Antiproliferative Activity of a Liposomal Delivery System of Mitoxantrone on Rabbit Subconjunctival Fibroblasts in an Ex-Vivo Model

Abstract

Wound healing is the main cause of the failure of filtering surgery in glaucoma. We developed a liposomal delivery system of mitoxantrone (MITX), an anthracyclin derivative, to allow a single adjuvant administration and to lessen ocular side-effects of the drug. In order to evaluate the antiproliferative activity of liposomal MITX, an ex vivo model consisting in the culture of subconjunctival tissue explants from rabbits pretreated with subconjunctival injections of free or liposomal MITX was used. We found that both forms of MITX decreased the growth rate as well as the explant proliferation surfaces 15 days or 1 month after a single administration of the drug in vivo. A morphometric analysis of the cells showed that the surface of the fibroblasts exposed to both forms of MITX was from 10 to 12 times as important as that of the control cells exposed to the empty liposomes and to the control buffer. A radioautographic study showed that more than 95% of the fibroblasts exposed to both forms of MITX were in the G1 phase of the cell cycle, while the control cell population was equally distributed among the different phases of the cell cycle.

Effects of Different Formulations of Mitoxantrone (Solutions, Nanospheres, Liposomes) on Glaucoma Surgery in Rabbits

“…These results were in agreement with the demonstration of the cytotoxic effect of other intercalating agents such as daunorubicin [8], More interestingly, we observed that MTO in liposomes and solu tion exhibited this potent antiproliferative ac tivity towards subconjunctival fibroblasts at 15 days and at 1 month after 1 single injection in the rabbit eye [10]. These results led us to perform an evaluation o f different formula tions of MTO after subconjunctival injections on IOP levels in rabbits prior to and after fil tration surgery.…”

“…These results led us to perform an evaluation o f different formula tions of MTO after subconjunctival injections on IOP levels in rabbits prior to and after fil tration surgery. In contrast to what we ob served ex vivo, when injected 15 days before surgery, MTO in its different formulations did not potentiate in vivo the IOP-lowering effect of surgery [10]. In a previous study.…”

“…Interestingly, we observed corneal edemas in 5/6 animals treated with MTO solution We previously demonstrated that MTO so lution and MTO liposomal dispersion in duced a blockade in subconjunctival fibro blastic proliferation [10]. These results were in agreement with the demonstration of the cytotoxic effect of other intercalating agents such as daunorubicin [8], More interestingly, we observed that MTO in liposomes and solu tion exhibited this potent antiproliferative ac tivity towards subconjunctival fibroblasts at 15 days and at 1 month after 1 single injection in the rabbit eye [10].…”

“…In a previous study, we demonstrated on an ex vivo model that two formulations of MTO (solution and liposomal dispersion) may induce blockade of subcon junctival fibroblastic proliferation 15 days or 1 month after a single subconjunctival injec tion, with no significant differences between the efficacy of the two formulations [10],…”

“…The conjunctival incision was closed with a running Vicryl 7.0 suture. Doses of MTO had been determined previously by measurement of the cytotoxic effect of MTO for subconjunctival fibroblastic proliferation in tissue cultures (ID50:0.8 gg/ml) [10].…”