Possibility of active targeting to tumor tissues with liposomes
Introduction
It was German bacteriologist Paul Ehrlich who, in the late nineteenth century, coined the term “magic bullet”, meaning a chemical that travels through the body and selectively kills diseased cells without harming neighboring healthy ones [1]. Drug delivery with “magic bullet” to cells, tissues or organs is defined as “active targeting”. Many different approaches using various physical and biochemical principles have been proposed and examined to develop a system to achieve a therapeutically acceptable degree of target specificity [2], [3], [4], [5]. With the availability of a suitable ligands, this approach takes advantage of a relatively abundant expression of a particular receptor on the target cell.
Among the different approaches of active targeting, immunoliposomes using an antibody as a targeting ligand and a lipid vesicle as a carrier for both hydrophobic and hydrophilic drugs, have attracted much attention [6], [7]. The rationale of this approach has been well established in various in vitro systems. The use of an antibody molecule as a homing device has been especially facilitated by the development of the hybridoma technology, which makes it possible to produce a large quantity of a monoclonal antibody to a wide variety of cell determinants [8]. However, only a limited number of preclinical studies report successful targeting of immunoliposomes in vivo [9]. Studies in vivo have revealed that coating liposomes with antibody leads to enhanced uptake of the immunoliposomes by the reticuloendothelial system [10], [11] and the immunotargeting efficiency depends on the antibody density on the surface [12]. Thus, highly efficient targeting and a relatively low level of RES uptake of immunoliposomes are apparently mutually exclusive.
Given a suitable antibody with high specificity and affinity for the target antigen, the critical factor is the accessibility of target cells to immunoliposomes. Efficient target binding of the injected immunoliposomes occurs only when the target cell is in the intravascular compartment or can be accessible through leaky vascular structures. Thus, in terms of targeting drug delivery by immunoliposomes, two anatomical compartments are considerable for targeting sites. One is located at a readily accessible site in intravascular, such as the vascular endothelial surface, T cells, B cells or thrombus. Another is a much less accessible target site located in the extravascular. This site involves a solid tumor, an infection site, or an inflammation site, which vascular structure is leaky.
In this review, we describe the current status of the active targeting by immunoliposomes. To characterize the parameters for such immunoliposome targeting in vivo, two different targeting models in mice were employed; the mouse lung targeting model for a readily accessible site and the implanted mouse solid tumor model for a less accessible site located in extravascular. We discuss its associated problems and future perspectives, with emphasis being placed on applications of immunoliposomes in vivo.
Section snippets
Anatomical barriers of tumor tissue
In general, tumor vessels are inherently leaky, due to the wide inter-endothelial junctions, large number of fenestrae and transendothelial channels formed by vesicles, and discontinuous or absent basement membrane [13], [14]. In contrast, the blood vessels in most normal tissues are nonfenestrated capillaries. These blood vessels are composed of a single layer of endothelial cell with tight junctions. The endothelial barrier may prevent liposomes to traverse intact vessels. The cartoon of
Rapid uptake of immunoliposomes by reticuloendothelial system (RES)
Liposomes have been proposed to be useful drug carriers for targeted drug delivery systems, and are under investigation in several therapeutic fields [18], [19]. In order to achieve maximum targeting, liposomes should remain in the systemic circulation for a relatively long period of time. However, formulations of liposomes used in the past were rapidly removed from the circulation by the reticuloendothelial system (RES) [20], [21]. Furthermore, it is known that coating liposomes with
Long-circulating (RES-avoiding) liposome and passive targeting to tumor tissue
It has been demonstrated recently that newly developed liposomes, containing either monosialoganglioside GM1 (GM1) [22] or amphipathic polyethylene glycol (PEG) derivatives [23], [24], [25], are not readily taken up by the macrophages in the RES and hence stay in the circulation for a relatively long period of time (Fig. 2). Particularly, PEG is useful because of its ease of preparation, relatively low cost, controllability of molecular weight and linkability to lipids or protein including the
Pendant type immunoliposome design
Immunoliposomes for the treatment of 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-conjugated 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. Immunoliposome must allow efficient loading and retention
Anatomical barriers
The blood vessels in most normal tissue are nonfenestrated capillaries. Given a suitable antibody with high specificity and affinity for the target antigen, the critical factor is the accessibility of immunoliposomes to the target cells localized on the other side of the endothelium. Another potential approach from described here is utilization of the transcytosis function of endothelial cells [36]. In transcytosis, certain ligand–receptor complexes are, upon endocytosis, transported across the
Conclusion
We have designed a new type of long-circulating immunoliposome, which were PEG-immunoliposomes attached antibodies at the distal end of PEG chain, so called the pendant type immunoliposome, and discussed the active targeting to the two different anatomical compartments by the pendant type immunoliposomes. One is located a readily accessible site in intravascular, such as pulmonary endothelial cells, and another is a much less accessible target site located in the extravascular, such as solid
Abbreviations
- 21B2
monoclonal antibody IgG1 antibody, specific for the human carcinoembryonic antigen
- CEA
human carcinoembryonic antigen
- Chol
cholesterol
- DiI
1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate
- DPPC
dipalmitoyl phosphatidylcholine
- DPPE-PEG-Mal
dipalmitoyl phosphatidylethanolamine derivative of PEG with a terminal maleimidyl group
- DSPC
distearoyl phosphatidylethanolamine
- DSPE
distearoyl phosphatidylcholine
- DSPE-PEG
distearoyl-N-(monomethoxy polyethyleneglycol succinyl)phosphatidylethanolamine
Acknowledgements
Work done in this laboratory is supported by the Grant-Aid for Scientific Research (No. 04671332, 08672568 and 10470254) from the Ministry of Education, Science and Culture, and the Grant-Aid for Cancer Research (No. 9-Specified) from the Ministry of Health and Welfare.
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