Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain

Abstract

Treatment of glioblastoma with platinum compounds modestly improves progression-free survival and may cause toxic effects which prevent use at higher dose that would otherwise improve the antineoplastic effect. To reduce toxicity, we propose to encapsulate the platinum drug in a liposome. We have also tested three methods of drug administration (intra-venous, intra-arterial and intra-arterial combined with blood brain barrier disruption) to determine which one optimizes the tumor cell uptake, limits the toxicity and delivers the best concomitance effect with radiotherapy. Cisplatin, oxaliplatin, their respective liposomal formulations, Lipoplatin ™ and Lipoxal ™ , and carboplatin were assessed in F98 glioma, orthotopically implanted in Fischer rats. We found that the modest accumulation of drugs in tumor cells after intra-venous injection was significantly improved when the intra-arterial route was used and further increased after the transient opening of the blood brain barrier with mannitol. The liposomal formulations have largely reduced the toxicity and have allowed a better exploitation of the anti-cancer activity of platinum agent. Although the liposomes Lipoplatin ™ and Lipoxal ™ have shown a similar ability to CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript that of carboplatin, to accumulate in brain tumors, the highest additive effect with radiotherapy was obtained with carboplatin. We conclude that the intra-arterial infusion of carboplatin or Lipoxal ™ in concomitance with radiation therapy leads to the best tumor control as measured by an increase of mean survival time in Fischer rats implanted with the F98 glioma with a benefit in survival time of 13.4 and 6.5 days respectively compared to intra-venous.

Convection-enhancement delivery of platinum-based drugs and LipoplatinTM to optimize the concomitant effect with radiotherapy in F98 glioma rat model

“…The Gamma Knife was chosen because of its high precision to irradiate tumors implanted in rats. Only a single dose of radiation was delivered to rats with the Gamma Knife because it is easier to evaluate the concomitant effect of chemotherapy and radiation with a single dose as well as to compare our previous results [29,30] with those reported in the present study.…”

“…in the same GBM model, as part of another study by our group (Table 5, Fig. S2) [29]. A MeST of 17 days was measured in the group treated with cisplatin injected i.v., whereas it was only 13 days when an i.a.…”

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…2011; Charest et al. 2013). Potential consequences of peripheral neurotoxicity include interference of ion channel function and disruption of primary afferent metabolism, which, upon repeated exposure to oxaliplatin, could lead to persistent axonal degeneration and eventually cell death (Jaggi and Singh 2012; Han and Smith 2013).…”

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…Some formulations demonstrated their ability to improve activity of anticancer drugs in vivo, such as topotecan, 220 irinotecan, 214,230,235,259 arsenic trioxide, 255 cisplatin, 237,240,268 and oxaliplatin, 237 and codelivery of synergistic two-drug combinations 257 …”