The Effect of Therapy Regimen on Antitumor Efficacy of the Nanosomal Doxorubicin against Rat Glioblastoma 101.8.

One of the key problems of glioblastoma treatment is the low effectiveness of chemotherapeutic drugs. Incorporation of doxorubicin into PLGA nanoparticles allows increasing the antitumor effect of the cytostatics against experimental rat glioblastoma 101.8. Animal survival, tumor volume, and oncogene expression in tumor cells were compared after early (days 2, 5, and 8 after tumor implantation) and late (days 8, 11, and 14) start of the therapy. At late start, a significant increase in the expression of oncogenes Gdnf, Pdgfra, and Melk and genes determining the development of multidrug resistance Abcb1b and Mgmt was revealed. At early start of therapy, only the expression of oncogenes Gdnf, Pdgfra, and Melk was enhanced. Early start of treatment prolonged the survival time and increased tumor growth inhibition by 141.4 and 95.7%, respectively, in comparison with the untreated group; these differences were not observed in the group with late start of therapy. The results indicate that the time of initiation of therapy is a critical parameter affecting the antitumor efficacy of DOX-PLGA.

[Nitric oxide donor nitrosorbide potentiates the antitumor effect of doxorubicin against experimental glioblastoma]. / Donor oksida azota izosorbida dinitrat povyshaet protivoopukholevyi effekt doksorubitsina pri khimioterapii eksperimental'noi glioblastomy.

BACKGROUND: Doxorubicin is a well-known antitumor drug that is not employed for chemotherapy of brain tumors. Indeed, doxorubicin does not penetrate across the blood-brain barrier in therapeutic concentrations. OBJECTIVE: To study the antitumor effect of doxorubicin combined with nitrosorbide on intracranial experimental glioblastoma 101/8 in rats. MATERIAL AND METHODS: Male Wistar rats (n=86) with intracranial implanted glioblastoma 101/8 received doxorubicin (i.v. 1.5 mg/kg thrice) alone or in combination with nitrosorbide (i.v or orally, 0.5 mg/kg thrice) in 2, 5 and 8 days after implantation. Efficacy was assessed considering survival and brain tumor volume in 14 days after tumor implantation. RESULTS: Combination of doxorubicin and nitrosorbide significantly increased survival (57% and 155%, respectively) and slowed down tumor growth (16±12 and 8±6 mm3, respectively) compared to doxorubicin alone. Effectiveness of nitrosorbide alone was trivial. CONCLUSION: Nitric oxide donor nitrosorbide considerably potentiated the antitumor effect of doxorubicin against intracranial 101/8 glioblastoma in rats.

[Toxicological Evaluation of Intravenous Formulation of Rifapentine.]

Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD50 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application.

Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma.

Polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (NP) were shown to enable the transport of a number of drugs including the anti-tumour antibiotic doxorubicin (DOX) across the blood-brain barrier (BBB) to the brain after intravenous administration and to considerably reduce the growth of brain tumours in rats. The objective of the present study was to evaluate the acute toxicity of DOX associated with polysorbate 80-coated NP in healthy rats and to establish a therapeutic dose range for this formulation in rats with intracranially implanted 101/8 glioblastoma. Single intravenous administration of empty poly(butyl cyanoacrylate) NP in the dose range 100-400 mg/kg did not cause mortality within the period of observation. NP also did not affect body weight or weight of internal organs. Association of DOX with poly(butyl cyanoacrylate) NP did not produce significant changes of quantitative parameters of acute toxicity of the anti-tumour agent. Likewise, the presence of polysorbate 80 in the formulations was not associated with changes in toxicity compared with free or nanoparticulate drug. Dose regimen of 3x1.5 mg/kg on days 2, 5, 8 after tumour implantation did not cause drug-induced mortality. The results in tumour-bearing rats were similar to those in healthy rats. These results demonstrate that the toxicity of DOX bound to NP was similar or even lower than that of free DOX.

Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles.

PURPOSE: To investigate the possibility of delivering of anticancer drugs into the brain using colloidal carriers (nanoparticles). METHODS: Rats obtained 5 mg/kg of doxorubicin by i.v. injection in form of 4 preparations: 1. a simple solution in saline, 2. a simple solution in polysorbate 80 1% in saline, 3. bound to poly(butyl cyanoacrylate) nanoparticles, and 4. bound to poly(butyl cyanoacrylate) nanoparticles overcoated with 1% polysorbate 80 (Tween 80). After sacrifice of the animals after 10 min, 1, 2, 4, 6, and 8 hours, the doxorubicin concentrations in plasma, liver, spleen, lungs, kidneys, heart and brain were determined after extraction by HPLC. RESULTS: No significant difference in the body distribution was observed between the two solution formulations. The two nanoparticle formulations very significantly decreased the heart concentrations. High brain concentrations of doxorubicin (>6 microg/g) were achieved with the nanoparticles overcoated with polysorbate 80 between 2 and 4 hours. The brain concentrations observed with the other three preparations were always below the detection limit (< 0.1 microg/g). CONCLUSIONS: The present study demonstrates that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant polysorbate 80. It is highly probable that coated particles reached the brain intact and released the drug after endocytosis by the brain blood vessel endothelial cells.