In order to examine the efficacy of paclitaxel (Taxol, Bristol-Myers Squibb) after administration locally at the tumor site, we have developed a thermo-reversible gelling formulation in poloxamer 407 (Pluronic F-127) solution. Paclitaxel was incorporated in poloxamer 407 [20% (w/w)] at 0.5- and 1.0-mg/mL concentrations. The in vitro release studies were carried out in phosphate-buffered saline (pH 7.4) at 37 degrees C. Control and paclitaxel-poloxamer 407 formulations were administered intratumorally at a dose of 20 mg/kg in B16F1 melanoma-bearing mice. The change in tumor volume as a function of time and the survival of treated animals were used as measures of efficacy. Poloxamer 407 solution undergoes a reversible sol-gel transition when the temperature is raised to above 21 degrees C. In vitro paclitaxel release from poloxamer 407 gels was very slow (only 6.1% after 6 hr) probably due to the poor aqueous solubility of the drug. Significant enhancement in the anti-tumor efficacy was noted following intratumoral administration of paclitaxel-poloxamer 407 formulation. The initial tumor growth rate was delayed by 67% and the tumor volume doubling time was increased by 72% relative to saline control. In addition, more than 91% of the tumor-bearing animals that received paclitaxel in poloxamer 407 gel survived on day 15 post-administration as compared to 58% in the control group. The results of this study show significant benefit of paclitaxel for solid tumor when administered locally in an in situ gelling poloxamer 407 formulation.
ABSTRACT:In order to develop blood compatible membranes with controlled porosity, we have fabricated and examined the properties of physical interpenetrating network (PIN) of chitosan and poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO/PPO/ PEO) triblock copolymers (Pluronics ). Degree of equilibrium swelling, scanning electron microscopy, and electron spectroscopy for chemical analysis (ESCA) were used to characterize the bulk and surface properties. Vitamin B 12 and human serum albumin were used as permeability markers. Platelet adhesion and activation were used to determine the blood-interaction properties of the PIN membranes. Unlike chitosan membranes that were nonporous, the chitosan-Pluronic PIN membranes were highly porous with the pore size, depending on the type of incorporated Pluronic polyol. ESCA results showed a significant increase in the OCOOO signal of C1s spectra on the PIN membranes that correlates with the presence of PEO chains on the surface. The permeability coefficients of vitamin B 12 and albumin were higher in the chitosan-Pluronic PIN membranes than in the control. The number of adherent platelets and the extent of activation were significantly reduced on the chitosan-Pluronic PIN membranes. The decrease in platelet adhesion and activation correlated positively with the PEO chain length of the incorporated Pluronic polyols. The results of this study show that chitosan-Pluronic PIN membranes offer a blood-compatible alternative with a higher-molecular-weight cutoff for use in hemodialysis and related applications.
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