PEGylated-liposomes

Liposomal encapsulation of DOX or DNR Preferred anthracycline delivery to the tumor Breast cancer, ovarian cancer, AIDS-related Kaposi s sarcoma, multiple myeloma (pegylated liposomal DOX). Breast cancer (uncoated liposomal DOX). AIDS-related Kaposi s sarcoma, acute mye-loblastic leukemia, multiple myeloma, non-Hodgkin s lymphomas (uncoated liposomal DNR)... 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

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. 

Fig. 11 Methods for the construction of PEGylated liposomes, (a) Liposomes possessing reactive groups, such as amino and carboxyl groups, can be prepared by incorporating lipophilic components containing these functional groups into a bilayer membrane. Functionalized liposomes can be PEGylated by reaction with activated PEG derivatives, (b) Preparation of PEGylated liposomes using PEG derivatives possessing lipid moieties...

Yatuv R, Robinson M, Dayan I, Baru M (2010) Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes a case of FVIII, FVIIa and G-CSF. Expert Opin Drug Deliv 7 187-201... 

Ishida T, Kiwada H (2008) Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes. Int J Pharm 354 56-62... 

Xu H, Wang KQ, Deng YH, da Chen W (2010) Effects of cleavable PEG-cholesterol derivatives on the accelerated blood clearance of PEGylated liposomes. Biomaterials 31 4757-4763... 

Jiang W, Lionberger R, Yu LX (2011) In vitro and in vivo characterizations of PEGylated liposomal doxorubicin. Bioanalysis 3 333-344... 

Ferrying of molecules into cells via entry through caveolae may represent a way to traffic specifically cytotoxic molecules to specific action sites. For example, elevating the intracellular level of the sphingolipid ceramide is known to exert antimitogenic and proapoptotic effects. While ceramide is cell-permeable and displays antiapoptotic properties in vitro, systemic in vivo use of ceramide is hampered by its hydrophobicity. Using a C6-ceramide formulation in pegylated liposomes was shown to elicit a sixfold reduction in solid phase tumors, when compared to unloaded liposomes in a mouse model of breast adenocarcinoma [68],... 

Cordon, A.N. et al.. Recurrent epithelial ovarian carcinoma a randomized phase III study of pegylated liposomal doxorubicin versus topotecan, /. Clin. Oncol., 19, 3312-3322,2001. 

Gabizon A, Barenholz Y. Liposomal anthracyclines— from basics to clinical approval of PEGylated liposomal doxorubicin. In Janoff AS, ed. Liposomes Rational Design. New York Marcel Dekker, 1999 343-362. 

Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal Doxorubicin review of animal and human studies. Clin Pharmacokinetics 2003 42 419 36. 

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. 

Northfelt DW, Dezube BJ, Thommes JA, et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi s sarcoma results of a randomized phase III clinical trial. J Clin Oncol 1998 16 2445. 

Harrington KJ, et al. Targeted radiosensitisation by pegylated liposome-encapsulated 3, 5 -0-dipalmitoyl 5-iodo-2 -deoxyuridine in a head and neck cancer xenograft model. Br J Cancer 2004 91 366. 

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. 

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. 

Harrington K, Rowlinson-Busza G, Syrigos KN, Uster PS, Vile RG, Stewart JSW. Pegylated liposomes have potential as vehicles for intratumoral and subcutaneous drug delivery. Clin Cancer Res 2000 6 2528. 

Harrington KJ, Mohammadtaghi S, Uster PS, et al. Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 7, 243, 2001. 

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. 

Tsavaris N, Kosmas C, Vadiaka M, et al. Pegylated liposomal doxorubicin in the CHOP regimen for older patients with aggressive (stage III/V) non-Hodgkin s lymphoma. Anticancer Res 2002 22 1845. 

Skubitz KM. Phase II trial of pegylated-liposomal doxirubicin (Doxil) in sarcoma. Cancer Investig 2003 21 167. 

Insertion of PEG-lipid into conventional liposome phospholipid bilayer had substantially increased their circulation half-life. Pharmacokinetic of PEGylated liposome is clearly modified by the presence of the PEG-lipid extended circulation time was reported as reviewed (4). 

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... 

Kaye SB, Lubinski J, Matulonis U et al (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCAI or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30 372-379... 

In addition to the passive targeting of tumors due to the EPR effect, active targeting of PEGylated liposomes has also been successful. A study by Huwyler and coworkers (1996), for example, showed that coupling a monoclonal antibody to the surface of PEGylated liposomes resulted in significant transfer of the liposomes across the blood-brain barrier, which is difficult to achieve otherwise. The attached... 

---