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Toxicity of a particulate formulation for the intraperitoneal application of mitoxantrone
C P Luftensteiner1, I Schwendenwein, H G Eichler
1Institute of Pharmaceutical Technology, University of Vienna, Althanstrasse 14, A-1090, Vienna, Austria.
Abstract:
Mitoxantrone (MXN) has demonstrated therapeutic efficacy in the intraperitoneal treatment of malignancies. However, severe local toxicity is dose limiting. Therefore, a particulate formulation of MXN, the drug incorporated in albumin microspheres, was evaluated concerning tolerability. Survival rates as well as alterations in body weight, food intake, water intake, urine volume, urine specific gravity, urine protein content, and complete blood count were observed following single or multiple intraperitoneal injections of MXN solution, dispersions containing MXN-loaded microspheres or unloaded microspheres, and the injection vehicle to female and male Sprague-Dawley rats. Applied MXN dosage was equivalent to 30 mg/m2 body surface area. Unloaded microspheres were well tolerated without signs of toxicity. Application of MXN solution or MXN-loaded microspheres resulted in similar survival rates (56% 9 weeks after single injection) and in a comparable bone marrow toxicity (mainly leucopenia). Body weight, food and water intake as well as urine volume were decreased following application of MXN solution, whereas a progressive gain in weight and no remarkable alterations in nutrition and urine excretion were noted after administration of MXN-loaded and unloaded microspheres, or of the injection vehicle. In conclusion, intraperitoneal injection of MXN incorporated in albumin microspheres exhibits in part less toxicity than conventional treatment.
Insights
Albumin microspheres reduce the local toxicity of mitoxantrone (MXN) in intraperitoneal cancer treatment. This formulation improved tolerability and reduced side effects compared to standard MXN injections.
Area of Science:
- Oncology
- Pharmacology
- Biomaterials
Background:
- Mitoxantrone (MXN) is effective for intraperitoneal cancer treatment.
- Severe local toxicity limits MXN dosage.
- Albumin microspheres offer a potential solution for targeted drug delivery.
Purpose of the Study:
- To evaluate the tolerability of MXN-loaded albumin microspheres for intraperitoneal administration.
- To compare the toxicity profile of microsphere-based MXN delivery with conventional MXN solution.
- To assess the impact on survival rates and physiological parameters in rats.
Main Methods:
- Female and male Sprague-Dawley rats received single or multiple intraperitoneal injections.
- Formulations included MXN solution, MXN-loaded albumin microspheres, unloaded microspheres, and vehicle.
- Dosage was standardized to 30 mg/m2 body surface area.
- Parameters monitored: survival, body weight, food/water intake, urine output, and complete blood count.
Main Results:
- Unloaded microspheres showed no toxicity.
- MXN-loaded microspheres and MXN solution yielded similar survival rates (56% at 9 weeks) and bone marrow toxicity (leukopenia).
- MXN solution caused decreased body weight and altered intake/excretion; microspheres mitigated these effects.
Conclusions:
- Intraperitoneal administration of MXN in albumin microspheres demonstrates reduced local toxicity compared to MXN solution.
- Albumin microspheres represent a promising strategy for improving the tolerability of intraperitoneal mitoxantrone therapy.
- This formulation may enhance therapeutic outcomes by mitigating dose-limiting toxicities.