Tunable pH-sensitive linker for controlled drug release
A novel acid labile linker for targeted delivery and/or controlled release of agents is introduced herein. There is further disclosed a method of developing a therapeutic or diagnostic conjugate for targeted cell-specific delivery. More specifically, the invention is focused on linkers used to deliver anticancer agents to specific tumor cells.
1. A conjugate or a salt thereof having formula (I)
X L m Y formula (I),
wherein,
X is a therapeutic or diagnostic agent comprising a moiety for attaching to L or directly to Y,
L is a spacer comprising a moiety for attaching to Y;
m is 0 or 1;
when m is 0,
X comprises a moiety NR 1 , S, or O for attaching to Y; and
R 1 is H, acyl, formyl, aryl, heteroaryl, heterocycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl-aryl, substituted or unsubstituted alkyl-heteroaryl, or substituted or unsubstituted cycloalkyl-heteroaryl;
when m is 1,
X comprises NR 1 , S or O for attaching to L;
L comprises a moiety NR 1 , S, or O for attaching to Y; and
R 1 is H, acyl, formyl, aryl, heteroaryl, heterocycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl-aryl, substituted or unsubstituted alkyl-heteroaryl, or substituted or unsubstituted cycloalkyl-heteroaryl;
Y is a hydrolysable linker having formula (II) or formula (III)
wherein,
W is O, S, or Se;
Q is N, O, S, or Se;
R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl-aryl, substituted or unsubstituted alkyl-heteroaryl, or substituted or unsubstituted cycloalkyl-heteroaryl;
R 3 is an ionizable group;
R 4 is H, lower alkyl, aryl, or a substituent comprising a functional group for attachment to a molecule;
R 5 and R 6 are independently, H, lower alkylene or arylene;
T is O, S, alkylene, arylene, acyl, formyl, or substituted or unsubstituted alkylarylene; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.
2. The conjugate of claim 1 or a salt thereof, wherein the ionizable group is selected from the group consisting of a carboxylic acid; an ester of a carboxylic acid; a sulfonic acid; an ester of a sulfonic acid; a phosphoric acid; an ester of a phosphoric acid; a phosphonic acid; an ester of a phosphonic acid; a substituted or unsubstituted aromatic ring containing one or more carboxylic acids, esters of carboxylic acids, sulfonic acids, esters of a sulfonic acids, phosphoric acids, esters of a phosphoric acids, phosphonic acids, and esters of a phosphonic acids, a substituted or unsubstituted heterocyclic aromatic group containing one or more nitrogen atoms; a substituted or unsubstituted fused heterocyclic aromatic group containing one or more nitrogen atoms and containing one or more aromatic or aliphatic rings; a substituted or unsubstituted aniline group; and a substituted or unsubstituted fused aniline group containing one or more nitrogen atoms and containing one or more aromatic or aliphatic rings.
3. The conjugate of claim 1 or a salt thereof, wherein the therapeutic agent is selected from the group consisting an anti-angiogenic agent, a cytotoxic agent, a cytokine, a chemokine, an apoptotic agent, a prodrug, a toxin, an enzyme, a radioisotope, an immunomodulator, an antibiotic, an agent active in the CNS and a hormone.
4. The conjugate of claim 3 or a salt thereof, wherein the therapeutic agent contains an amine group.
5. The conjugate of claim 4 or a salt thereof, wherein the therapeutic agent is monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), and doxorubicin.
6. The conjugate of claim 1 or a salt thereof, wherein the diagnostic agent is selected from the group consisting of a radioisotope, an imaging agent, a fluorescent dye, a near-IR dye, an enzyme, a chemiluminescent agent, a bioluminescent agent, a paramagnetic ion, an ultrasound label, and a radioacoustic label.
7. The conjugate of claim 1 or a salt thereof, wherein L comprises a self-immolating spacer, wherein the self-immolating spacer is a peptide or a protein.
8. The conjugate of claim 1 or a salt thereof, wherein R 4 is a substituent comprising a chemical or biorthogonal functional group for covalent attachment to a molecule.
9. The conjugate of claim 8 or a salt thereof, wherein the substituent comprises an azide, an alkyne, a maleimide, an iodoacetamide, a thiol, a disulfide, a NHS ester, a tetrazine, a trans-cyclooctene, a ketone/aldehyde, a hydrazine, a hydrazide, or a thioacid.
10. The conjugate of claim 8 or a salt thereof, wherein the conjugate further comprises a molecule attached through the functional group of R 4 , wherein the molecule is a targeting molecule, a polymer, a solid support, an attachment handle, or masking agent.
11. The conjugate of claim 1 or a salt thereof, wherein
X is an agent comprising the substituent NR 1 ;
R 1 is H or alkyl;
T is O;
W is O;
Q is O;
R 2 is H;
R 3 is an ionizable group selected from the group consisting of is a carboxylic acid, an ester of a carboxylic acid, and a substituted or unsubstituted heterocyclic aromatic group containing one or more nitrogen atoms; and
R 4 is a substituent comprising a functional group for attachment to a molecule.
12. The conjugate of claim 11 or a salt thereof, wherein R 4 is a substituent selected from the group consisting of an azide, an alkyne, a maleimide, an iodoacetamide, a thiol, a disulfide, a NHS ester, a tetrazine, a trans-cyclooctene, a ketone/aldehyde, a hydrazine, a hydrazide, and a thioacid.
13. The conjugate of claim 12 or a salt thereof, wherein the conjugate or a salt thereof further comprises a molecule and wherein the molecule is a targeting molecule attached through the substituent.
14. The conjugate of claim 13 or a salt thereof, wherein the targeting molecule is selected from the group consisting of a ligand, a substrate, a protein, a peptide, an aptamer, a carbohydrate, or a small molecule.
15. The conjugate of claim 13 or a salt thereof, wherein the targeting molecule targets tumors.
16. The conjugate of claim 15 or a salt thereof, wherein the targeting molecule targets prostate specific membrane antigen.
17. A composition comprising the conjugate of claim 1 or a salt thereof and a carrier.
18. A pharmaceutical composition comprising the conjugate of claim 1 or a salt thereof and a pharmaceutically acceptable carrier.
19. A method of delivering a therapeutic agent to a subject, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition of claim 18 to a subject in need of such therapeutic agent, wherein X is a therapeutic agent.
20. The method of claim 19 , wherein the conjugate or a salt thereof further comprises a targeting molecule attached through the substituent of R 4 .
21. A method of treating cancer, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition of claim 18 to a subject in need of such treatment, wherein X is a therapeutic agent and wherein the conjugate or a salt thereof further comprises a targeting molecule attached through the substituent of R 4 .
22. A method of diagnosing cancer, wherein the method comprises
(a) administering an effective amount of the pharmaceutical composition of claim 18 to a subject in need of such diagnosis, wherein is X a diagnostic agent and wherein the conjugate or a salt thereof further comprises a targeting molecule attached through the functional group of R 4 ; and
(b) detecting the diagnostic agent.
23. The method of claim 21 , wherein the targeting molecule targets a prostate specific membrane antigen on the tumor.
24. The conjugate of claim 1 , wherein R 4 is H, lower alkyl, or aryl; and wherein R 3 is attached to a molecule.
25. The conjugate of claim 24 , wherein the molecule is a targeting molecule, a detectable label, a polymer, or a solid support.
26. The conjugate of claim 24 , wherein the molecule is attached to R 3 through a spacer.
27. The conjugate of claim 24 , wherein R 3 further comprises a functional group for attaching to the molecule.
28. The conjugate of claim 10 or a salt thereof, wherein the targeting molecule, the polymer, the solid support, the attachment handle, or the masking agent is attached to the functional group of R 4 through a spacer.
29. The conjugate of claim 28 or a salt thereof, wherein the functional group of R 4 comprises an amide group or an amino group.