Surfactant dependent toxicity of lipid nanocapsules in HaCaT cells

Lipid nanocapsules (LNC) have been suggested for a variety of pharmaceutical applications. Among them approaches for drug delivery to the skin appear particularly interesting. The current standard composition has been modified to better understand their properties by selecting a variety of different surfactants. LNC have been prepared using different non-ionic surfactants (Solutol(?) HS15: Polyoxyl 15 Hydroxystearate; Cremophor(?) EL: Polyoxyl 35 Castor Oil; Simulsol(?) 4000: Polyoxyl 40 Hydrogenated Castor Oil; Vitamin E TPGS(?): alpha-tocopheryl poly(ethylene glycol) succinate; Polysorbate 20 and 80) and analysed for their size, stability, drug release and toxicity on keratinocytes in cell culture. The feasibility of LNC using different surfactant was surprisingly easy and led to a variety of stable formulations that were selected for further investigations. Surfactants led to a variability of the release kinetics (t50% release varied from Polysorbate 20: 2.5h to Simulsol(?) 4000: 5.0h), however different formulations from the same surfactant did not differ significantly. In vitro toxicity of LNC was surfactant type dependent and a correlation between LNC and the pure respective surfactant was found. This toxicity was found to be mainly independent from the surface active properties. The surfactant type in LNC is easily interchangeable from formulation point of view. LNC appear to be appropriate as carrier for cutaneous delivery however toxicity can vary distinctly depending on the surfactant used for the preparation.     

Differential Effect of Imatinib and Synergism of Combination Treatment with Chemotherapeutic Agents in Malignant Glioma Cells

Abstract: Imatinib mesylate (STI571, Gleevec^®) is a signal transduction inhibitor and novel anti‐cancer agent. It selectively inhibits aberrantly activated tyrosine kinases in malignant cells, for example, bcr‐abl in leukaemia, platelet‐derived growth factor receptor and stem cell factor receptor (c‐Kit) in solid cancers including malignant glioma. However, recently published clinical studies with imatinib monotherapy in patients with malignant glioma demonstrated only very modest anti‐tumour activity. The aim of this study was to investigate the biological activity of imatinib, its cellular mechanisms of action and its synergism with other chemotherapeutic agents in human malignant glioma cells in culture. Expression of PDGF/R and c‐Kit was analyzed by RT‐PCR. Proliferation was measured by MTT assays and drug synergy was assessed by the Chou–Talalay method. Cell cycle and apoptosis were analyzed by flow cytometry and migration by monolayer migration assays. Multi‐immunoblot was performed on imatinib‐treated and control malignant glioma cells. Results indicate that imatinib is more effective in inhibiting cell colony formation and migration rather than proliferation. Imatinib treatment caused cell cycle arrest of glioma cells in G0–G1 or G2/M, with significant elevation of a few cyclin‐dependent kinases. Furthermore, imatinib acted synergistically with chemotherapy agents, such as the DNA alkylating agent, temozolomide, and riboneucleotide reductase inhibitors, for example, hydroxyurea at varied effective dose levels. In conclusion, imatinib exerts varied biological effects on malignant glioma cells in culture. Synergistic interaction of imatinib with chemotherapy agents may be related to cell cycle control mechanisms and could be potentially important in a clinical setting.     

Improved short-term survival with polyethylene glycol modified hemoglobin liposomes in critical normovolemic anemia

OBJECTIVE: To investigate the efficacy of a polyethylene glycol (PEG) modified formulation of liposome-encapsulated hemoglobin (LEH) as an oxygen-carrying blood substitute in the treatment of critical normovolemic anemia. DESIGN AND SETTING: Prospective, controlled, randomized experimental study in a university research facility. SUBJECTS: 14 anesthetized and mechanically ventilated beagle dogs. INTERVENTIONS: Animals were splenectomized and hemodiluted by exchange of whole blood for iso-oncotic hetastarch (HES). Target parameter of the hemodilution protocol was the individual critical hemoglobin concentration (Hb(crit)) corresponding with the onset of O(2) supply dependency of total body O(2) consumption. At Hb(crit) animals were randomized to receive a bolus infusion (20[Symbol: see text]ml/kg) of either LEH (n[Symbol: see text]=[Symbol: see text]7) or normal saline (NS; n[Symbol: see text]=[Symbol: see text]7). Subsequently animals were observed without further intervention. MEASUREMENTS AND RESULTS: The primary endpoint was survival time after the completion of treatment; secondary endpoints were parameters of central hemodynamics, O(2) transport and tissue oxygenation. Animals in the LEH group survived significantly longer after completion of treatment (149[Symbol: see text]+/-[Symbol: see text]109 vs. 43[Symbol: see text]+/-[Symbol: see text]56[Symbol: see text]min). Immediately after treatment LEH-treated animals presented with a more stable cardiovascular condition. After 30[Symbol: see text]min tissue O(2) tension on the surface of a skeletal muscle was significantly higher in the LEH group (23[Symbol: see text]+/-[Symbol: see text]8 vs. 9[Symbol: see text]+/-[Symbol: see text]2[Symbol: see text]mmHg). Nevertheless, treatment with LEH did not decrease mortality within the observation period. CONCLUSIONS: In this present experimental study the infusion of a PEG-modified LEH provided adequate tissue oxygenation, hemodynamic stability, and a prolongation of survival time after critical anemia. However, these effects were sustained for only a short period of time.