Tumour-targeted theranostic
The present inventors have harnessed the targeting of nanoparticles to tumor sites, combined with the tumor site specific elevated MMP-14 activity within one conjugate to simultaneously deliver a vascular disrupting agent (VDA) and a MRI contrast agent to a tumor site. The MMP activatable conjugate of the present invention provides both therapeutic and diagnostic functions—and is referred to as a “theranostic”. The theranostic conjugate of the present invention achieves the benefits of tumor site specificity, VDA delivery and MRI contrast agent delivery in a single theranostic conjugate. Consequently, the present invention provides a cancer “theranostic” which improves therapeutic efficacy while simultaneously reducing dose-limiting systemic toxicities and provides a tool for rapidly and non-invasively identifying tumor location, monitoring drug delivery and pharmacodynamics.
1. A matrix metalloprotease (MMP) activatable conjugate lacking folate and comprising:
a vascular disrupting agent (VDA) which binds to the colchicine binding site of tubulin and wherein the VDA is selected from the group consisting of azademethylcolchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine and N-acetylcolchinol-O-phosphate,
a MMP cleavable peptide comprising the amino acid sequence -Gly-Hof-Tyr-Leu- (SEQ ID NO: 1) or -Arg-Ser-Cit-Gly-Hof-Tyr- (SEQ ID NO: 2), and
a nanoparticle comprising a magnetic resonance imaging (MRI) contrast agent, the MRI contrast agent comprising an ion selected from the group consisting of gadolinium, iron, platinum, manganese, copper, gold and barium.
2. A conjugate according to claim 1 wherein the MMP cleavable peptide comprises the amino acid sequence -Gly-Hof-Tyr-Leu- (SEQ ID NO: 1).
3. A conjugate according to claim 1 or 2 , wherein the MMP cleavable peptide further comprises a -Cys- at the N- or C-terminus of SEQ ID NO:1 or SEQ ID NO: 2.
4. A conjugate according to claim 1 , wherein the nanoparticle is from 3 to 200 nanometers (nm) in diameter.
5. A conjugate according to claim 1 , wherein the MRI contrast agent comprises an iron ion and is selected from the group consisting of iron oxides, magnetite (Fe 3 O 4 ) and maghemite (Fe 2 O 3 ).
6. A conjugate according to claim 5 , wherein the iron oxide is superparamagnetic iron oxide (SPIO) or ultrasmall superparamagnetic iron oxide (USPIO).
7. A conjugate according to claim 5 , wherein the MRI contrast agent is a carbohydrate coated iron oxide particle.
8. A conjugate according to claim 1 , wherein the VDA is azademethylcolchicine.
9. A matrix metalloprotease 14 (MMP-14) activatable conjugate lacking folate and comprising:
a VDA which binds to the colchicine binding site of tubulin, and wherein the VDA is selected from the group consisting of Azademethylcolchicine, Azacolchicine, N-methyl desacetylcolchicine, Desacetylcolchicine and N-acetylcolchinol-O-phosphate,
a MMP-14 cleavable peptide comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 6), and
a nanoparticle of 3 to 200 nm in diameter comprising a magnetic resonance imaging (MRI) contrast agent, the MRI contrast agent comprising an ion selected from gadolinium, iron, platinum, manganese, copper, gold or barium.
10. A pharmaceutical composition comprising the conjugate of claim 1 or 9 , and a pharmaceutically acceptable carrier, vehicle, diluent or excipient.
11. A method for treating a tumour comprising administering to a subject in need thereof an effective amount of the conjugate of claim 1 or 9 .
12. A method for treating and imaging a tumour comprising administering to a subject in need thereof an effective amount of the conjugate of claim 1 or 9 , the method further comprising obtaining an MRI image of the subject's tumour site.
13. A method for treating a tumour and monitoring VDA delivery to the tumour in a subject, the method comprising administering the conjugate of claim 1 or 9 to a subject in need thereof and obtaining one or more MRI images of the subject's tumour site.
14. A method according to claim 13 , wherein a first MRI image of the tumour site is obtained at a first point in time and a second MRI image of the tumour site is obtained at a subsequent second point in time, thereby enabling VDA delivery to the tumour site to be monitored.
15. The conjugate of claim 2 , wherein the MMP cleavable peptide comprises an amino acid sequence selected from the group consisting of -Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID: 4), -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 6), -βAla-Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 9) and -βAla-Arg-Ser-Cit-Gly-Hof-Tyr-Leu-Tyr- (SEQ ID NO: 10).
16. The conjugate of claim 7 , wherein the iron oxide particle is coated with dextran.
17. The conjugate of claim 7 , wherein the iron oxide particle is ferumoxytol.
18. The conjugate of claim 9 , wherein the MMP cleavable peptide further comprises a -Cys- at the N- or C-terminus of SEQ ID NO:6.