Dual acting prodrugs
A prodrug is provided which includes at least two different pharmaceutically and/or diagnostically active compounds independently bound by cleavable linkers and a protein-binding moiety which is capable of binding to carrier a molecule.
1. A prodrug comprising
(i) at least a first pharmaceutically and/or diagnostically active compound, the first pharmaceutically and/or diagnostically active compound is a member selected from the group consisting of topotecan, irinotecan, 9-aminocamptothecin, camptothecin and derivatives thereof,
(ii) at least a second pharmaceutically and/or diagnostically active compound, the second pharmaceutically and/or diagnostically active compound is a third generation multidrug resistance (MDR) modulator,
(iii) two or more cleavable linkers, the cleavable linker is a p-aminobenzyloxycarbonyl (PABC) linker, and
(iv) a protein-binding moiety, the protein-binding moiety is a maleinimide group,
wherein the first and the second pharmaceutically and/or diagnostically active compounds are each bound to the cleavable linker, and wherein the first and the second pharmaceutically and/or diagnostically active compounds are different from each other.
2. The prodrug according to claim 1 , wherein the third generation MDR modulator is selected from the group consisting of XR9576, LY335979, OC-144093, R101933, GF120918, MS-209, S-9788, reversin 205 and 121, or derivatives thereof.
3. The prodrug according to claim 1 , wherein the protein-binding moiety binds to a serum protein, an antibody or antibody fragments, a synthetic polymer, a peptide, a growth factor, a polysaccharide, or a sugar.
4. The prodrug according to claim 1 , wherein the protein- binding moiety binds in situ to cysteine-34 of albumin.
5. The prodrug according to claim 1 , wherein the two or more cleavable linkers can independently be cleaved hydrolytically and/or enzymatically and/or pH-dependently.
6. The prodrug according to claim 1 , wherein at least one of the first or second pharmaceutically and/or diagnostically active compounds contains one or more radionuclides, one or more positron emitters, one or more NMR contrast agents, one or more fluorescent compound(s), or one or more near-infrared contrast agents.
7. A pharmaceutical composition comprising the prodrug according to claim 1 , and optionally a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable adjuvent and/or a diluent.