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 a conjugate of formula:
D-L-PEP;
wherein D is 1 or more hydrophobic drug molecules;
L is 1 or more biodegradable linkers; and
PEP is a hydrophilic peptide selected from the group consisting of GVQIVYKK (SEQ ID NO: 1), CGNNQQNYKK (SEQ ID NO: 5), CGVQIVYKK (SEQ ID NO: 6), GNNQQNYKK (SEQ ID NO: 7), and CCKGNNQQNYKK (SEQ ID NO: 10); and wherein
the conjugate is selected from the group consisting of: camptothecin-(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (mCPT-buSS-Tau); (camptothecin) 2 -(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (dCPT-buSS-Tau); (camptothecin) 4 -(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (qCPT-buSS-Tau); (camptothecin) 4 -(4-(pyridin-2-yldisulfanyl)butanoate)-CGNNQQNYKK (qCPT-buSS-Sup35); camptothecin-disulfanylcarbonate-CGVQIVYKK (mCPT-etcSS-Tau); paclitaxel-(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (PXL-buSS-Tau); camptothecin-Cys-GNNQQNYKK (CPT-Cys-Sup35); paclitaxel-Cys-GNNQQNYKK (PXL-Cys-Sup35); (camptothecin) 2 -CCKGNNQQNYKK (dCPT-Sup35); (paclitaxel) 2 -CCKGNNQQNYKK (dPXL-Sup35); and camptothecin-paclitaxel-CCKGNNQQNYKK (CPT-PXL-Sup35).
2. The composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
3. The composition of claim 2 , further comprising at least one additional biologically active agent.
4. A composition comprising a conjugate of formula:
D-L-PEP-T;
wherein D is 1 or more hydrophobic drug molecules;
L is 1 or more biodegradable linkers;
PEP is a hydrophilic peptide selected from the group consisting of GVQIVYKK (SEQ ID NO: 1), CGNNQQNYKK (SEQ ID NO: 5), CGVQIVYKK (SEQ ID NO: 6), GNNQQNYKK (SEQ ID NO: 7), and CCKGNNQQNYKK (SEQ ID NO: 10); and wherein the D-L-PEP in the conjugate is selected from the group consisting of: camptothecin-(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (mCPT-buSS-Tau); (camptothecin) 2 -(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (dCPT-buSS-Tau); (camptothecin) 4 -(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (qCPT-buSS-Tau); (camptothecin) 4 -(4-(pyridin-2-yldisulfanyl)butanoate)-CGNNQQNYKK (qCPT-buSS-Sup35); camptothecin-disulfanylcarbonate-CGVQIVYKK (mCPT-etcSS-Tau); paclitaxel-(4-(pyridin-2-yldisulfanyl)butanoate)-GVQIVYKK (PXL-buSS-Tau); camptothecin-Cys-GNNQQNYKK (CPT-Cys-Sup35); paclitaxel-Cys-GNNQQNYKK (PXL-Cys-Sup35); (camptothecin) 2 -CCKGNNQQNYKK (dCPT-Sup35); (paclitaxel) 2 -CCKGNNQQNYKK (dPXL-Sup35); and camptothecin-paclitaxel-CCKGNNQQNYKK (CPT-PXL-Sup35); and
T is a targeting ligand selected from the group consisting of RGD, RGDS (SEQ ID NO: 13), folate and methotrexate.
5. The composition of claim 4 , further comprising a pharmaceutically acceptable carrier.
6. The composition of claim 4 , further comprising at least one additional biologically active agent.