Self-assembling drug amphiphiles and methods for synthesis and use
The present invention provides herein the design of monodisperse, amphiphilic anticancer drugs—which are now termed “drug amphiphiles” (DAs)—that can spontaneously associate into discrete, stable supramolecular nanostructures with the potential for self-delivery (no additional carriers are needed). The quantitative drug loading in the resulting nanostructures is ensured by the very nature of the molecular design. The DA is a composition comprising: D-L-PEP; wherein D is 1 to 4 hydrophobic drug molecules which can be the same or different; L is 1 to 4 biodegradable linkers which can be the same or different; and PEP is a peptide that can spontaneously associate into discrete, stable supramolecular nanostructures. In an alternate embodiment, the DA composition also comprises a targeting ligand (T). Methods of making DA molecules, as well as their use in treatment of disease are also provided.
1. A composition comprising:
D-L-PEP;
wherein D is 1 to 4 hydrophobic drug molecules, wherein the drug molecules are chemotherapeutic agents having a water solubility of less than 10 mg/ml;
L is 1 or more biodegradable linkers selected from the group consisting of disulfanylcarbonate (etcSS) and disulfanylbutanoate (buSS); and
PEP is a hydrophilic peptide selected from the group consisting of GVQIVYKK (SEQ ID NO: 1), CGVQIVYKK (SEQ ID NO: 6), and VQIVYK (SEQ ID NO: 9).
2. The composition of claim 1 , wherein the linker L is cleaved intracellularly by glutathione.
3. The composition of claim 1 , wherein D is 2 hydrophobic drug molecules, or 3 hydrophobic drug molecules, or 4 hydrophobic drug molecules.
4. The composition of claim 1 , wherein D is 1 to 4 hydrophobic drug molecules which are the same or different.
5. The composition of claim 1 , wherein the 1 to 4 hydrophobic drug molecules are selected from the group consisting of paclitaxel, camptothecin, anthracyclines, carboplatin, cisplatin, daunorubicin, doxorubicin, methotrexate, vinblastine, and vincristine.
6. The composition of claim 1 , wherein the linker is disulfanylbutanoate.
7. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
8. The composition of claim 7 , further comprising at least one additional biologically active agent.
9. A composition comprising 1 to 4 hydrophobic chemotherapeutic molecules linked via 1 to 4 disulfanylbutanoate linking molecules to the peptide CGVQIVYKK (SEQ ID NO: 6).
10. The composition of claim 9 , wherein the chemotherapeutic molecule is selected from the group consisting of paclitaxel, camptothecin, or combinations thereof.
11. The composition of claim 10 , further comprising a pharmaceutically acceptable carrier.
12. The composition of claim 11 , further comprising at least one additional biologically active agent.
13. A composition comprising:
D-L-PEP-T;
wherein D is 1 or more hydrophobic drug molecules, wherein the drug molecules are chemotherapeutic agents having a water solubility of less than 10 mg/ml;
L is 1 or more biodegradable linkers selected from the group consisting of disulfanylcarbonate (etcSS) and disulfanylbutanoate (buSS);
PEP is a hydrophilic peptide selected from the group consisting of GVQIVYKK (SEQ ID NO: 1), CGVQIVYKK (SEQ ID NO: 6), and VQIVYK (SEQ ID NO: 9); and
T is a targeting ligand selected from the group consisting of RGD, RGDS (SEQ ID NO: 13), folate and methotrexate.
14. The composition of claim 13 , wherein the linker L is cleaved intracellularly by glutathione.
15. The composition of claim 13 , wherein D is 2 hydrophobic drug molecules, or 3 hydrophobic drug molecules, or 4 hydrophobic drug molecules.
16. The composition of claim 13 , wherein D is 1 to 4 hydrophobic drug molecules which are the same or different.