Polymeric nano-carriers with a linear dual response mechanism and uses thereof
The present invention features compositions in which nano-carriers are synthesized with polymers that respond to lower pH and/or ROS by being degraded. The compositions may be utilized to selectively deliver payloads within patients by responding to lower pH and/or ROS at localities within the patient. The present invention also features methods of synthesizing nano-carriers that are degraded by lower pH and/or ROS.
1. A composition comprising a logic gate nano-carrier wherein the logic gate nano-carrier comprises at least one polymer having a backbone that is stable at normal physiological pH and/or oxidative conditions, the backbone having a first backbone response element comprising an acid-labile ketal moiety and a second backbone element comprising a trigger moiety adapted for triggering a change in a hydrophilic-hydrophobic balance in the backbone, and wherein the element trigger moiety responds to one of lower pH and reactive oxygen species (“ROS”), and wherein the ketal moiety rapidly hydrolyzes to fragment the nano-carrier after activation of the trigger moiety, wherein the polymer comprises a repeat unit selected from the group consisting of
or a derivative thereof.
2. The composition of claim 1 , wherein the logic gate nano-carrier encapsulates a payload adapted to be released upon activation of the ketal moiety.
3. The composition of claim 1 , wherein the trigger moiety is an aminoester responsive to lower pH and the backbone becomes more hydrophilic when the trigger moiety is activated.
4. The composition of claim 1 , wherein the trigger moiety is responsive to ROS and the backbone becomes more hydrophilic when the trigger moiety is activated.
5. The composition of claim 1 , wherein the ketal moiety responds to lower pH by degrading the nano-carrier to release a payload.
6. The composition of claim 4 , wherein the trigger moiety is a thioether.
7. The composition of claim 1 , wherein the payload comprises a bioactive agent.
8. The composition of claim 1 , wherein the payload comprises an imaging agent.
9. The composition of claim 1 , wherein the payload comprises an MRI imaging agent.
10. The composition of claim 1 , wherein the payload comprises a gadolinium-based MRI imaging agent.
11. The composition of claim 1 , wherein the payload comprises a protein.
12. The composition of claim 1 , wherein the polymer is a molecularly-engineered polymer.
13. The composition of claim 1 , wherein the ROS is hydrogen peroxide.
14. The composition of claim 1 , wherein the pH that the response element responds to is between about 7.2 and 5.0.
15. The composition of claim 1 , wherein the payload is protein or DNA.
16. A composition comprising: an AND logic gate nano-carrier comprising at least one polymer comprising a polymer backbone having a hydrophobic-hydrophilic balance at normal physiological pH and/or oxidative conditions, the polymer backbone having a first response element comprising an acid-labile ketal moiety adapted to hydrolyze in the presence of lower pH and a second response element comprising a trigger moiety, wherein the second response element degrades in response to one of lower pH and a reactive oxygen species (“ROS”) to make the backbone more hydrophilic, and wherein the ketal moiety undergoes accelerated hydrolysis after activation of the trigger moiety to rapidly fragment the nano-carrier, wherein the polymer comprises a repeat unit selected from the group consisting of
or a derivative thereof.
17. The composition of claims 16 , further comprising a payload encapsulated within the nano-carrier, wherein the nano-carrier is adapted to release the payload upon hydrolysis of the ketal moiety.
18. The composition of claim 16 , wherein the second response element is an aminoester moiety.
19. The composition of claim 16 , wherein the second response element is a sulfur atom.
20. The composition of claim 16 , wherein the lower pH is within a range of about 7.2 and 5.0.
21. A polymer comprising an AND logic gate nano-carrier having A backbone with dual response elements and a payload encapsulated within the nano-carrier, wherein the backbone has a hydrophobic-hydrophilic balance that is stable under normal physiological pH and/or oxidative conditions, wherein the dual response elements are triggered sequentially by a trigger moiety that changes the hydrophobic-hydrophilic balance of the backbone to be more hydrophilic in response to one of lower pH and a reactive oxygen species (“ROS”), and second by accelerated hydrolysis of an acid-labile ketal moiety that degrades and fragments the polymer to release the payload, wherein the polymer comprises a repeat unit selected from the group consisting of
or a derivative thereof.
22. The polymer of claim 21 , wherein the trigger moiety is an aminoester responsive to lower pH.
23. The polymer of claim 21 , wherein the trigger moiety is a sulfur atom responsive to ROS.
24. The polymer of claim 21 , wherein the lower pH is within a range of about 7.2 to 5.0.
25. The polymer of claim 21 , wherein the lower pH is within a range of about 6.5 to 6.0.
26. The composition of claim 16 , wherein the lower pH is within a range of about 6.5 to 6.0.
27. The composition of claim 1 , wherein the lower pH is within a range of about 6.5 to 6.0.