title: Delivering wasp venom for cancer therapy.
abstract: Cytolytic peptides with potential therapeutic properties have appeared during the last three decades. However, the use of these natural weapons is relatively narrow due to their non-specific cytolytic activity as well as their rapid degradation and excretion when injected in blood. In order to rescue the use of these lytic peptides, we have designed pro-cytotoxic systems based on cytotoxic peptides conjugated to poly(l-glutamic acid) PGA polymer through specific cleavage sequences that are sensitive over-expressed tumor proteases, such as the metalloproteinase-2 (MMP-2) or cathepsin B. The potent cytotoxic peptide tested here, Mitoparan, is inactive when conjugated to the polymer and then become active again once released through the tumor proteases. Furthermore, this pro-cytotoxic system was decorated by a particular targeting peptide which binds to HER2 receptors over-expressed in some types of breast tumor cells, thereby increasing the selective release of cytolytic peptides inside tumor cell with exquisite spatiotemporal control. In this way, the system would improve the maximum tolerated dose and the pharmacokinetic parameters of cytotoxic peptides in vivo.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain. Electronic address: miguel.moreno@irbbarcelona.org.
authors.forename: Miguel
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Zurita
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain. Electronic address: ernest.giralt@irbbarcelona.org.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D011099:Polyglutamic Acid / Q000737:chemistry; D014862:Wasp Venoms / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D014862:Wasp Venoms; C529760:mitoparan; D011099:Polyglutamic Acid
keywords: Cytolytic peptides; HER2+ breast cancer; Overexpressed tumor proteases; Polyglutamic acid; Pro-cytotoxic systems; Targeting peptides