Design, synthesis, and evaluation of cisplatin-containing EGFR targeting bioconjugates as potential therapeutic agents for brain tumors

Abstract

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.

Preparation and characterization of Fe3O4@Au-C225 composite targeted nanoparticles for MRI of human glioma

“…C225 can inhibit the progression of the cell cycle from the G1 stage to S stage, induce apoptosis of tumor cells, inhibit tumor angiogenesis and inhibit the invasion and metastasis of tumors by a variety of activators [ 17 ]. Increased antitumor effects of cytotoxic drugs and restored sensitivity of resistant cells were observed when C225 was combined with antitumor drug [ 18 ]. C225 can prevent radiation injuries of tumor cells.…”

EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise

“…A recent clinical trial established the safety of selective osmotic blood–brain barrier opening with intra-arterial mannitol infusion followed by intra-arterial infusion of cetuximab [ 52 ]. Other cetuximab-based developments include the boronation of the EGFR with antibodies [ 53 ] or later the construction of conjugates with cytotoxic platinum derivatives [ 54 ]. The boronated cetuximab compounds that were used in experimental boron neutron capture radiation therapy were found to be largely ineffective and the cetuximab-based bio-conjugates used with platinum compounds were also very limited in their efficacy.…”

Convection-enhanced drug delivery for glioblastoma: A systematic review focused on methodological differences in the use of the convection-enhanced delivery method

“…Several studies investigated specific receptor targeting such as insulin-like growth factor receptor and epidermal growth factor receptor. [ 23 40 ] Only a few of the studies mentioned specific properties of the molecules they used, such as drug charge, hydrophilicity, or tissue affinity, although these properties influence the effective distribution of drugs in the brain by CED. [ 48 ]…”