Evaluation of nanoparticle delivered cisplatin in beagles.

Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg(-1) or 2 mg kg(-1) or 2.2 mg kg(-1) (with respect to Platin-M) of T-Platin-M-NPs. At all doses over the 14-day period, no neurotoxicity was observed based upon periodic neurological examinations and cerebrospinal fluid analysis. These studies demonstrated the translational nature of T-Platin-M-NPs for applications in the treatment of brain tumors.

Ototoxicity of carboplatin delivered locally in a monkey brainstem.

Ototoxicity is a common side effect of platinum-based chemotherapy. Intratumoral drug delivery theoretically could reduce the ototoxic effects of systemic drug infusions. However, local delivery to central nervous system (CNS) tumors might promote ototoxicity through drug release into cerebrospinal fluid (CSF). This report describes an examination of the cytoarchitecture of vestibular cells of cynomolgus monkeys that had chronic brainstem infusions with the maximum tolerated dose (MTD) of carboplatin. The brainstems of adult monkeys were infused for 30 days at 0.42 mu l/h with 0.025 to 0.25 mg/kg (MTD) of carboplatin. The vestibular sensory epithelia of eight drug-treated animals were isolated for microscopic examination of vestibular hair cells and support cells. Local infusions produced chronic elevated CSF levels of platinum, neurological symptoms, and radiographic evidence of pontine injury. Histology revealed significant cell damage at the infusion sites. Microscopic examinations of vestibular support cells and hair cells demonstrate a small reduction in cell counts in the drug-treated monkeys compared to a noninfused control animal. Parametric and nonparametric tests show no effect of dose in predicting the vestibular cell counts. In this single study of eight monkeys, a dose-dependent reduction of vestibular hair cells or support cells was not observed in animals infused with brainstem infusions of 0.025 to 0.25 mg/kg of carboplatin.

Toxicity and cerebrospinal fluid levels of carboplatin chronically infused into the brainstem of a primate.

PURPOSE: Carboplatin was infused into the brainstem of cynomolgus monkeys to investigate neurotoxicity and systemic exposures following chronic local delivery. METHODS: Infusions at 0.42 microl/h were intended to deliver 0.025 (n = 2), 0.075 (n = 3), 0.25 (n = 5), and 0.75 (n = 3) mg/kg by day 30. Laboratory tests, radiographic measurements, and clinical observations were used to monitor toxicity. Blood and cerebrospinal fluid (CSF) were sampled for platinum. RESULTS: Lethargy and ataxia were observed after week 4 in the monkeys given 0.075 mg/kg, and week 2 in the monkeys given 0.25 mg/kg when the infused doses were approximately 250 and 400 microg, respectively. Rapidly progressive neurotoxicity with the 0.75 mg/kg dose required termination of the infusions at days 4-10. Hematology and chemistry values were unremarkable in all groups. Blood levels of platinum remained undetectable in 0.025 and 0.075 mg/kg dose groups. Levels in the 0.25 mg/kg group were 3.1 +/- 0.6 microg/l at 2 weeks and 5.2 +/- 0.8 microg/l at 1 month. The CSF platinum levels varied. Animals in the 0.25 mg/kg group had higher CSF levels at 2 weeks (avg. 65 microg/l, range 36-89) compared to their 1 month value (avg. 60 microg/l, range 7-170), despite the constant infusion. CONCLUSION: Carboplatin can be chronically infused into monkey brainstems. Neurotoxicity is the predominant side effect and is dose-dependent. Pharmacokinetics of local and systemic delivery are different for carboplatin. Further studies are needed to monitor toxicity at higher flow rates and to investigate drug binding to abnormal central nervous system (CNS) tissues.

Cerebrospinal fluid content of manganese, platinum, and strontium in patients with cerebral tumors, leukemia, and other noncerebral neoplasms.

Electrothermal atomic absorption spectrophotometry was employed to measure the concentrations of manganese, platinum, and strontium in the cerebrospinal fluid (CSF) of 47 patients with brain neoplasms (34 benign and 13 malignant), 17 leukemic patients, 10 patients with lymphoma or non-cerebral solid tumors, and 27 control patients. According to the data obtained, manganese appears to be significantly (p less than 0.015) depleted from the CSF of leukemic patients, whereas platinum is diminished in CSF of patients with brain tumors, leukemia, lymphoma, or noncerebral solid tumors; the ratios for the mean CSF concentration of platinum in these tumor patients/control patients ranged between 0.52 and 0.7. There was no significant difference in CSF concentrations of strontium among the groups examined.

Peak cerebrospinal fluid platinum levels in a patient with ependymoma: evaluation of two different methods of cisplatin administration.

Peak CSF and serum platinum levels were examined in a patient with ependymoma after each of four consecutive cisplatin doses of 100 mg/m2 administered by either 30-minute or 3-hour infusion. Both infusion lengths produced similar peak CSF platinum levels within 2 hours after the completion. Ultrafiltrate serum platinum levels correlated with the CSF platinum levels, whereas total plasma platinum did not. No differences in clinical toxicity or response were seen between the two methods of administration. Based on these preliminary results, similar peak CSF platinum concentrations are achieved by 30-minute or 3-hour infusions, and ultrafiltrate serum platinum concentrations can be used to predict these levels.

Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma.

Ultrafiltrate and total plasma and cerebrospinal fluid (CSF) platinum concentrations were examined in a patient with neuroblastoma following a 2-hour infusion of 120 mg/m2 of cisplatin. Total plasma platinum was 93.4% bound, while the ultrafiltrate of plasma accounted for the remaining 6.6%. The CSF ultrafiltrate resulted in equivalent concentrations of platinum to total CSF platinum. CSF concentrations were 2.9% of the total plasma platinum and 43.5% of the ultrafiltrate plasma platinum 2 hours after the end of the infusion.

Seizures and transient cortical blindness associated with cis-platinum (II) diamminedichloride (PDD) therapy in a thirty-year-old man.

Cis-Platinum is a phase II chemotherapeutic agent effective against a variety of tumors. Known toxic effects include gastrointestinal, renal, audiologic, and hematologic as well as idiosyncratic and atopic. A 30-year-old male who was treated with cis-Platinum diamminedichloride II for disseminated embryonal cell carcinoma of the testicle developed seizures and cortical blindness.