Environmentally sensitive compositions comprising a pH-triggered membrane protein and methods of use thereof in the treatment and diagnosis of tumors

1. An environmentally sensitive composition comprising a pH-triggered membrane peptide comprising

(a) at least 8 contiguous amino acids of SEQ ID NO: 3-11, 14, 18, 19, 21, 24, 25, 31-37, 274, 275, or 283, wherein,

(b) at least 6 of the contiguous 8 amino acids of said membrane peptide are non-polar,

(c) at least one of the at least 8 amino acids of said membrane peptide is protonatable, and

(d) the peptide has a higher affinity to a membrane lipid bilayer at pH 5.0 compared to at pH 8.0, wherein said pH-triggered peptide does not comprise the amino acid sequence of SEQ ID NO: 1.

2. The composition of claim 1 , wherein the pH-triggered membrane peptide has 13-25 residues.

3. The composition of claim 1 , further comprising a single flanking domain at its N-terminus or at its C-terminus of said membrane peptide.

4. The composition of claim 3 , further comprising a first flanking domain at said C-terminus and a second flanking domain at said N-terminus.

5. The composition of claim 4 , further comprising a cargo attached to one of said flanking domains, wherein said cargo is selected from a therapeutic, diagnostic, radiation-enhancing, radiation-sensitizing, imaging, gene regulation, cytotoxic, apoptotic, or research reagent.

6. The composition of claim 5 , wherein said cargo is attached to said flanking region via a thiol linkage.

7. The composition of claim 1 , wherein one or more atoms are replaced by a radioactive isotope or a stable isotope.

8. The composition of claim 1 , wherein one or more of the amino acid side chains are chemically modified to render them radioactive or detectable by probing radiation.

9. The composition of claim 1 , comprising one or more cargoes attached to said peptide, wherein said cargo is used as a therapeutic, diagnostic, imaging, immune activation, gene regulation or cell function regulation agent, radiation-enhancing agent, radiation-sensitizing agent, or as a research tool.

10. The composition of claim 1 , for use as an agent to deliver a functional cargo across cell membranes to cells in a diseased tissue with a naturally acidic extracellular environment or in a tissue with an artificially induced acidic extracellular environment relative to normal physiological pH.

11. The composition of claim 10 , wherein said diseased tissue is selected from the group consisting of inflamed tissue, ischemic tissue, arthritic tissue, tissue infected with a microorganism, and atherosclerotic tissue.

12. The composition of claim 1 , for use as an agent to deliver a functional cargo to cell surfaces in a diseased tissue with a naturally acidic extracellular environment or in a tissue with an artificially induced acidic extracellular environment relative to normal physiological pH.

13. The composition of claim 5 , wherein said cargo comprises phalloidin, phallo toxin, amanitin toxin, a DNA intercalator, or a peptide nucleic acid.

14. The composition of claim 1 , wherein said sequence comprises residues 20-27 of SEQ ID NO: 3 or 18.

15. The composition of claim 5 , wherein said cargo comprises a dye, a fluorescent protein, a nanoparticle, or a radioactive isotope.

16. The composition of claim 15 , wherein the dye is a fluorescent dye.

17. The composition of claim 15 ,

(a) comprising a dye selected from the group consisting of rhodamine, Alexa Fluor® 750 dye, or Cy5.5;

(b) comprising a fluorescent protein, wherein the fluorescent protein is green fluorescent protein;

(c) comprising a nanoparticle that comprises gold; or

(d) comprising a radioactive isotope selected from the group consisting of Fluorine-18, Copper-64, Thallium-201, Iodine-123, Gallium-67, Strontium-82, Cadmium-113, Tellurium-123, Cobalt-60, or Technetium-99m.

18. The composition of claim 9 , comprising a magnetic resonance, positron emission tomography, single photon emission computed tomography, or fluorescence imaging agent.

19. The composition of claim 9 , comprising a positron emission tomography agent.

20. The composition of claim 19 , wherein said positron emission tomography agent comprises a Copper-64 or Fluorine-18 radioactive isotope.

21. A diagnostic conjugate comprising the composition of claim 1 and a pharmaceutically acceptable detectable marker linked thereto.

22. The conjugate of claim 21 , wherein said detectable marker comprises a dye.

23. The conjugate of claim 22 , wherein the dye comprises a fluorescent dye.

24. The conjugate of claim 21 , wherein said detectable marker comprises a nanoparticle.

25. A therapeutic conjugate comprising the composition of claim 1 , further comprising a first cargo comprising a cytotoxic agent and a second cargo comprising a hydrophobicity-balancing cargo.

26. The conjugate of claim 25 , wherein said cytotoxic agent is selected from the group consisting of phalloidin, phallo toxin, amanitin toxin, a boron-containing compound, and a DNA intercalator.

27. A method of determining the aggressiveness or risk of increased metastasis from a primary tumor, comprising contacting said tumor with the conjugate of claim 21 , wherein an increased level of binding of said composition compared to a control level of binding indicates the aggressiveness or risk of increased metastasis from said primary tumor.

28. The composition of claim 1 , wherein said composition further comprises a therapeutic cargo.

29. The composition of claim 28 , wherein the therapeutic cargo comprises phalloidin, phallo toxin, amanitin toxin, a DNA intercalator, or a peptide nucleic acid and wherein tumor cells are preferentially inhibited compared to normal non-tumor cells.

30. A method of guiding surgical tumor excision, comprising administering to an anatomical site comprising a tumor the conjugate of claim 21 , removing a primary tumor from said site, detecting residual tumor cells by binding of said conjugate to said residual tumor cells, and excising said residual tumor cells.