Nucleic acid based therapeutics for tumor therapy.
Although being a heterogeneous disease, cancer has certain characteristic features which can be utilized for treatment with novel macromolecular therapeutics. The active cycling status of tumor cells, proliferating tumor endothelium and a leaky vasculature allow the targeted delivery of therapeutically active nucleic acids into tumor tissue. We and others have developed polycationic gene carriers forming so called polyplexes with nucleic acids. Cellular aspects like binding, internalization and intracellular fate were enlightened. Additionally, virus like domains were incorporated into the polyplex. Hydrophilic shielding domains protect the polyplex from unspecific interaction with blood components, targeting ligands allow cell specific binding and internalization into target cells, and membrane active peptides have a favorable influence on intracellular trafficking. Physical targeting of polyplexes, like locoregional hyperthermia and photochemical internalization (PCI) have been further used to enhance the efficiency of nucleic acid transfer. Therapeutic concepts were carried out in different tumor models in mice. Local application of synthetic, double stranded RNA led to eradication of intracranial glioblastoma. A gene directed enzyme prodrug approach utilizing site directed activation of cyclophosphamide with cytochrome P450 gave first, promising results.
Ogris
Manfred
M
Pharmaceutical Biology-Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität, Butenandtstr 5-13, Munich, Germany. Manfred.Ogris@cup.uni-muenchen.de
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009696:Nucleic Acids / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use
D018906:Antineoplastic Agents, Alkylating; D004337:Drug Carriers; D009696:Nucleic Acids; D011355:Prodrugs; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System