Tumor-activated prodrug compounds and treatment

A method for selectively delivering a therapeutic agent to a tumor cell, comprising:

• contacting a tumor activated prodrug, W-Z-M, with the tumor cell;
• and
• allowing the tumor activated prodrug to be selectively cleaved by a factor secreted by the tumor cell, such that the therapeutic agent is selectively delivered to the tumor cell,
• wherein said tumor activated prodrug, W-Z-M, comprises a component, M, wherein M is a therapeutic agent, said M being linked to a ligand, W-Z, said ligand comprising an arm, Z, linked to a terminal group, W, wherein linkage in the arm, Z, of the ligand, W-Z, or between the arm, Z, and the component, M, prevents intracellular entry of the compound, W-Z-M, wherein said linkage can be selectively cleaved by a factor or factors secreted by a tumor cell so as to permit entry of the therapeutic agent into said tumor cell, wherein the terminal group, W, includes β-alanyl.

A method for selectively delivering a therapeutic agent to a tumor cell, comprising:

• contacting a tumor activated prodrug, W-Z-M, with the tumor cell;
• and
• allowing the tumor activated prodrug to be selectively cleaved by a factor secreted by the tumor cell, such that the therapeutic agent is selectively delivered to the tumor cell,
• wherein said tumor activated prodrug, W-Z-M, comprises a component, M, wherein M is a therapeutic agent, said M being linked to a ligand, W-Z, said ligand comprising an arm, Z, linked to a terminal group, W, wherein linkage in the arm, Z, of the ligand, W-Z, or between the arm, Z, and the component, M, prevents intracellular entry of the compound, W-Z-M, wherein said linkage can be selectively cleaved by a factor or factors secreted by a target cell so as to permit entry of the therapeutic agent into said target cell, wherein the arm, Z, of the ligand, W-Z, is a peptide selected from the group consisting of L-leucyl-L-alanyl-L-leucyl, L-leucyl-L-alanyl, L-alanyl-L-leucyl-L-phenylalanyl, and L-alanyl-L-leucyl, and further wherein the terminal group, W, includes β-alanyl.

A method for making a tumor-activated prodrug-form of a therapeutic agent, the therapeutic agent having desired activity in a tumor cell, wherein the tumor-activated prodrug is capable of providing the therapeutic agent selectively to the tumor cell in the presence of a normal cell, the method comprising:

• a. identifying a substrate of an enzyme that is secreted by the tumor cell, wherein the enzyme is not secreted by normal cells;
• b. covalently attaching the substrate to the therapeutic agent to form a prospective tumor-activated prodrug;
• c. testing to determine:
• i. whether the enzyme cleaves the prospective tumor-activated prodrug into fragments when the prospective tumor-activated prodrug contacts an extracellular medium surrounding the tumor cell, one of the fragments being referred to as a prospective active fragment;
• ii. whether the prospective active fragment enters the tumor cell from the extracellular medium;
• iii. whether the prospective active fragment is active in the tumor cell, in which case the prospective active fragment is referred to as an active fragment;
• iv. whether the prospective tumor-activated prodrug enters the normal cell;
• d. identifying as a tumor-activated prodrug any prospective tumor-activated prodrug that meets the following conditions:
• i. cleavage by the enzyme produces a prospective active fragment when the propsective tumor-active prodrug contacts the extracellular medium surrounding the tumor cell;
• ii. the prospective active fragment enters the tumor cell;
• iii. the prospective active fragment is an active fragment;
• iv. the prosepective tumor-activated prodrug does not enter the normal cell.