Passive targeting with liposomal drug carriers

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 G_M1 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 G_M1 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 Kaposi's sarcoma revealed an in creased therapeutic efficacy compared to free-drug. Solid tumors generally possess the following pathophysiological characteris tics : (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-calIed 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. PEGliposome 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 administer ed systemically in the bloodstream. Antigen binding site of the liposome-cunjugat ed 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, EG-liposomes offer the development of immunoliposomes with both lonPg sur vival 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 Fe 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. For the active targeting following the passive targeting to the solid tumor tissue, Fab' fragment of 21B2 antibody which is anti-human CEA or transferrin (TF) was conjugated to preapared the pendant type immunoliposome(Fab'-PEG-LP or TFPEG-ILP). Both immunoliposoines showed the low RES uptake and the long circulation time, and resulted in enhanced accumulation of the liposomes in the solid tumor. TF-PEG-LP could internalized into tumor cells with receptor mediat ed endocytosis folIowing extravasation into tumor tissue. The pendant type im munoliposome can escape from the gaps between adjacent endothelial cells and openings at the vessel termini during tumor angiogenesis by passive convective transport much rather than ligand directed targeting. Targeting to tumor tissue with the pendant type immtuloliposome is particularly important for many highly toxic anticancer drugs for cancer chemotherapy. An ultimate goal of pendant type immunoliposome is the incorporation of a fusogenic molecule that would induce fusion of liposome following their binding to the target cells or their internalization by endocytosis. Such liposomal formula tions should be useful for endocytotic internalization of plasmid DNA and other bioactive materials.