NEUROTENSIN RECEPTOR BINDING CONJUGATES AND FORMULATIONS THEREOF
Conjugates of an active agent attached to a neurotensin receptor-binding targeting moiety via a linker have been designed. Nanoparticles and microparticles comprising such conjugates can provide improved temporospatial delivery of the active agent and/or improved biodistribution. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer or other diseases.
1 . A conjugate comprising an active agent coupled to a neurotensin receptor targeting moiety by a linker.
2 . The conjugate of claim 1 , wherein the neurotensin receptor is neurotensin receptor 1 (NTSR1).
3 . The conjugate of claim 1 , wherein the conjugate comprises a formula selected from the group X—Y—Z, X—Y—Z—Y—X, X—(Y—Z) n , (X—Y) n —Z, X—Y—Z n , X n —Y—Z, and (X—Y—Z—Y) n —Z;
wherein X is the targeting moiety,
Y is the linker,
Z is the active agent, and
n is an integer between 2 and 1,000.
4 . The conjugate of claim 3 , wherein the conjugate comprises the formula X—Y—Z;
wherein X is the targeting moiety,
Y is the linker, and
Z is the active agent.
5 .- 7 . (canceled)
8 . The conjugate of claim 1 , wherein the linker is not a cleavable linker.
9 . The conjugate of claim 1 , wherein the linker is a cleavable linker.
10 . The conjugate of claim 9 , wherein the linker comprises an ester bond, disulfide, boronic ester, hydrazine, amide, acylhydrazone, ether, carbamate, carbonate, or urea.
11 . The conjugate of claim 9 , wherein the linker is cleavable by an enzyme.
12 . The conjugate of claim 11 , wherein the linker is cleavable by a lysosomal enzyme.
13 . The conjugate of claim 12 , wherein the linker is cleavable by a cathepsin or a glucruonidase.
14 . The conjugate of claim 9 , wherein the linker comprises a peptide.
15 . The conjugate of claim 14 , wherein the peptide has a sequence of Val-Ala, Val-Cit, or Gly-Phe-Leu-Gly.
16 . The conjugate of claim 1 , wherein the targeting moiety is selected from the group consisting of peptides, nonpeptidic molecules, polypeptides, antibody mimetics, nucleic acids, glycoproteins, small molecules, carbohydrate, and lipids.
17 . The conjugate of claim 16 , wherein the targeting moiety is neurotensin or a derivative or analog thereof.
18 . The conjugate of claim 17 , wherein the targeting moiety comprises NMeArg-Arg-Pro-Tyr-Tle-Leu-OH or DArg-Arg-Pro-Tyr-Ile-TMSAla-OH.
19 . The conjugate of claim 1 , wherein the targeting moiety is a biased agonist of the neurotensin receptor.
20 . The conjugate of claim 19 , wherein the targeting moiety is ML314.
21 . The conjugate of claim 1 , wherein the active agent is selected from the group consisting of therapeutic, prophylactic, nutraceutical, and diagnostic agents.
22 . The conjugate of claim 21 , wherein the active agent is a small molecule, protein, peptide, lipid, carbohydrate, sugar, nucleic acid, or combination thereof.
23 . The conjugate of claim 22 , wherein the active agent is bortezomib, cabazitaxel, DM1, doxorubicin, Monomethyl auristatin E (MMAE), SN-38, or an analog, derivative, prodrug, or pharmaceutically acceptable salt thereof.
24 . The conjugate of claim 23 , wherein the conjugate is selected from the group consisting of Compound 1 to Compound 68 and Compound B1 to Compound B5.
25 . A particle comprising a conjugate of claim 1 and at least one polymeric matrix.
26 . The particle of claim 25 , wherein the polymeric matrix comprises one or more polymers selected from the group consisting of hydrophobic polymers, hydrophilic polymers, and copolymers thereof.
27 .- 28 . (canceled)
29 . The particle of claim 25 , wherein the polymeric matrix comprises one or more polymers selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and copolymers thereof.
30 . The particle of claim 25 , wherein the polymeric matrix comprises two or more different polymers.
31 . The particle of claim 25 , wherein the particle has a diameter between 10 nm and 5000 nm.
32 . (canceled)
33 . The particle of claim 25 , wherein the conjugate is present in an amount between 0.05% and 50% (w/w) based upon the weight of the particle.
34 . A pharmaceutical composition comprising the conjugate of claim 1 and at least one pharmaceutically acceptable excipient.
35 . A method of treating cancer of subject, comprising administering the pharmaceutical composition of claim 34 to the subject.
36 . The method of claim 35 , wherein the cancer is selected from lung cancer, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, colorectal cancer, bladder cancer, prostate cancer, cervical cancer, renal cancer, leukemia, myeloma, and melanoma.