Liposomal doxorubicin formulations

Barenholz Y, Amselem S, Goren D, et al. Stability of liposomal-doxorubicin formulation problems and prospects. Med Res Rev 1993 13 449-491. 

Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004 1663(1-2) 167. 

The method presented is appropriate to produce sterile liposomal doxorubicin formulations with a final concentration of 2 mg/mL doxorubicin, which can be applied not only in vitro but also in vivo. 

This chapter introduces loading via an ammonium sulfate gradient as shown in Fig. 1. It is one of the most common remote loading procedures which is also employed for the commercially available liposomal doxorubicin formulation Caelyx . 

Because of its clinical importance and the expected benefits of the drug in liposomal form for cancer treatment, all three American "liposome enterprises" (i.e.. Liposome Technology Inc., Erbamont, LyphoMed/Vestar joint ventures, and the Liposome Company, Inc.) are developing a formulation of liposomal doxorubicin. Clinical studies already show promising results as far as the acute toxicity is concerned (less vomiting, nausea, and hair loss) (Gabizon et al., 1989 Treat et al., 1989),... 

In addition to the remote or active loading techniques mentioned above, metal complexation reactions have been demonstrated to achieve accumulation of doxorubicin in liposomes [148,149], Furthermore, copper-topotecan complexation has been recently seen to mediate drug accumulation into liposomes and is proposed as a methodology to prepare liposomal camptothecin formulations [72],... 

Liposomal formulations, type of tumor, anticancer agent, delivery pathway, day of treatment, and general conclusions are given in Table 6. DaunoXome (liposomal daunorubicin) and Doxil (liposomal doxorubicin) have been proved to have good response in clinical trials, in the range of approximately 40%. 

Using PEGylated liposomal doxorubicin (Caelyx), Keller et al. [427] compared the efficacy of the liposomal formulation with that of a common regimen in patients with taxane-refractory advanced breast cancer. The regimen scheme was Caelyx (50 mg/m2 every 28 weeks) or vinorelbine (30 mg/m2) or mitomycin C (10 mg/m2 every 28 days) plus vinblastine (5mg/m2 at days 1,14, 28, 42). Finally, progression free survival and overall survival were similar for Caelyx and the comparative regimen. 

Sterically stabilized liposomal doxorubicin (pegylated liposomal doxorubicin Caelyx/Doxil) is coated with polyethylene glycol (3), which results in so-called stealth liposomes. In liposomal daunorubicin the liposome consists of a lipid bilayer of distearoylphosphati-dylcholine and cholesterol in a 2 1 molar ratio (4). Both formulations have a hydrophilic outer layer, which attracts a coating of water around the liposomal shell. This increases the circulation time by making the formulation virtually invisible to the reticuloendothelial system. 

PEGylated liposomal doxorubicin (DOXIL /Caelyx ) was the first and is still the only stealth liposome formulation to be approved in both USA and Europe for treatment of Kaposi s sarcoma (67) and recurrent ovarian cancer (68, 69). Currently, (DOXIL /Caelyx ) is undergoing trials for treatment of other malignancies such as multiple myelomas (70), breast cancer (71, 72), and recurrent high-grade glioma (73). 

Beyer, U., Rothen-Rutishauser, B., Unger, C., Wunderli-Allenspach, H., Kratz, F., Differences in the intracellular distribution of acid-sensitive doxorubicin-protein conjugates in comparison to free and liposomal formulated doxorubicin as shown by confocal microscopy. Pharm Res 18, 29-38 (2001). 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

Recently, this method was adapted to label two commercially available liposomal formulations doxorubicin encapsulated in polyethylene glycol (PEG)-coated liposomes (Caelyx /Doxil ) (14) and daunorubicin encapsulated in small distearoyl-phosphatidyl-choline/cholesterol liposomes (Daunoxome ) (15). Although no DTPA was encapsulated in these liposomes, the labeling efficiency was typically between 70% and 80% and the radiolabeled preparations were stable in vivo during the time course of the experiment (four hours). Most likely, the lipophilic In-oxine avidly associates with the lipid bilayer and encapsulation of DTPA might not be necessary when the experimental observation period does not exceed four to six hours. 

Also known as Doxil PEG-coated liposome formulation with doxorubicin. 

Phosphatidylcholine/cholesterol liposomal formulation with doxorubicin. 

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