Cell-penetrating, guanidinium-rich oligophosphotriesters for drug and probe delivery
Guanidinium-rich oligophosphotriesters transporter compounds and methods of making and using the same are provided. Also provided are pharmaceutical compositions that include the subject transporter compounds, where the transporter can be joined to a cargo of interest, and is formulated with a pharmaceutically acceptable excipient. Formulations may be provided in a unit dose, where the dose provides an amount of the compound effective to afford a desired therapeutic effect. Methods of using the subject transporter compounds to deliver a cargo moiety to a cell are provided, where the method can include contacting a target cell with the transporter compound. The subject methods can be performed in vitro or in vivo.
1. A transporter compound of the formula:
wherein:
Z 1 is a cargo moiety, a reactive functional group or a protected functional group;
L 1 is an optional linker;
X is O, S or NH;
L 2 is a linker;
Z 2 is an guanidine group or a protected guanidine group;
R 3 is H, an alkyl, a substituted alkyl, an acyl, a substituted acyl, an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl;
R 1 and R 2 are independently H, an alkyl or a substituted alkyl;
each p is independently 1, 2 or 3; and
m is between 2 and 50.
2. A transporter compound of the formula:
wherein:
Z 1 is a cargo moiety, a reactive functional group or a protected functional group;
L 1 is an optional linker;
X is O, S or NH;
L 2 is a linker;
Z 2 is a guanidine group or a protected guanidine group;
R 3 is H, an alkyl, a substituted alkyl, an acyl, a substituted acyl, an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl;
R 1 and R 2 are independently H, an alkyl or a substituted alkyl;
each p is independently 1, 2 or 3; and
wherein n is 1 to 25 and m is 5 to 30.
3. The transporter compound of claim 2 , wherein:
R 3 is H;
X is O;
p is 1; and
n is 4 to 10.
4. The transporter compound of claim 1 , wherein Z 1 is a cargo moiety.
5. The transporter compound of claim 4 , wherein the cargo moiety is a chemotherapeutic drug, a dye, a protein or a polynucleotide.
6. The transporter compound of claim 4 , wherein L 1 is a cleavable linker.
7. A method of delivering a cargo moiety to a cell, the method comprising contacting a cell with a transporter compound of the formula:
wherein:
Z 1 is a cargo moiety;
L 1 is an optional linker;
X is O, S or NH;
L 2 is a linker;
Z 2 is an guanidine group or a protected guanidine group;
R 3 is H, an alkyl, a substituted alkyl, an acyl, a substituted acyl, an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl;
R 1 and R 2 are independently H, an alkyl or a substituted alkyl;
each p is independently 1, 2 or 3; and
m is between 2 and 50;
under conditions to deliver the cargo moiety to the cell.
8. The method of claim 7 , wherein L 1 is a cleavable linker and the method further comprises cleaving L 1 to release the cargo moiety.
9. The method of claim 7 , wherein Z 1 is a chemotherapeutic drug or a dye.
10. A method of synthesizing a compound of claim 1 , the method comprising: initiating organocatalytic ring-opening polymerization (OROP) of cyclic phospholane monomers of the formula:
wherein:
L 2 is a linker;
Z 2 is an guanidine group or a protected guanidine group;
R 1 and R 2 are independently H, an alkyl or a substituted alkyl; and
each p is independently 1, 2 or 3;
with an initiator of the formula Z 1 -L 1 -XH, wherein:
Z 1 is a cargo moiety or a protected functional group;
L 1 is an optional linker; and
X is O, S or NH.
11. The method of claim 10 , wherein Z 2 is a protected guanidine group and the method further comprises deprotecting Z 2 to produce a guanidine group.
12. The method of claim 10 , wherein Z 1 is a cargo moiety.
13. The method of claim 6 , wherein Z 1 is a protected thiol.
14. The method of claim 13 , further comprising deprotecting Z 1 to produce a reactive functional group and conjugating the reactive functional group to a cargo moiety.
15. A pharmaceutical composition comprising the composition of claim 1 , and a pharmaceutically acceptable excipient.
16. A method of treating a subject for a disease condition, the method comprising administering to the subject an effective amount of the composition of claim 1 ;
to treat the subject for the disease condition.
17. The compound of claim 4 , wherein the cargo moiety is paclitaxel.
18. The compound of claim 1 , wherein Z 1 is a chemotherapeutic drug or a dye.
19. The compound of claim 1 , Z 2 is a protected guanidine group.
20. The compound of claim 1 , wherein Z 1 is a protected thiol.
21. The compound of claim 1 , wherein z 1 is an antibiotic.