Liposomal formulations of carboplatin injected by convection-enhanced delivery increases the median survival time of F98 glioma bearing rats

Abstract

BackgroundEffectiveness of chemotherapy for treating glioblastoma (GBM) brain tumors is hampered by the blood–brain barrier which limits the entry into the brain of most drugs from the blood. To bypass this barrier, convection-enhanced delivery (CED) was proposed to directly inject drugs in tumor. However, the benefit of CED may be hampered when drugs diffuse outside the tumor to then induce neurotoxicity. Encapsulation of drugs into liposome aims at increasing tumor cells specificity and reduces neurotoxicity. However, the most appropriate liposomal formulation to inject drugs into brain tumor by CED still remains to be determined. In this study, four liposomal carboplatin formulations were prepared and tested in vitro on F98 glioma cells and in Fischer rats carrying F98 tumor implanted in the brain. Impact of pegylation on liposomal surface and relevance of positive or negative charge were assessed.ResultsThe cationic non-pegylated (L1) and pegylated (L2) liposomes greatly improved the toxicity of carboplatin in vitro compared to free carboplatin, whereas only a modest improvement and even a reduction of efficiency were measured with the anionic non-pegylated (L3) and the pegylated (L4) liposomes. Conversely, only the L4 liposome significantly increased the median survival time of Fisher rats implanted with the F98 tumor, compared to free carboplatin. Neurotoxicity assays performed with the empty L4′ liposome showed that the lipid components of L4 were not toxic. These results suggest that the positive charge on liposomes L1 and L2, which is known to promote binding to cell membrane, facilitates carboplatin accumulation in cancer cells explaining their higher efficacy in vitro. Conversely, negatively charged and pegylated liposome (L4) seems to diffuse over a larger distance in the tumor, and consequently significantly increased the median survival time of the animals.ConclusionsSelection of the best liposomal formulation based on in vitro studies or animal model can result in contradictory conclusions. The negatively charged and pegylated liposome (L4) which was the less efficient formulation in vitro showed the best therapeutic effect in animal model of GBM. These results support that relevant animal model of GBM must be considered to determine the optimal physicochemical properties of liposomal formulations.

Immunological and Toxicological Considerations for the Design of Liposomes

“…For example, Shi et al showed the median lethal concentration (LC 50 ) using F98 glioma cells was 6.07 µM for empty DPPC-based cationic liposomes while DSPC-based anionic liposomes had an LC 50 > 509 µM. Within an intracranial F98 glioma rat model, carboplatin loaded cationic pegylated liposomes resulted in a median survival time of 29 days, while anionic pegylated liposomes had a median survival of 49.5 days [62]. Similarly, Fan et al showed that cationic liposomes incubated with bone marrow-derived dendritic cells had an LC 50 around 0.2 mg/mL, while ovalbumin-loaded anionic liposomes had an LC 50 > 4 mg/mL [63].…”

Chlorotoxin peptide-functionalized polyethylenimine-entrapped gold nanoparticles for glioma SPECT/CT imaging and radionuclide therapy

“…To meet this challenge, nanoparticle-based platforms have been widely investigated owing to their potential clinical values for the diagnosis and treatment of diseases [7–14]. Nanoplatforms are capable of precise diagnosis, drug delivery, and therapy monitoring through integrating diagnostic and therapeutic functions [15–18].…”

Dendritic cells transduced with glioma-expressed antigen 2 recombinant adenovirus induces specific cytotoxic lymphocyte response and anti-tumor effect in mice

“…Resection, chemo-embolization, surgery ablation and radiotherapy are the most commonly curative treatments in the clinic [22][23][24]. However, the postoperative 2-year recurrence rate remains high and the long-term survival prognosis of patients is still poor [25][26][27].…”