Adventures in Targeting

Abstract

An overview of our experiences in the field of immunoliposomal anticancer drugs is provided with respect to choice of ligand, and choice of model system, in order to provide some guidance as to the rational use of this new technology. Liposomes targeted by either peptide or monoclonal antibodies showed significantly higher binding to their respective target cells in vitro compared to non-targeted liposomes in all model systems examined. This higher binding led to higher cytotoxicities relative to non-targeted liposomes. For the immunoliposomes to deliver their entrapped drug to target cell in vivo, long circulations half-lives are required. We have evaluated the pharmacokinetics of liposomes prepared by several different coupling techniques, and have found significant differences in the clearance of these immunoliposomes from the circulation. Immunoliposomes prepared with whole anti-CD19 IgG coupled by the Mal-PEG-DSPE method demonstrated a short plasma half-life, which may reflect the random orientation of the MAb on the liposome surface. Coupling methods that mask or eliminate the Fc region result in immunoliposomes that have clearance rates more similar to untargeted liposomes. Insertion of peptides or antibodies into pre-formed liposomes through incubation with ligand-coupled PEG micelles resulted in immunoliposomes, termed post-insertion liposomes, that demonstrated comparable in vitro binding, pharmacokinetic profiles and in vivo therapeutic efficacy to liposomes made by conventional coupling methods. The therapeutic efficacy of liposomes, prepared by various coupling methods and targeted by different ligands, was compared in several different animal models of either haematological malignancies, pseudometastatic disease or solid tumours. In our hands, successful in vivo targeting has been obtained when the target is either small or readily accessible from the vasculature, where the liposomes have longer circulating half-lives and/or where a ligand against an internalizing epitope has been chosen. These results should aid in the rational design of applications for immunoliposomal drugs in the future.

Drug transport to brain with targeted liposomes

“…Formulations of pegylated liposomes have been on the market for many years. We have now the technologies at hand (using efficient coupling strategies for vectors such as postinsertion techniques 32 and biotinstreptavidin coupling strategies 35 ) to expand the use of such liposomal formulations to the targeted delivery of drugs to organs and tissues. Once produced, liposomal formulations should be applied immediately or within short periods of time to minimize leakage of the liposomal content.…”

“…Therapeutic effect, cytotoxicity and binding of immunoliposomes made by the postinsertion technique was comparable with the ones of immunoliposomes made by a conventional coupling technique. 32 We have introduced a coupling procedure that makes use of a biotinylated PEG-phospholipid and a streptavidin-conjugated antibody. 35 Preformed and purified biotin-PEG-liposomes are thereby simply mixed with the streptavidin-conjugated antibody to result immediately in a quantitative coupling.…”

“…The target recognition by the coupled antibody may also depend on the orientation (i.e., random or defined) of the antibody or a FabЈ on the liposome surface and the resulting accessibility of the antibody binding sites to their respective epitopes. 32 Covalent binding protocols rely in general on chemically reactive PEG-phospholipid derivatives that are part of the phospholipid/cholesterol mix used for the synthesis of the PEG liposomes. The liposomes are loaded with drug, reduced in size and purified before the actual cou- pling procedure is performed by addition of the vector.…”

Synthesis of Monomethoxypolyethyleneglycol—Cholesteryl Ester and Effect of its Incorporation in Liposomes

“…They have potential applications as drug carriers due to properties such as sustained release (1), altered pharmacokinetics (2,3), increased drug stability (4), ability to overcome drug resistance (4,5), and target specific tissues (5,6). However, their use as a drug delivery system is limited due to their rapid clearance from systemic circulation by mononuclear phagocytic system.…”

Local delivery of magnetic resonance (MR) contrast agent in kidney using thermosensitive liposomes and MR imaging‐guided local hyperthermia: A feasibility study in vivo

“…Local release was suggested to increase the local drug concentration and thereby limit toxic side effects. Several systems have been suggested for local drug release based on the use of liposomes as pharmacological nanocarriers, in combination with ligand-targeted products (1), with a gas-filled compartment collapsing under an ultrasound pressure wave (2), or, as in this study, with temperature-sensitive liposomes becoming permeable with local hyperthermia (3)(4)(5). The initial interest was focused on liver and kidney, as they are highly blood irrigated organs.…”