Poly(I:C)-mediated tumor growth suppression in EGF-receptor overexpressing tumors using EGF-polyethylene glycol-linear polyethylenimine as carrier.
OBJECTIVE
To develop a novel polyethylenimine (PEI)-based polymeric carrier for tumor-targeted delivery of cytotoxic double-stranded RNA polyinosinic:polycytidylic acid, poly(I:C). The novel carrier should be chemically less complex but at least as effective as a previously developed tetra-conjugate containing epidermal growth factor (EGF) as targeting ligand, polyethylene glycol (PEG) as shielding spacer, 25 kDa branched PEI as RNA binding and endosomal buffering agent, and melittin as endosomal escape agent.


METHODS
Novel conjugates were designed employing a simplified synthetic strategy based on 22 kDa linear polyethylenimine (LPEI), PEG spacers, and recombinant EGF. The efficacy of various conjugates (different PEG spacers, with and without targeting EGF) in poly(I:C)-mediated cell killing was evaluated in vitro using two human U87MG glioma cell lines. The most effective polyplex was tested for in vivo activity in A431 tumor xenografts.


RESULTS
Targeting conjugate LPEI-PEG2 kDa-EGF was found as most effective in poly(I:C)-triggered killing of tumor cells in vitro. The efficacy correlated with glioma cell EGFR levels. Repeated intravenous administration of poly(I:C) polypexes strongly retarded growth of A431 human tumor xenograft in mice.


CONCLUSIONS
The optimized LPEI-PEG2 kDa-EGF conjugate displays reduced chemical complexity and efficient poly(I:C)-mediated killing of EGFR overexpressing tumors in vitro and in vivo.
Schaffert
David
D
Pharmaceutical Biotechnology, Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität Munich, Butenandtstr. 5-13, 81377, Munich, Germany. david.schaffert@cup.uni-muenchen.de
Kiss
Melinda
M
Rödl
Wolfgang
W
Shir
Alexei
A
Levitzki
Alexander
A
Ogris
Manfred
M
Wagner
Ernst
E
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004815:Epidermal Growth Factor / Q000737:chemistry*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011092:Polyethylene Glycols; D004815:Epidermal Growth Factor; D011094:Polyethyleneimine; D066246:ErbB Receptors; D011070:Poly I-C