Doxorubicin liposomal Doxil

Doxorubicin-liposomal DOXIL (Alza/J J) Kaposi s sarcoma... 

DOXORUBICIN, LIPOSOMAL (Doxil solution for injection equivalent to 2 mg/mL doxorubicin hydrochloride liposomal in single-use 10 or 30 mLvials)... 

For insertion into premade doxorubicin-loaded liposomes (Doxil), mix equal volumes of liposomes and lipidation reaction mixture and incubate at 37°C for 12-16 h (see Note 7). Purification of unreacted lipid and protein is not necessary at this step, because they do not interfere with insertion process and will be removed eventually by gel-filtration of decorated liposomes on Sepharose CL-4B. 

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 (Caelyx/Doxil) and liposomal daunorubicin (DaunoXome) produce lower peak plasma concentrations and longer circulation times than free drug (7). 

Therapentic uses—doxorubicin (Adriamycin, others) is available for intravenous use. The recommended dose is 50 to 75 mg/m, administered as a single rapid intravenous infusion repeated after 21 days. Care should be taken to avoid extravasation as severe local vesicant action and tissue necrosis may resnlt. A doxorubicin liposomal product (Doxil) is available for treatment of AIDS-related Kaposi s sarcoma and is given intravenously in a dose of 20 mg/m over 30 minntes and repeated every 3 weeks. 

Several liposome-based drugs have been approved for clinical application [64]. One of the clinically approved liposomes is Doxil, a PEGylated liposome containing doxorubicin (DOX), which is used for the treatment of a number of diseases [65]. As shown in this case, in the field of liposome drug development, PEG is widely used to protect the liposome from recognition by opsonins, thereby reducing liposome clearance. 

Pegulated liposomal doxorubicin (Doxil) Liposome encapsulated doxorubicin Ovarian Phase II data... 

Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL(R)/CAELYX(R)) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma, a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001 37 870. 

Chanan-Khan A, Szebeni J, Savay S, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil) possible role in hypersensitivity reactions. Ann Oncol 2003 14 1430. 

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. 

Bao A, Goins B, Klipper R, Negrete G, Phillips WT. Direct Tc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies. J Pharmacol Exp Ther 2004 308 419. 

In September 2007, the EMEA approved the use of trabectidin against ovarian cancer (OC) and STS. In November 2009, Yondelis received its second marketing authorization from the European Commission for its administration in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer presently, trabectedin (36) is under Phase II trials for the treatment of paediatric sarcomas as well as breast and prostate cancers. The European Commission and the US Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and... 

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

There are three liposomal forms of doxorubicin or daunorubicin on the market (Table 8.6). Doxil and DaunoXome have been approved for the treatment of AIDS-related Kaposi s sarcoma and are being evaluated in clinical trials for the treatment of a variety of cancers [148-151]. Evacet (liposomal doxorubicin) has recently been tested in large phase II and III clinical trials for the treatment of metastatic breast cancer and is awaiting approval by the FDA [151], Data obtained from trials thus far suggest that all three liposomal drugs offer significant therapeutic benefit compared with the free drug [113]. 

Doxil (doxorubicin HC1 liposome injection, 2 mg/mL) from Ortho Biotech. 

Long circulating liposomes can exploit the EPR effect to accumulate at sites where pathological reactions occur. For example, the commercial product Doxil (marketed as Caelyx in Europe) consists of smallsized PEGylated liposomes, encapsulating the cytostatic doxorubicin. The resulting long circulation times and small size of the vesicles facilitate their accumulation in tumor tissue via the EPR effect. 

Daunorabicin (DaunoXome, Gilead Sciences, Inc.) Doxorubicin (Doxil/Caelyx, Ortho Biotech ProductsLP/Sequus Pharmaceuticals) Amphotericin B (Ambisome/Abelcet, Fujisawa Healthcare, Wyeth Pharmaceuticals) Doxorubicin (Myocet/Evacet, Sopherion/ Liposome Company) Hepatitis A virus envelope proteins (Epaxal, Berna Biotech) Influenza virus (Inflexal V, Berna Biotech) Verteporfin (Visudyne, Novartis Ophthalmics) Kaposi s sarcoma Kaposi s sarcoma Fungal infections in immunocompromised patients Metastatic breast cancer Hepatitis A Influenza Age-related macular degeneration... 

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%. 

A variety of new molecules either in combination with liposomal doxorubicin or not are in development at the moment [457]. For example, a phase III study will be conducted to test the efficacy and safety of pattupilone versus PEG-liposomal DXR in taxane/platinum refractory/resistant patients with recurrent epithelial ovarian, primary fallopian, or primary peritoneal cancer. A phase III randomized study of Telcyta with Doxil/Caelyx versus Doxil/Caelyx has been planned in patients with platinum-refractory or platinum-resistant ovarian cancer. A phase II study relevant to side effects and best dose of ixabepilone combined with liposomal DXR will be assessed in patients with advanced ovarian epithelial, peritoneal cavity, or fallopian tube cancer or metastatic breast cancer. 

Marina, N. M., Cochrane, D., Harney, E., Zomorodi, K., Blaney, S.,Winick, N., Bernstein, M., and Link, M. P. (2002), Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors A pediatric oncology group study, Clin. Cancer Res., 8, 413-418. 

Frenkel, V., Etherington, A., Greene, M., Quijano, J., Xie, J., Hunter, F., Dromi, S., and Li, K. C. P. (2006), Delivery of liposomal doxorubicin (Doxil) in a breast cancer tumor model Investigation of potential enhancement by pulsed-high intensity focused ultrasound exposure, Acad. Radiol., 13,467-479. 

Vineland, NJ) or over-the-counter cosmetic creams promoted for improved hydration (L Oreal, Paris and Dior, Paris). More recently, parenteral liposome formulations of amphotericin B, doxorubicin, and dau-norubicin have been approved and marketed (ABELCET, Elan, the Liposome Co., Inc, Princeton, NJ AmBisome and DaunoXome, Nexstar/Fujisawa, Deerfield Park, IL Amphotec and Doxil, Sequus/ Alza, Menlo Park, CA), with others on the horizon for applications in photodynamic therapy. Although the vast majority of liposome preparations are constructed from phospholipids, other nonphospholipid materials can be used either alone or in mixtures to form bilayer arrays. One such example is Amphotec, which utilizes sodium cholesteryl sulfate as the primary lipid. Other liposome forming materials may include but are not limited to fatty-acid compositions, ionized fatty acids, or fatty acyl amino acids, longchain fatty alcohols plus surfactants, ionized lysophospholipids or combinations, non-ionic or ionic surfactants and amphiphiles, alkyl maltosides, a-tocopherol esters, cholesterol esters, polyoxyethylene alkyl ethers, sorbitan alkyl esters, and polymerized phospholipid compositions. ° ... 

---