fluorescent compound is associated with the nanoparticle or within the core of the nanoparticle.
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 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 . A method of treating cancer comprising administering to a subject in need thereof the NDC of claim 1 .
21 . The method of claim 20 , wherein the targeting moieties bind to receptors on tumor cells.
22 . The method of claim 20 , wherein the silica nanoparticle of the NDC comprises a core comprising a silica matrix and a fluorescent compound is incorporated into the silica matrix.
23 . The method of claim 22 , wherein the fluorescent compound is Cy5 or Cy5.5.