Many drugs that are potentially efficacious for treating diseases such as cancer have limited usefulness because they are relatively toxic. Even approved cancer therapeutics can cause adverse side effects such as hypertension, skin disorders and osteoporosis.

Gene Directed Enzyme Prodrug Therapy (GDEPT) is a strategy for minimizing the side effects associated with systemic administration of anticancer drugs. GDEPT works by expressing a gene that encodes a prodrug-activating enzyme in tumor cells. Typically, delivery vectors carrying the gene are transported to the tumor site. Then a non-toxic prodrug is injected intravenously. Only the cells that express the enzyme convert the prodrug into the active, but toxic, anticancer agent, minimizing the negative effects on normal tissues.

Although GDEPT has great potential, it has yet to be fully developed, in part because it is difficult to deliver the enzyme-encoding gene to tumor cells. Viral methods of gene delivery are one option, but potential problems exist with immunogenicity and other safety risks. And current non-viral gene delivery methods have many drawbacks, including inadequate vector delivery and toxicity. Improved non-viral methods of delivering genes and prodrugs to cells are needed for GDEPT to reach its potential.

UW-Madison researchers have developed improved compositions for the tunable and specific delivery of genes and/or prodrugs into cells. The invention uses polyethylene glycol (PEG)-polycationic copolymers, such as poly(Aspartate-Hydrazone-PEG)-b-poly(L-Lysine) block copolymers, to deliver therapeutic agents, including genes and/or prodrugs, to target cells. The block copolymers form polyplex micelles that encapsulate the therapeutic agents within a central core region. The water-soluble and membrane-permeable PEG side groups form a hydrophilic shell around this core region that enables the nanoscopic polyplex micelles to circulate through the bloodstream and be incorporated into cells.

When the copolymers experience an environment with slightly lower than physiological pH, the PEG residues are removed via hydrolysis of hydrazone bonds, enabling cell entry of polyplex micelles and enhanced gene transfection. Because cancerous cells have a more acidic extracellular environment than normal cells, this causes the prodrug and/or the gene encoding the prodrug-activating enzyme to be preferentially delivered to tumors.

File Number: P07169US