US2023241243A1PendingUtilityA1
Carrier particle-drug conjugates, self-immolative linkers, and uses thereof
Est. expiryOct 27, 2040(~14.3 yrs left)· nominal 20-yr term from priority
Inventors:Aranapakam Mudumbai VenkatesanKai MaFeng-Jing ChenFei WuMelik Z. TurkerThomas C. GardinierGeno J. Germano, Jr.Gregory P. AdamsFrancis Y. Lee
A61K 47/6923A61K 47/10A61K 47/551A61K 31/4192A61P 35/00A61K 47/6929A61K 47/552A61K 49/0093A61K 49/0032A61K 51/1244A61K 47/558A61K 47/545A61K 47/60
70
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The disclosure relates to carrier particle-drug conjugates, including nanoparticle drug conjugates (NDC), that can be used in the delivery of a drug to a biological target (e.g., for targeted delivery of a cytotoxic drug to a cancer cell or tumor). Also disclosed are self-immolative linkers and linker-payload conjugates suitable for use in a carrier particle drug conjugate, and methods of making the same, and methods for treating cancer.
Claims
exact text as granted — not AI-modified1 . A nanoparticle-drug conjugate (NDC) comprising:
(a) a silica nanoparticle that comprises polyethylene glycol (PEG) covalently bonded to the surface of the silica nanoparticle; (b) a targeting ligand selected from the group consisting of folic acid, dihydrofolic acid, tetrahydrofolic acid, and folate receptor binding derivatives of any of the foregoing, and wherein the targeting ligand is attached to the silica nanoparticle directly or indirectly through a spacer group; and (c) a linker-payload conjugate, wherein the payload is a cytotoxic agent; wherein the linker-payload conjugate is attached to the silica nanoparticle directly or indirectly through a spacer group; wherein the cytotoxic agent is released upon cleavage of the linker; and wherein the linker in the linker-payload conjugate is selected from a group consisting of protease-cleavable linkers, redox-sensitive linkers, and pH-sensitive linkers.
2 . The NDC of claim 1 , wherein the NDC has an average diameter between about 1 nm and about 10 nm.
3 . (canceled)
4 . The NDC of claim 1 , wherein the average silica nanoparticle to payload ratio ranges from 1 to 80.
5 . (canceled)
6 . The NDC of claim 1 , wherein the average nanoparticle to targeting ligand ratio ranges from 1 to 50.
7 - 8 . (canceled)
9 . The NDC of claim 1 , further comprising a fluorescent compound covalently encapsulated within the silica nanoparticle.
10 . The NDC of claim 1 , comprising a structure of Formula (NP).
wherein
x is an integer of 0 to 20;
the silicon atom (Si) is a part of the silica nanoparticle; and
the adjacent to the triazole moiety denotes a point of attachment to a targeting ligand or payload-linker conjugate, either directly or indirectly.
11 . The NDC of claim 1 , wherein the payload is selected from a group consisting of dihydrofolate reductase inhibitors, thymidylate synthase inhibitors, and topoisomerase inhibitors.
12 . (canceled)
13 . The NDC of claim 1 , wherein the payload is a topoisomerase inhibitor selected from a group consisting of SN38, exatecan, and analogs thereof.
14 . The NDC of claim 1 , wherein the NDC comprises a structure of Formula (S-1)
wherein
Payload is a cytotoxic agent;
Linker is selected from a group consisting of protease-cleavable linkers, redox-sensitive linkers, and pH-sensitive linkers, and
the silicon atom (Si) is a part of the silica nanoparticle.
15 . (canceled)
16 . The NDC of claim 1 , wherein the NDC comprises a structure of Formula (S-2):
wherein the silicon atom (si) is a part of the silica nanoparticle.
17 . (canceled)
18 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (I):
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
A is a dipeptide selected from the group consisting of Val-Cit, Phe-Lys, Trp-Lys, Asp-Lys, Val- Lys, Val-Arg, and Val-Ala, or
A is a tetrapeptide selected from the group consisting of Val-Phe-Gly-Sar, Val-Cit-Gly-Sar, Val-Lys-Gly-Sar, Val-Ala-Gly-Sar, Val-Phe-Gly-Pro, Val-Cit-Gly-Pro, Val-Lys-Gly-Pro, Val-Ala-Gly-Pro, Val-Cit-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Phe-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Ala-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Phe-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, and Trp-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid;
Payload is a residue of a cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 1 and R 2 in each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, or hydroxy;
R 3 and R 4 in each occurrence is independently hydrogen, halo, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy;
R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted C 5-6 heterocycloalkyl;
with the proviso that, when A is a dipeptide, R 5 is H;
R a , R b and R c in each occurrence is independently hydrogen, or substituted or unsubstituted C 1-6 alkyl;
X is absent, —O—, —CO— or —NR a —;
Y is absent,
wherein the carbonyl in
is bonded to Z;
with the proviso that, when Y is
X is absent and n is 1;
with the proviso that, when Y is
X is absent and n is 0;
with the proviso that, when Y is
X is absent and n is 0 or 1;
with the proviso that, when X is —CO—, Y is absent and n is 0;
X 1 and X 2 are independently —CH— or —N—;
X 3 is —CH—;
X 4 is —CH—;
Z is —NR c — or —O—;
n is 0 or 1; and
q is 1 to 3.
19 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (II)
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
A is a dipeptide selected from the group consisting of Val-Cit, Phe-Lys, Trp- Lys, Asp-Lys, Val- Lys, Val-Arg, and Val-Ala, or
A is a tetrapeptide selected from the group consisting of Val-Phe-Gly-Sar, Val-Cit-Gly-Sar, Val-Lys-Gly-Sar, Val-Ala-Gly-Sar, Val-Phe-Gly-Pro, Val-Cit-Gly-Pro, Val-Lys-Gly-Pro, Val-Ala-Gly-Pro, Val-Cit-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Phe-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Ala-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Phe-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, and Trp-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 1 is hydrogen or substituted or unsubstituted C 1-6 alkyl;
R 3 and R 4 in each occurrence is independently hydrogen, halo, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy;
R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl; substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted C 5-6 heterocycloalkyl;
with the proviso that, when A is a dipeptide, R 5 is H;
R a , R b and R c in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
X 1 and X 2 are independently —CH— or —N—;
X 3 is —CH—;
X 4 is —CH—;
Y 1 is
and
Z is —NR c — or —O—.
20 . (canceled)
21 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (IV):
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
A is a dipeptide selected from the group consisting of Val-Cit, Phe-Lys, Trp-Lys, Asp-Lys, Val- Lys, Val-Arg, and Val-Ala, or
A is a tetrapeptide selected from the group consisting of Val-Phe-Gly-Sar, Val-Cit-Gly-Sar, Val-Lys-Gly-Sar, Val-Ala-Gly-Sar, Val-Phe-Gly-Pro, Val-Cit-Gly-Pro, Val-Lys-Gly-Pro, Val-Ala-Gly-Pro, Val-Cit-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Phe-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Val-Ala-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, Phe-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid, and Trp-Lys-Gly-any natural or unnatural N-alkyl substituted alpha amino acid;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R c is selected from a group consisting of hydrogen or substituted or unsubstituted C 1-6 alkyl; and
Z is —NR c — or —O—.
22 . (canceled)
23 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (V)
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 1 , R 2 , R 5 , R 6 and R 7 in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R 3 and R 4 in each occurrence is independently hydrogen, halo, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy;
R a , R b and R c in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
X is absent, —O— or —NR a —;
Y is absent,
wherein the carbonyl in
is bonded to Z;
X 1 and X 2 are independently —CH— or —N—;
X 3 is —CH—;
X 4 is —CH—;
Z is —NR c — or —O—;
n is 0 or 1;
p is 1 to 3 and
q is 1 to 3.
24 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (VI):
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 1 , R 5 , R 6 and R 7 in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R 3 and R 4 in each occurrence is independently hydrogen, halo, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy;
R a , R b and R c in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
X 1 and X 2 are independently —CH— or —N—;
X 3 is —CH—;
X 4 is —CH—;
Y 1 is
Z is —NR c — or —O— and
p is 1 to 3.
25 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (VII):
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 1 , R 2 , R 5 , R 6 and R 7 in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R c is selected from a group consisting of hydrogen or substituted or unsubstituted C 1-6 alkyl;
Y is
wherein the carbonyl in
is
bonded to Z;
Z is —NR c — or —O—′ and
p is 1 to 3.
26 . (canceled)
27 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (IX):
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 1 , R 2 , R 5 , R 6 and R 7 in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R c is selected from a group consisting of hydrogen or substituted or unsubstituted C 1-6 alkyl;
Z is —NR c — or —O—;
m is 1 to 3; and
p is 1 to 3.
28 . The NDC of claim 1 , wherein the linker-payload conjugate comprises a structure of Formula (X):
or a salt thereof, wherein,
line represents a direct bond to the nanoparticle or an indirect bond to the nanoparticle through a spacer group;
Payload is a residue of cytotoxic moiety, and when Payload is a separate molecular entity it contains an amino or hydroxyl group that provides the nitrogen or oxygen atom at Z;
R 5 , R 6 and R 7 in each occurrence is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R 3 and R 4 in each occurrence is independently hydrogen, halo, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxy;
R c is selected from a group consisting of hydrogen or substituted or unsubstituted C 1-6 alkyl;
X 1 and X 2 are independently —CH— or —N—;
X 3 is —CH—;
X 4 is —CH—;
Z is —NR c — or —O—; and
p is 1 to 3.
29 - 32 . (canceled)
33 . A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a nanoparticle drug conjugate (NDC), wherein the NDC comprises:
(a) a silica nanoparticle that comprises polyethylene glycol (PEG) covalently bonded to the surface of the silica nanoparticle; (b) a targeting ligand that binds to a folate receptor: and (c) a linker-payload conjugate, wherein the linker-payload conjugate is attached to the silica nanoparticle directly or indirectly through a spacer group: and wherein the payload is released upon cleavage of the linker.
34 - 35 . (canceled)
36 . The method of claim 33 , wherein the NDC is administered to the subject intravenously.
37 . The method of claim 33 , wherein the subject has a cancer selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer breast cancer, lung cancer, mesothelioma, uterine cancer, gastrointestinal cancer, pancreatic cancer, bladder cancer, kidney cancer, liver cancer, head and neck cancer, brain cancer, thyroid cancer, skin cancer, prostate cancer, testicular cancer, acute myeloid leukemia and chronic myelogenous leukemia (CML).
38 - 46 . (canceled)
47 . A pharmaceutical composition comprising an NDC of claim 1 , and a pharmaceutically acceptable excipient.
48 - 50 . (canceled)
51 . A linker-drug conjugate of any one of Formulae (I)-(XII) or I-B-XII-B).
52 . The linker-drug conjugate of claim 51 , comprising a carrier particle selected from the group consisting of a nanoparticle, a liposome, a nanogel, a nanoring, a nanocage, a microsphere, an antibody, an antigen-binding portion or fragment of an antibody, a minibody, and a nanobody.
53 . A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a linker-drug conjugate of claim 51 .
54 - 55 . (canceled)
56 . A linker of any one of Formulae (I-A)-(X-A).Join the waitlist — get patent alerts
Track US2023241243A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.