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

Abstract

The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin ™ -liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9-to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CEDbased chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later.

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

“…27 F98 cells (10,000 cells in 5 µL) were prepared and implanted into the right caudate nucleus (1 mm anterior, 3 mm right of the bregma, and 6 mm deep) of the brain in 5 min. The convection-enhanced delivery (CED) procedure 28 was performed 10 days after implantation of F98 cells, at the same injection site using a 33 gauge Hamilton syringe. Before infusion, the burr was filled with bone wax and the needle was inserted 6.5 mm deep, retained there for 5 min and then withdrawn to 6 mm.…”

“…For this reason, we choose to assess Cu(DDC) 2 (prepared in DSPC/Chol liposomes) in an orthotopic F98 (rat glioblastoma) model, where treatment was administered directly into the site of tumor inoculation by CED. 28 The glioblastoma line was of interest because previous publications suggested that DSF and its metabolite DDC in the presence ) were inoculated subcutaneously into rag-2M mice and the tumors were treated intravenously with vehicle (sh buffer, ), coppercontaining liposomes (1.3 mg/kg, ) or cu(DDc) 2 (8 mg/kg, ) formulated in DsPc/chol liposomes using a M, W, F ×2 dosing schedule. Tumor volumes were measured 3 times a week and are plotted as mean ± standard error of the man (up to 9 mice per group).…”

“…The difference between the MST of those animals treated with the controls and Cu(DDC) 2 was statistically significant (P,0.05) and comparable to previous studies demonstrating a 11.3% increase in MST when the F98 glioblastoma model rats were treated with lipoplatin (a liposomal formulation of cisplatin). 28 enhancing the circulation longevity of cu(DDc) 2 Although the results presented thus far suggest that the Cu(DDC) 2 formulation prepared in DSPC/Chol liposomes is therapeutically active, a significant advantage of the technology used here to create the first injectable Cu(DDC) 2 formulation is that the synthesis reaction to form Cu(DDC) 2 can be completed in liposomes of different lipid compositions and the environment within the liposome can be controlled. As it is possible that the efficacy of Cu(DDC) 2 may be enhanced through strategies that enhance its circulation lifetime, a number of strategies were pursued to gain an understanding of the factors influencing Cu(DDC) 2 retention in the liposomes.…”

Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model

“…Ten days after the implantation of F98 cells, CED procedure was performed with a 33 Ga Hamilton syringe (Hamilton Company, Reno, NV). Oxaliplatin and Lipoxal™ infusions were initiated at the same position as the F98 cell implantation, and done at a rate of 0.5 μl/min for 20 min [25]. Before and after infusion, the needle was maintained in a stationary position for 5 min and finally slowly withdrawn during 6 min.…”

Commentary: Current status of intratumoral therapy for glioblastoma

“…For example, platinum drugs were previously abandoned for treatment of glioma due to their poor passage across the blood-CNS barrier, but are now being re-explored for localized delivery. Adding to the fact that they are not a substrate for principle efflux transporters in the brain, the inability of these agents to cross the blood-CNS barrier may now prove to be an advantage in prolonging the half-life and therapeutic effect of the drug [11][12][13] . Gliadel wafers, a carmustine-imbedded polyanhydride copolymer matrix implant, have perhaps been the most successful localized therapy and are FDA approved for newly diagnosed and recurrent glioblastoma, modestly extending overall survival of both groups 14 .…”