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Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil or Caelyx) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20-30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi's sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m(2) is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1-3 hours and a second phase with a half-life of 30-90 hours. The AUC after a dose of 50 mg/m(2) is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.

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A new method is described for the preparation of homogeneously sized, single-lamellar phospholipid vesicles. This method, wich is based on differential high-speed ultracentrifugation, has the advantages of a higher vesicle yield without dilution and rapidity of preparation when compared to the molecular-sieve technique. The homogeneity of vesicle dispersions, prepared by this new method, is examined by several physical techniques and found to be comparable to the best samples prepared by molecular-sieve chromatography.

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The fluorescence deplorarization associated with the hydrophobic fluorescent probe 1,6-diphenyl-1,3,5-hexatriene is used to monitor changes in fluidity accompanying the gel-liquid crystalline phase transition in phosphatidylcholine dispersions. In this way, the parameters of the phase transition are determined for both large, multilamellar liposomes and small, single-lamellar vesicles composed of three mixtures of phosphatidycholines: dimyristoyl-dipalmitoyl, dimyristoyl-distearoyl, and dioleyl-dipalmitoyl. Phase diagrams for these mixed-lipid vesicles are constructed by plotting the delimiting temperatures of the phase transition vs. the lipid compostion of the vesicle. The phase diagrams are interpreted to suggest that the miscibilities of the lipids studied are markedly different in small, single-lamellar vesicles and large multilamellar liposomes. These results are discussed in terms of the effects of high curvature on the structure of biological membranes.