Design, synthesis, and evaluation of cisplatin-containing EGFR targeting bioconjugates as potential therapeutic agents for brain tumors.
The aim of this study was to evaluate four different platinated bioconjugates containing a cisplatin (cis-diamminedichloroplatinum [cis-DDP]) fragment and epidermal growth factor receptor (EGFR)-targeting moieties as potential therapeutic agents for the treatment of brain tumors using a human EGFR-expressing transfectant of the F98 rat glioma (F98EGFR) to assess their efficacy. The first two bioconjugates employed the monoclonal antibody cetuximab (C225 or Erbitux(®)) as the targeting moiety, and the second two used genetically engineered EGF peptides. C225-G5-Pt was produced by reacting cis-DDP with a fifth-generation polyamidoamine dendrimer (G5) and then linking it to C225 by means of two heterobifunctional reagents. The second bioconjugate (C225-PG-Pt) employed the same methodology except that polyglutamic acid was used as the carrier. The third and fourth bioconjugates used two different EGF peptides, PEP382 and PEP455, with direct coordination to the Pt center of the cis-DDP fragment. In vivo studies with C225-G5-Pt failed to demonstrate therapeutic activity following intracerebral (ic) convection-enhanced delivery (CED) to F98EGFR glioma-bearing rats. The second bioconjugate, C225-PG-Pt, failed to show in vitro cytotoxicity. Furthermore, because of its high molecular weight, we decided that lower molecular weight peptides might provide better targeting and microdistribution within the tumor. Both PEP382-Pt and PEP455-Pt bioconjugates were cytotoxic in vitro and, based on this, a pilot study was initiated using PEP455-Pt. The end point for this study was tumor size at 6 weeks following tumor cell implantation and 4 weeks following ic CED of PEP455-Pt to F98 glioma-bearing rats. Neuropathologic examination revealed that five of seven rats were either tumor-free or only had microscopic tumors at 42 days following tumor implantation compared to a mean survival time of 20.5 and 26.3 days for untreated controls. In conclusion, we have succeeded in reformatting the toxicity profile of cis-DDP and demonstrated the therapeutic efficacy of the PEP455-Pt bioconjugate in F98 glioma-bearing rats.
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Rolf F
RF
Barth
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Gong
G
Wu
Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA.
W Hans
WH
Meisen
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Robin J
RJ
Nakkula
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Weilian
W
Yang
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Tianyao
T
Huo
Department of Pathology, The Ohio State University, Columbus, OH, USA.
David A
DA
Kellough
Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH, USA; Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA.
Pravin
P
Kaumaya
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Claudia
C
Turro
Department of Pathology, Mater Dei Hospital, University of Malta Medical School, Msida, Malta.
Lawrence M
LM
Agius
Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA.
Balveen
B
Kaur
F98EGFR rat glioma; cisplatin; molecular targets; monoclonal antibodies; peptides