Biomedical subjects

N L Boman

Publications and source records attributed to N L Boman.

7 recordsLinked to original sources

PubMed1998

Antibacterial efficacy against an in vivo Salmonella typhimurium infection model and pharmacokinetics of a liposomal ciprofloxacin formulation.

The fluoroquinolone antibiotic ciprofloxacin has been encapsulated into large unilamellar vesicles (LUV) at efficiencies approaching 100%. Drug accumulation proceeded in response to a transmembrane gradient of methylammonium sulfate and occurred concomitantly with the efflux of methylamine. A mechanism for the encapsulation process is described. LUV composed of dipalmitoylphosphatidylcholine-cholesterol (DPPC/chol), distearoylphosphatidylcholine-cholesterol (DSPC/chol), or sphingomyelin-cholesterol (SM/chol) increased the circulation lifetime of ciprofloxacin after intravenous (i.v.) administration by > 15-fold. The retention of ciprofloxacin in liposomes in the circulation decreased in the sequence SM/chol > DSPC/chol > DPPC/chol. Increased circulation lifetimes were associated with enhanced delivery of the drug to the livers, spleens, kidneys, and lungs of mice. Encapsulation of ciprofloxacin also conferred significant increases in the longevity of the drug in the plasma after intraperitoneal administration and in the lungs after intratracheal administration in comparison to free ciprofloxacin. The efficacy of a single i.v. administration of an SM/chol formulation of ciprofloxacin was measured in a Salmonella typhimurium infection model. At 20 mg of ciprofloxacin per kg of body weight, the encapsulated formulation resulted in 10(3)- to 10(4)-fold fewer viable bacteria in the livers and spleens of infected mice than was observed for animals treated with free ciprofloxacin. These results show the utility of liposomal encapsulation of ciprofloxacin in improving the pharmacokinetics, biodistribution, and antibacterial efficacy of the antibiotic. In addition, these formulations are well suited for i.v., intraperitoneal, and intratracheal or aerosol administration.

Animals↗

PubMed1996

Vincristine-induced dermal toxicity is significantly reduced when the drug is given in liposomes.

A problem associated with the intravenous delivery of vincristine concerns drug extravasation at the site of injection or infusion. This can result in extensive local soft-tissue damage. A new formulation of vincristine has recently been developed based on encapsulation of the drug in liposomes. The liposomal drug is somewhat less toxic and substantially more efficacious than free drug. The studies described here assessed, using a murine model of drug extravasation, whether vincristine encapsulation in liposomes influences drug-induced dermal toxicity. It was shown that subcutaneous injection of vincristine in liposomes does not result in the gross skin necrosis and ulceration observed following injection of free drug. Histological analysis of the dermal tissue surrounding the injection site suggests that free drug induces a pronounced inflammatory reaction as judged by the presence of infiltrating leukocytes. In contrast, the liposomal formulation of vincristine engenders a mild prolonged inflammatory condition. These toxicological studies were correlated with an evaluation of drug retention at the site of administration. It was shown using radiolabelled vincristine as a drug marker, that free vincristine is rapidly eliminated from the injection site. In contrast, the level of drug at the site of injection was far greater when the drug was given in liposomal form.

Animals↗

PubMed1996

Liposomal doxorubicin.

Doxorubicin is a potent antineoplastic agent with activity against numerous human cancers. Encapsulation of doxorubicin inside a liposome alters bioavailability, biodistribution and thus its biological activity significantly. The physical properties of the liposome (size, lipid components and lipid dose) play a major role in determining drug retention and pharmacokinetics. The therapeutic benefits of liposomal doxorubicin will therefore depend on these physical characteristics. Here we review the toxicity and efficacy of liposomal doxorubicin determined for various liposome compositions (size, lipid composition and drug-to-lipid ratio). These physical properties can be independently varied using the transmembrane pH gradient-dependent drug encapsulation procedure. The results show that the toxicity of the formulation is related to drug retention in the circulation. The antitumor activity is more sensitive to the size of the liposomes. By optimizing these parameters, liposomal doxorubicin formulations can be optimized for improved therapeutic activity.

Antibiotics, Antineoplastic↗

PubMed1995

Pharmacology of liposomal vincristine in mice bearing L1210 ascitic and B16/BL6 solid tumours.

Vincristine pharmacokinetic, tumour uptake and therapeutic characteristics were investigated here in order to elucidate the processes underlying the enhanced efficacy observed for vincristine entrapped in small (120 nm) distearoylphosphatidylcholine/cholesterol liposomes. Plasma vincristine levels after intravenous (i.v.) injection are elevated more than 100-fold in the liposomal formulation compared with free drug in tumour-bearing as well as non-tumour-bearing mice over 24 h. Biodistribution studies demonstrate that the extent and duration of tumour exposure to vincristine is dramatically improved when the drug is administered i.v. in liposomal form. Specifically, 72 h trapezoidal area under the curve values for liposomal vincristine in the murine L1210 ascitic and B16/BL6 solid tumours are 12.9- to 4.1-fold larger, respectively, than observed for free drug. Similar to previous results with the L1210 model, increased drug delivery to the B16 tumour results in significant inhibition of tumour growth, whereas no anti-tumour activity is observed with free vincristine. Comparisons of drug and liposomal lipid accumulation in tumour and muscle tissue indicate that the enhanced efficacy of liposomal vincristine is related predominantly to drug delivered by liposomes to the tumour site rather than drug released from liposomes in the circulation. Consequently, improvements in liposomal vincristine formulations must focus on factors that increase uptake of liposomes into tumour sites as well as enhance liposomal drug retention in the circulation.

Animals↗

PubMed1994

Liposomal vincristine which exhibits increased drug retention and increased circulation longevity cures mice bearing P388 tumors.

Prolonged exposure to vincristine correlates with improved therapeutic activity. In this work, two methods are used to increase the circulation longevity of liposomal formulations of vincristine. The first involves incorporation of the ganglioside GM1, which acts to increase the circulation longevity of liposomal carriers, while the second approach relies on a modification of the vincristine encapsulation procedure which enhances drug retention. It is shown that these approaches are synergistic and increase the circulation half-life of vincristine from approximately 1 h to greater than 12 h. This results in a dramatic improvement in the therapeutic activity of liposomal vincristine as measured using a murine P388 lymphocytic leukemia model. At doses above 2 mg/kg, the optimized liposomal vincristine formulation cures greater than 50% of mice bearing the P388 tumor, whereas free vincristine results in no cures.

Animals↗

PubMed1993

Optimization of the retention properties of vincristine in liposomal systems.

The influence of lipid composition, internal pH and internal buffering capacity on the retention properties of vincristine loaded into large unilamellar vesicle (LUV) systems in response to transmembrane pH gradients has been assessed. It is shown that increasing the (saturated) acyl chain length of the phosphatidylcholine molecule, increasing the internal buffering capacity, and decreasing the internal pH all result in increased drug retention. Further, a study of the pH dependence on the rates of accumulation indicate that uptake proceeds via the neutral form of the vincristine molecule. This uptake is associated with an activation energy of 37 kcal/mol for DSPC/Chol LUVs. It is shown that the major improvement in drug retention in vitro is achieved by employing low initial internal pH values, where 90% retention is obtained over 24 h for an initial internal pH of 2. Improved retention in vivo was also observed where a drug-to-lipid ratio approx. 4-fold greater at 24 h was maintained.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1993

Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia.

The influence of vesicle lipid composition, size and drug-to-lipid ratio on the antitumour activity of liposomal vincristine was assessed in the murine L1210 ascitic leukemia model. A pH gradient-dependent entrapment procedure was used to encapsulate vincristine and allowed such vesicle properties to be independently varied. Free vincristine delivered i.v. at the maximum tolerated dose (2.0 mg/kg) resulted in a 27.8% increase in the life span (ILS) of mice inoculated i.p. with L1210 cells. Encapsulation of the drug in egg phosphatidylcholine/cholesterol vesicles did not significantly increase the antitumour efficacy of vincristine (ILS, 38.9%). In contrast, administration of vincristine entrapped in vesicles composed of distearoylphosphatidylcholine (DSPC)/cholesterol resulted in ILS values as high as 133%. This enhanced antitumour activity of the DSPC/cholesterol formulations was sensitive to the size of the liposomes; increasing the vesicle size from 100 nm to 1 micron decreased the ILS from 133.3% to 55.6% at a drug dose of 2.0 mg/kg. Decreasing the drug-to-lipid ratio from 0.1:1 to 0.05:1 (w/w) had negligible effects on the activity of liposomal vincristine; however, a further decrease in the drug-to-lipid ratio to 0.01:1 (w/w) decreased the antitumour potency at all drug doses studied. Pharmacology studies indicated that the antitumour activities of free and various liposomal forms of vincristine correlated well with the residence time of the drug in the circulation. These studies indicate that efforts to enhance the therapeutic activity of vincristine through liposome encapsulation must address not only the circulation lifetime of the vesicle systems but also the capacity of the liposomes to retain entrapped drug in vivo.

Animals↗