Novel pegylated liposomal formulation of docetaxel with 3-n-pentadecylphenol derivative for cancer therapy.

The taxanes are commonly used in the treatment of many types of cancer. The disadvantages of using taxanes in therapy are their low solubility in water, the toxicity or relatively poor pharmacokinetics of existing formulations. Using liposomes as carriers would help in overcoming these problems, however, their use is limited by the low incorporation efficiency of taxane molecules within bilayer and by subsequent drug crystallization. Most of published taxanes liposomal formulations use natural soy phosphatidylcholine (PC) as main liposomes lipid. This allows a relatively good drug retention during the liposomes storage, but on the other hand, the use of liposomes with more liquid bilayer facilitates fast drug release after its intravenous administration. In order to decrease the drug release from liposomes in circulation, we used pegylated HSPC (hydrogenated soy PC) liposomes containing a novel synthetic 3-n-pentadecylphenol derivative - KW101, that showed a remarkably stabilizing action for the docetaxel (DTX) dopped HSPC liposomes over 30 days, expressed by the inhibition of DTX crystallization. The resulting liposomes with DTX showed similar cytotoxicity on MCF-7 and MDA-MB-231 breast cancer cell lines and higher toxicity in drug-resistant NCI/ADR-RES cell line in comparison with the free DTX. Moreover, this formulation has good pharmacokinetics in mice, in comparison to control pegylated DTX formulation composed of egg phosphatidylcholine (ePC). This novel liposomal formulation of docetaxel consisting of HSPC with the stabilizing compound KW101, appears to be a promising carrier for DTX cancer therapy.

Efficient human breast cancer xenograft regression after a single treatment with a novel liposomal formulation of epirubicin prepared using the EDTA ion gradient method.

Liposomes act as efficient drug carriers. Recently, epirubicin (EPI) formulation was developed using a novel EDTA ion gradient method for drug encapsulation. This formulation displayed very good stability and drug retention in vitro in a two-year long-term stability experiment. The cryo-TEM images show drug precipitate structures different than ones formed with ammonium sulfate method, which is usually used to encapsulate anthracyclines. Its pharmacokinetic properties and its efficacy in the human breast MDA-MB-231 cancer xenograft model were also determined. The liposomal EPI formulation is eliminated slowly with an AUC of 7.6487, while the free drug has an AUC of only 0.0097. The formulation also had a much higher overall antitumor efficacy than the free drug.

Reduced uptake of liposomal idarubicin in the perfused rat heart.

Although idarubicin is one of the most important anthracyclines and liposomal formulations seemed less cardiotoxic than free drug formulations, there are no definite data on cardiac uptake of liposomal encapsulated idarubicin. This study has been designed to determine uptake and negative inotropic action of liposomal idarubicin in the single-pass isolated perfused rat heart. Idarubicin-bearing liposomes, composed of 1,2-distearoyl-sn-glicero-phosphocholine, 1,2-distearoyl-sn-glicero-phosphoethanolamine-N-[poly(ethylene glycol)2000], and cholesterol were administered as a 10-min constant infusion of 1 mg followed by a 70-min washout period. Outflow concentration and left ventricular-developed pressure were measured and compared with data of free idarubicin observed previously under the same experimental conditions. Liposomal encapsulation significantly reduced cardiac uptake of idarubicin to about 15% and extensively diminished its negative inotropic action to less than 5% of the values observed for free idarubicin.

Pharmacokinetics of liposomes designed to carry glucocorticoids.

Over the past decade, particulate drug formulations have been successfully employed to reduce undesired side effects and improve drug biodistribution. Despite numerous experimental data, there are relatively few theoretical studies regarding the pharmacokinetics of such formulations. A quantitative pharmacokinetic description of particulate drug forms requires serious adjustments in existing theoretical approaches, due to formulation size. Thus, blood vessel permeabilization and the immunological system need to be accounted for. In this paper, we present a pharmacokinetic model intended to describe the distribution of glucocorticoid (prednisolone phosphate) encapsulated in long-circulated liposomes and its qualitative analysis. In order to achieve qualitative and quantitative agreement with experimental patterns of time-dependent liposome concentration changes in blood, liver and spleen, the existence of two hypothetical liposome populations was assumed. The two populations differ in their accumulation capacities, dosage and time constants. The first population is accumulated in the liver with a time constant of 50 s(-1) and a saturation level of 0.005 micromol/animal, whereas the second with 0.003 s(-1) and 50 micromol/animal, respectively. Such liposome parameterization results from the theoretical model used, however, it may have a physiological foundation. If the two opsonin and/or macrophage types that interact with the liposomes are assumed to have different characteristics, then the pharmacokinetic data obtained experimentally in an animal model can be described correctly.