Immunoliposomes for the targeted delivery of antitumor drugs
Introduction
An attractive strategy to enhance the therapeutic index of anticancer drugs is to specifically deliver these agents to tumor cells thereby keeping them away from non-malignant cells sensitive to the toxic effects of the drug. This would allow for more effective treatments achieved with doses that are better tolerated. Among the colloidal drug carrier systems proposed for site-specific drug delivery, liposomes have attracted considerable attention [1], [2], [3], [4], [5], [6]. Liposomes consist of one or more concentric phospholipid bilayers, each enclosing an aqueous compartment. A large variety of therapeutically active molecules (e.g. antitumor drugs, oligonucleotides, DNA, enzymes, peptides and hormones) have been successfully incorporated in liposomes. Especially in the field of cancer chemotherapy, much effort has been invested to realize site-specific drug delivery with liposomal systems. Active targeting of liposomes to tumor cells is generally attempted by conjugating ligands to the liposomal surface which allow a specific interaction with the tumor cells [6]. Several types of ligands have been used for this purpose, including antibodies or antibody fragments [7], [8], [9], [10], vitamins [11], glycoproteins [12], [13], peptides (RGD-sequences) [14], [15], and oligonucleotide aptamers [16]. This review will mainly focus on the use of antibodies or antibody fragments to actively target liposomes, as this is the type of targeting ligand mostly used.
The first report on antibody-targeted liposomes came from Torchilin et al. exactly 2 decades ago [17]. These antibody-targeted liposomes (further referred to as immunoliposomes) were shown to be able to specifically bind to the antigen that is expressed on the target cells. Since then, several coupling techniques have been described for conjugating antibodies or their fragments to liposomes, each with their own advantages and drawbacks [9], [18], [19]. Many in vitro experiments have demonstrated highly specific binding of immunoliposomes to target cells. However, despite the excellent targeting properties in vitro, successful results on targeting of immunoliposomes in tumor models are, up to now, scarce.
In this review we aim to present the current status regarding the application of immunoliposomes for anticancer drug delivery in vivo. First, problems will be listed that are encountered when immunoliposomes are used for systemic anticancer drug delivery and potential solutions will be discussed. Second, an update will be given on the results obtained with immunoliposomes in animal models. Finally, special emphasis will be placed on highlighting new developments regarding the utilization of immunoliposomes for the treatment of cancer.
Section snippets
Immunoliposomes in vivo: many rivers to cross
Accessibility of tumor cells is a critical issue when immunoliposomes are to be targeted to tumors. Unlike some types of tumors (e.g. hematological malignancies and tumors confined within a body cavity), many tumors are located at sites that are less accessible by intravenously (i.v.) injected liposomes. The process of targeted drug delivery with immunoliposomes can be roughly divided into two phases: the transport phase, in which the immunoliposomes travel from the site of administration
Immunoliposomes in vivo: current status
In early days, the utility of conventional immunoliposomes in vivo was strongly limited by their rapid clearance by the MPS. With the advent of long-circulating liposomes that are able to oppose uptake by the MPS, targeting of liposomes to tissues other than the MPS is now much more realistic. One of the most critical issues to consider when developing immunoliposomal systems is whether the surface-attached antibodies can access the tumor cell surface in vivo. It is clear that the route of
Recent advances
A general trend that can be deduced from the previous section is that, despite successful results in vitro, the results in vivo are somewhat disappointing: only a few examples of successful anticancer applications of immunoliposomes in vivo exist. Clearly, the immunoliposomal system needs further improvement in order to obtain an effective drug delivery vehicle for in vivo application. Several major problems have been identified. Recent developments to tackle these problems are discussed below.
Final remarks
We hope that this review on the current situation regarding the use of immunoliposomes for the use in cancer chemotherapy provides a realistic perspective on where the field is going and where opportunities can be found for rational improvement of the immunoliposome system. Ideally, two objectives should be met: (1) all administered immunoliposomes should bind to their target epitopes, and (2) all encapsulated drug molecules should become therapeutically available upon binding of
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