リポソームによるパッシブターゲティング

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Passive targeting with liposomal drug carrier systems was reviewed. The current status of the passive targeting by the pnlyethyleneglycol coated liposome (PEG-liposome) were described in this review. Newly developed liposomes, containing either monosialoganglioside GM1 or amphipathic polyethylene glycol (PEG) derivatives, are not readily taken up by the macrophages in the RES and hence stay in the circulation for a relatively long period of time. Particularly, PEG is useful because of its ease of preparation, relatively low cast, controllability of molecular weight and linkability to lipids or protein including the antibody by a variety of methods as compared with GM1 molecules. So many recent studies have focused on the use of liposomes with surface associated PEG. The presence of PEG reduces binding of serum protein, i.e. opsonins marking the lipnsome for clearance by MPS. Pharmacokinetic analysis and therapeutic studies with tumor bearing mice revealed that PEG-liposomes with an average diameter of 100-200 nm were accumulated efficiently in tumor tissue. Due to the capillary permeability of the endothelial barrier in newly vascularized tumors is significantly greater than that of normal tissues, PEG-liposomes could extravasate from blood circulation to tumor tissue. Results from clinical studies with doxorubicin encapsulated into PEG-liposomes (DOXIL®) in AIDS-related Kaposis sarcoma revealed an increased therapeutic efficacy compared to free-drug. Solid tumors generally possess the following pathophysiological characteristics : (a) hypervasculature, (b) incomplete vascular architecture, (c) secretion of vascular permeability factors that stimulate extravasation within the cancer, (d) little drainage (lack of lymph vessel) of macromolecules and particles, which results in their long-term retention in tumor tissue. These characteristics of solid tumors are the basis of the so-called EPR effect (enhanced permeability and retention effect). Thus, the permeability of the endothelial barrier in newly vascularized tumors is increased compared with that of healthy tissues. PEG-liposome can take advantage of the EPR effect for efficient targeting binding in the tumor. The localization of PEG-liposomes into the interstitial space between tumor cells by a process of extravasatiun from tumor vessels (EPR effect) was revealed by the electron microscopic observations. Immunoliposomes for the treatment of solid tumor should satisfy a number of requirements aimed at maximum targeting effect of immunoliposome administered systemically in the bloodstream. Antigen binding site of the liposome-cunjugated antibody must be accessible for unperturbed interaction with antigen on the surface of target cells. The blood clearance of immunoliposomes must be minimized in comparison with rate of extravasation in the tumor. As described above, PEG-liposomes offer the development of immunoliposomes with both long survival times in circulation and target recongnition being retained in vivo. A new type of long-circulating immunoliposome, which was PEG-immunoliposome attached antibody at the distal end of PEG chain, so called the pendant type immunoliposome, was designed. To assist extravasation, the liposomes were of uniform, small size (100-130 nm). Elimination of immunogenic effect of Fc portion and of the increased RES clearance through specific recognition by MPS cells carrying Fc receptor, was achieved by using Fab fragment instead of the whole antibody.
日本DDS学会の論文
1999-11-10

リポソームによるパッシブターゲティング

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