Stapled acid-sensitive endosome disrupting alginates
An agent comprising: an algin crosslinked with acetal linkages; and at least one cation coupled to the crosslinked algin.
1. An agent comprising:
an algin crosslinked with acetal linkages, wherein the acetal linkages have a structure of —X 1 -A-X 2 — wherein X 1 and X 2 are each independently —NH— or —O—, and A includes an acetal group; and
at least one cation coupled to the crosslinked algin; wherein A is:
wherein R 10 and R 11 are each independently an alkanediyl, and R 12 and R 13 are each optionally substituted alkyl.
2. An agent having a structure comprising:
wherein M is a cation; X 1 and X 2 are each independently —NH— or —O—, and wherein A is;
wherein R 10 and R 11 are each independently an alkanediyl, and R 12 and R 13 are each optionally substituted alkyl; or
wherein M is a cation; X 1 and X 2 are each independently —NH— or —O—, and A is:
wherein R 10 and R 11 are each independently an alkanediyl, and R 12 and R 13 are each optionally substituted alkyl;
or a combination of Formula IV and Formula V.
3. The agent of claim 1 , wherein the cation is selected from copper, iron, calcium, zinc, magnesium, selenium, aluminum, manganese, barium, strontium or a combination thereof.
4. The agent of claim 1 , wherein the acetal is derived from 2,2-bis(aminoethoxy)propane, 1-(2-Hydroxyethyl)-4-piperidone ethylene ketal, 1-Amino-4-oxocyclohexanecarboxylic acid ethylene ketal, or 4-Bromoacetophenone diethyl ketal.
5. The agent of claim 1 , wherein the algin is derived from alginic acid.
6. The agent of claim 1 , wherein the cation is chelated to the algin.
7. The agent of claim 1 , wherein the agent includes at least two different types of cations.
8. The agent of claim 1 , wherein the agent is endocytosable.
9. The agent of claim 1 , wherein the acetal linkages or groups are pH cleavable at endosomal pH.
10. A pharmaceutical composition comprising the agent of claim 1 and at least one pharmaceutically acceptable additive.
11. A pharmaceutical composition comprising the agent of claim 1 , and an active agent-loaded thermoresponsive gel.
12. The pharmaceutical composition of claim 11 , wherein the active agent is a therapeutically active agent.
13. A method for increasing the intracellular level of at least one cation above homeostatic level in a cell, comprising contacting the cell with the agent of claim 1 .
14. A method comprising delivering at least one cation to the cytosol of a cell, comprising contacting the cell with the agent of claim 1 .
15. A method for increasing the intracellular level of hydrogen peroxide above homeostatic level in a cell, comprising contacting the cell with the agent of claim 1 .
16. A method comprising delivering at least one cation to the cytosol of a prokaryotic or eukaryotic cell, comprising contacting the cell with the agent of claim 1 .
17. A method comprising delivering at least one cation to the extracellular space of a prokaryotic or eukaryotic cell, comprising not contacting the cell with the agent of claim 1 .
18. The agent of claim 1 , wherein the acetal is derived from 2,2-bis(aminoethoxy)propane.
19. The agent of claim 1 , wherein the cation is calcium.
20. The agent of claim 19 , wherein the acetal is derived from 2,2-bis(aminoethoxy)propane.
21. The agent of claim 1 , wherein a single type of cation is coupled to the crosslinked algin.
22. A particle comprising the agent of claim 1 .
23. A composition comprising a plurality of the particles of claim 22 .
24. The composition of claim 23 , wherein the particles have an average particle size of 1 nm to 10,000 μm.
25. A pharmaceutical composition comprising the composition of claim 23 .
26. A method for increasing the intracellular level of at least one cation above homeostatic level in a cell, comprising contacting the cell with the composition of claim 23 .
27. A method comprising delivering at least one cation to the cytosol of a cell, comprising contacting the cell with the composition of claim 23 .
28. A method for increasing the intracellular level of hydrogen peroxide above homeostatic level in a cell, comprising contacting the cell with the composition of claim 23 .
29. The particle of claim 22 , wherein the particle encapsulates an immunotherapeutic agent, a cancer cytotoxic agent, or both an immunotherapeutic agent, a cancer cytotoxic agent.
30. The particle of claim 22 , wherein the particle encapsulates a protein.