Selective delivery molecules and methods of use
Disclosed herein is a selective delivery molecule comprising: (a) an acidic sequence (portion A) which is effective to inhibit or prevent the uptake into cells or tissue retention, (b) a molecular transport or retention sequence (portion B), and (c) a linker between portion A and portion B, and (d) at least one cargo moiety.
1. A selective delivery molecule of Formula I, having the structure:
[D A - c A ]-A-[ c M -M]-X-B-[ c B -D B ] Formula I
wherein,
X is a peptide linker cleavable by a matrix metalloproteinase;
A is a peptide with a sequence comprising a series of 5 glutamates (SEQ ID NO:5);
B is a peptide with a sequence comprising a series of 8 arginines (SEQ ID NO:6);
c A , c B , and c M are each independently an amino acid;
M is a polyethylene glycol (PEG) polymer; and
D A and D B are a pair of acceptor and donor fluorescent moieties that are capable of undergoing Försters/fluorescence resonance energy transfer with the other; and
wherein [c M -M] is bound to at any position on X, [D A -c A ] is bound to any amino acid on A, [c B -D B ] is bound to any amino acid on B, and M is a PEG polymer having an average molecular weight of 500 Da to 10 kDa.
2. The molecule of claim 1 , wherein c A , c B , and c M are each independently selected from D-cysteine, D-glutamate, lysine, and para-4-acetyl L-phenylalanine.
3. The molecule of claim 2 , wherein c B is D-cysteine.
4. The molecule of claim 2 , wherein c A is D-glutamate.
5. The molecule of claim 2 , wherein c A is lysine.
6. The molecule of claim 2 , wherein c M is para-4-acetyl L-phenylalanine.
7. The molecule of claim 1 , wherein X comprises an amino acid sequence that is cleavable by MMP2, MMP7, MMP9, or MMP14.
8. The molecule of claim 7 , wherein X comprises an amino acid sequence selected from: PLGLAG (SEQ ID NO:2), PLG-C(me)-AG (SEQ ID NO:1), RPLALWRS (SEQ ID NO:7), ESPAYYTA (SEQ ID NO:8), DPRSFL (SEQ ID NO:9), PPRSFL (SEQ ID NO:10), RLQLKL (SEQ ID NO:11), and RLQLK(Ac) (SEQ ID NO:12).
9. The molecule of claim 1 , wherein D A and D B are Cy5 and Cy7.
10. The molecule of claim 1 , wherein D A and D B are Cy5 and IRDye750.
11. The molecule of claim 1 , wherein D A and D B are Cy5 and IRDye800.
12. The molecule of claim 1 , wherein D A and D B are Cy5 and ICG.
13. The molecule of claim 1 , wherein the molecule of Formula I is:
i) SDM-14
ii) SDM-15
iii) SDM-23
iv) SDM-24
v) SDM-25
vi) SDM-26
vii) SDM-27
viii) SDM-32; or
ix) SDM-35.
14. The molecule of claim 1 , wherein M is a PEG polymer having an average molecular weight of 500 Da.
15. The molecule of claim 1 , wherein M is a PEG polymer having an average molecular weight of 2 kDa.
16. The molecule of claim 1 , wherein M is a PEG polymer having an average molecular weight of 5 kDa.
17. The molecule of claim 1 , wherein M is a PEG polymer having an average molecular weight of 10 kDa.
18. The molecule of claim 7 , wherein X comprises an amino acid sequence selected from: PLGLAG (SEQ ID NO:2), PLG-C(me)-AG (SEQ ID NO:1), and RPLALWRS (SEQ ID NO:7).
19. The molecule of claim 7 , wherein X comprises the amino acid sequence PLG-C(me)-AG (SEQ ID NO:1).