TARGETED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF
Nanoparticles and microparticles, and pharmaceutical formulations thereof, containing conjugates of an active agent such as maytansinoid attached to a targeting moiety, such as a somatostatin receptor binding moiety, via a linker have been designed. Such nanoparticles and microparticles 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.
1 . A conjugate comprising an active agent coupled to a somatostatin receptor (SSTR) targeting moiety by a linker, wherein the active agent is maytansinoid.
2 . The conjugate of claim 1 , comprising 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 SSTR targeting moiety,
Y is the linker,
Z is the active agent, and
n is an integer between 2 and 1,000.
3 . The conjugate of claim 2 , comprising the formula X—Y—Z;
wherein X is the SSTR targeting moiety,
Y is the linker, and
Z is the active agent.
4 . (canceled)
5 . The conjugate of claim 1 , wherein the SSTR targeting moiety is a peptide.
6 . The conjugate of claim 5 , wherein the SSTR targeting moiety is selected from the group consisting of somatostatin, octreotide, octreotate, pasireotide, vapreotide, seglitide, lanreotide, and derivatives thereof.
7 . The conjugate of claim 1 , wherein the SSTR targeting moiety is cyclo(AA-Tyr-DTrp-Lys-Thr-Phe), wherein AA is α-N-Me lysine or N-Me glutamic acid.
8 . The conjugate of claim 7 , wherein the linker is connected to cyclo(AA-Tyr-DTrp-Lys-Thr-Phe) via a covalent bond.
9 . The conjugate of claim 8 , wherein the covalent bond is an amide bond.
10 . The conjugate of claim 5 , wherein the SSTR targeting moiety is Tyr 3 -octreotate (TATE) or its derivative.
11 . The conjugate of claim 10 , wherein the SSTR targeting moiety is truncated TATE.
12 . The conjugate of claim 5 , wherein the linker binds to the N-terminus of the peptide via a covalent bond.
13 . The conjugate of claim 12 , wherein the covalent bond is an amine bond an amide bond, or a urea bond.
14 .- 15 . (canceled)
16 . The conjugate of claim 5 , wherein the linker binds to the C-terminus of the peptide via a covalent bond.
17 . The conjugate of claim 16 , wherein the covalent bond is an amide bond.
18 . The conjugate of claim 5 , wherein the peptide comprises at least one D-Phe residue.
19 . (canceled)
20 . The conjugate of claim 1 , wherein the linker is not a cleavable linker.
21 . The conjugate of claim 1 , wherein the linker is a cleavable linker.
22 . The conjugate of claim 1 , wherein the linker comprises penicillamine or a derivative thereof.
23 . The conjugate of claim 1 , wherein the maytansinoid is DM1 or DM4.
24 . (canceled)
25 . The conjugate of claim 1 , wherein the conjugate has a molecular weight of less than 50,000 Da or between about 1000 Da and about 5000 Da.
26 . (canceled)
27 . The conjugate of claim 1 , wherein the conjugate has a structure of any of:
28 . The conjugate of claim 27 , wherein the conjugate is selected from Table 1 and Table 2.
29 . A particle comprising the conjugate of claim 1 and at least one polymeric matrix.
30 .- 33 . (canceled)
34 . The particle of 29 , wherein the polymeric matrix comprises one or more polymers selected from the group consisting of hydrophobic polymers, hydrophilic polymers, and copolymers thereof.
35 .- 36 . (canceled)
37 . The particle of claim 29 , 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), poly(ethylene oxide), poly(ethylene glycol), poly(propylene glycol), and copolymers thereof.
38 . The particle of claim 29 , wherein the particle has a diameter between 10 nm and 5000 nm, between 30 nm and 70 nm, between 70 nm and 120 nm, between 120 nm and 200 nm, between 200 nm and 5000 nm, between 500 nm and 1000 nm, less than 1 micrometer, or between 10 nm and 500 nm.
39 .- 42 . (canceled)
43 . The particle of claim 29 , wherein the conjugate is fully or partially encapsulated in the particle.
44 . The particle of claim 29 , wherein the conjugate is present in an amount between 0.05% and 50% (w/w) based upon the weight of the particle.
45 .- 46 . (canceled)
47 . The particle of claim 29 , wherein the particle is a controlled release particle.
48 .- 53 . (canceled)
54 . A pharmaceutical formulation comprising the conjugate of claim 1 and at least one pharmaceutically acceptable excipient.
55 . A pharmaceutical formulation comprising the particle of claim 29 and at least one pharmaceutically acceptable excipient.
56 . A method of treating a subject in need thereof comprising administering a therapeutically effective amount of the formulation of claim 54 .
57 . The method of claim 56 , wherein the subject has cancer or inflammation.
58 . (canceled)
59 . A method of inhibiting the rate of growth of a tumor, the size of a tumor or the volume of a tumor, the method comprising contacting the tumor with an effective amount of the formulation of claim 54 .
60 . A method of delivering maytansinoid to a tumor in a subject, the method comprising administering the formulation of claim 54 to the subject.
61 . The conjugate of claim 28 , wherein the conjugate is
or a pharmaceutically acceptable salt thereof.