title: Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels.
abstract: Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of apoptosis-inducing drugs. For this purpose, we conjugated the potent antimitotic agent monomethyl-auristatin-E (MMAE) via a lysosomal cleavable linker to human serum albumin (HSA) and further equipped this drug-albumin conjugate with cyclic c(RGDfK) peptides for multivalent interaction with alphavbeta3-integrin. The RGD-peptides were conjugated via either an extended poly(ethylene glycol) linker or a short alkyl linker. The resulting drug-targeting conjugates RGDPEG-MMAE-HSA and RGD-MMAE-HSA demonstrated high binding affinity and specificity for alphavbeta3-integrin expressing human umbilical vein endothelial cells (HUVEC). Both types of conjugates were internalized by endothelial cells and killed the target cells at low nM concentrations. Furthermore, we observed RGD-dependent binding of the conjugates to C26 carcinoma. Upon i.v. administration to C26-tumor bearing mice, both drug-targeting conjugates displayed excellent tumor homing properties. Our results demonstrate that RGD-modified albumins are suitable carriers for cell selective intracellular delivery of cytotoxic compounds, and further studies will be conducted to assess the antivascular and tumor inhibitory potential of RGDPEG-MMAE-HSA and RGD-MMAE-HSA.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, University of Groningen, Groningen, The Netherlands. k.temming@rug.nl
authors.forename: Kai
authors.initials: K
authors.lastname: Temming
authors.forename: Damon L
authors.initials: DL
authors.lastname: Meyer
authors.forename: Roger
authors.initials: R
authors.lastname: Zabinski
authors.forename: Eli C F
authors.initials: EC
authors.lastname: Dijkers
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D000418:Albumins / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry*; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000418:Albumins; D004337:Drug Carriers; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; C495575:monomethyl auristatin E