Tumor radiosensitization with monomethyl auristatin E (MMAE) and derivatives thereof
Disclosed herein, the invention pertains to methods and compositions that find use in radiosensitization of tumors and tumor samples based on the ability of a tumor sample to cleave a MTS molecule of the present invention. The MTS molecules of the present invention have a formula as disclosed herein and wherein A is a peptide with a sequence comprising 5 to 9 consecutive acidic amino acids, wherein the amino acids are selected from: aspartates and glutamates; B is a peptide with a sequence comprising 5 to 20 consecutive basic amino acids; X and Y are linkers; P is an optional pre-targeting moiety; M is an optional macromolecular carrier; and T is a radiosensitization agent for delivery to a target, including for example a therapeutic compound.
1. A method for inducing radiosensitization comprising administering to a subject in need thereof a molecule comprising the formula:
(A-X-B) n -M-(Y-T) i
wherein the molecule comprises:
a macromolecular carrier M bound to A or B;
a peptide A with a sequence comprising 5 to 9 consecutive acidic amino acids, wherein the amino acids are selected from the group consisting of aspartates and glutamates;
a first cleavable linker X;
a second cleavable linker Y;
a radiosensitizing agent T, wherein T is monomethyl auristatin E (MMAE) or a derivative thereof;
a peptide B with a sequence comprising 5 to 20 consecutive basic amino acids; and
n and i are independently integers between 1 and 20;
wherein said subject is radiosensitized.
2. The method of claim 1 , wherein X is selected from the group consisting of DPRSFL (SEQ ID NO: 1), PPRSFL (SEQ ID NO:2), Norleucine-TPRSFL (SEQ ID NO:3), and PLGC(Me)AG (SEQ ID NO:4).
3. The method of claim 1 , wherein M is a macromolecular carrier selected from the group consisting of a dendrimer, dextran, a PEG polymer, albumin, and lipid-coated perfluorocarbon droplet.
4. The method of claim 1 , wherein Y is Val-Cit-(p-amido)benzyloxycarbonyl.