Liposomal drug delivery systems: From concept to clinical applications☆
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Introduction: the pioneers
Since the internet has made literature searches relatively straightforward, there has been a tendency to overlook the early scientific literature and to forget, or fail to cite, the important contributions of the early pioneers in the liposome field. We have made a special effort in this paper to find those early references and give credit to the liposome pioneers — and put their contributions into context.
It is our intent to focus on the early work in the liposome field, especially work done
Drug loading and control of the drug release rate
It soon became clear that there were a number of problems associated with the in vivo use of the 1st generation liposomes, sometimes termed ‘classical’ or conventional liposomes. A very early observation was the difficulty in retaining some types of entrapped molecules in the liposome interior [16], [22], [38]. Drug release was shown to be affected by exposure to serum proteins [39], [40], [41]. Changing the content of the liposome bilayer, in particular by incorporation of cholesterol [40],
Receptor-mediated endocytosis of ligand-targeted liposomes
Early in the history of liposomes it was recognized that a means of increasing the selectivity of the interaction of liposomes with diseased cells was desirable. If this interaction triggered receptor-mediated endocytosis of the liposome and its cargo into the desired cellular target, then so much the better. Antibodies were used in early experiments to mediate their specific attachment target cells [100], [101], and receptor-mediated endocytosis of liposomes was demonstrated [102], [103], [104]
Triggered release
Stability of liposomes in the circulation with retention of their contents has long been recognized as a desirable liposome characteristic for successful drug delivery to diseased tissues. Over two decades ago, it was also recognized that being able to trigger the release of liposomal contents once they reached the target site would lead to improvements in therapeutic outcomes. Two main types of triggers have been explored, remote triggers such as heat, ultrasound and light, and local triggers
Delivery of nucleic acids and DNA
Soon after the first animal experiments began to show improved therapeutic outcomes for small molecule therapeutics, came the realization that liposomes could also be effective delivery systems for DNA [185], [186], and for nucleic acid-based therapeutics such as antisense oligonucleotides (asODN) and siRNA [187]. In vivo delivery of polynucleic acids using lipid-based systems began with an early report that a liposomally encapsulated plasmid for rat insulin could result in gene expression
Combination therapy
The principles of combination chemotherapy, i.e., the combination of therapies with different mechanisms of action and non-overlapping side effects, can be applied to the development of nanomedicines [228], [229], [230], [231], [232], [233], [234]. A variety of different types of combinations have been use in recent years, with at least additive increases in therapeutic outcomes for the combinations compared to individual therapies. Several different types of therapeutic combinations have been
Multi-functional, multi-component formulations
Increasingly, the formulation and use of multi-functional, multi-component liposomal nanoparticles, sometimes referred to as theragnostics, is being explored — formulations that carry within an individual lipidic nanoparticle functions such as site-specific targeting, biomarker and imaging capabilities, delivery of combinations of therapeutics, and response to external or internal triggers to control drug release [242]. As the complexity of lipidic nanoparticles increases, so do the expenses
Clinical development
Both ‘classical’ and ‘Stealth’ liposomes have entered the mainstream as sustained release drug delivery systems [243] for the in vivo delivery of everything from small molecule therapeutics to nucleic acids. Early papers that were important in the clinical development of liposomes include a 1985 paper by Morgan et al. that demonstrated accumulation of liposomes labeled with technetium 111 in sites of infection and inflammation in humans [244], and a subsequent paper that showed accumulation of
Conclusions
In the 40 plus years from the concept of the clinical utility of liposomes to their recognized position in the mainstream of drug delivery systems, the path has been long and winding. They have been explored in the clinic for applications as diverse as imaging tumors and sites of infection, for vaccine and gene medicine delivery, for treatment of infections and for cancer treatment, for lung disease and for skin conditions. In clinical applications, liposomal drugs have been proven to be most
Acknowledgements
The authors would like to acknowledge the outstanding contributions of the staff and trainees of their respective laboratories to the development of liposome technologies. We also thank the following agencies and companies for their funding support: Canadian Institutes for Health Research, Canadian Breast Cancer Association, National Cancer Institute of Canada, National Science and Engineering Research Council of Canada, Canada Foundation for Innovation, Centre for Drug Research and Development
References (292)
- et al.
Design considerations for liposomal vaccines: influence of formulation parameters on antibody and cell-mediated immune responses to liposome associated antigens
Vaccine
(2012) - et al.
The use of scintigraphic imaging as a tool in the development of liposome formulations
Prog. Lipid Res.
(2001) - et al.
APN/CD13-targeting as a strategy to alter the tumor accumulation of liposomes
J. Control. Release
(2011) - et al.
Skin structure and mode of action of vesicles
Adv. Drug Deliv. Rev.
(2002) - et al.
Phospholipid model membranes. II. Permeability properties of hydrated liquid crystals
Biochim. Biophys. Acta
(1967) - et al.
Single bilayer liposomes prepared without sonication
Biochim. Biophys. Acta
(1973) Drug entrapment in liposomes
FEBS Lett.
(1973)- et al.
Pharmacokinetics of liposome-entrapped anti-tumor drugs
Biochem. Pharmacol.
(1978) - et al.
Preparation of liposomes of defined size distribution by extrusion through polycarbonate membranes
Biochim. Biophys. Acta
(1979) - et al.
Production of large unilamellar vesicles by a rapid extrusion procedure. Characterization of size distribution, trapped volume and ability to maintain a membrane potential.
Biochim. Biophys. Acta
(1985)
Vesicles of variable sizes produced by a rapid extrusion procedure
Biochim. Biophys. Acta
Liposomal amphotericin B is toxic to fungal cells but not to mammalian cells
Biochim. Biophys. Acta
Systemic administration of doxorubicin-containing liposomes in cancer patients: a phase I study
Eur. J. Cancer Clin. Oncol.
Disintegration of phosphatidylcholine liposomes in plasma as a result of interaction with high-density lipoproteins
Biochim. Biophys. Acta
Serum-induced leakage of liposome contents
Biochim. Biophys. Acta
Is half-life of circulating liposomes determined by changes in their permeability?
FEBS Lett.
Lateral diffusion rates of phosphatidylcholine in vesicle membranes: effects of cholesterol and hydrocarbon phase transitions
FEBS Lett.
The effect of cholesterol on the structure of phosphatidylcholine bilayers
Biochim. Biophys. Acta
The bilayer stabilizing role of sphingomyelin in the presence of cholesterol: a 31P NMR study
Biochim. Biophys. Acta
A study of phospholipid interactions between high-density lipoproteins and small unilamellar vesicles
Biochim. Biophys. Acta
Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients
Biochim. Biophys. Acta
The response of fluorescent amines to pH gradients across liposome membranes
Biochim. Biophys. Acta
Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient
Biochim. Biophys. Acta
The accumulation of drugs within large unilamellar vesicles exhibiting a proton gradient: a survey
Chem. Phys. Lipids
Anomalous solubility behavior of the antibiotic ciprofloxacin encapsulated in liposomes: a 1H-NMR study
Biochim. Biophys. Acta
Development of a weak-base docetaxel derivative that can be loaded into lipid nanoparticles
J. Control. Release
Therapeutically optimized rates of drug release can be achieved by varying the drug-to-lipid ratio in liposomal vincristine formulations
Biochim. Biophys. Acta
Optimization of the retention properties of vincristine in liposomal systems
Biochim. Biophys. Acta
Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer
Biochim. Biophys. Acta
The effect of particle size and charge on the clearance rates of liposomes and liposome encapsulated drugs
Biochem. Biophys. Res. Commun.
Reversible depression of the reticuloendothelial system by liposomes
Biochim. Biophys. Acta
Interactions of liposomes with the reticuloendothelial system. Nonspecific and receptor-mediated uptake of liposomes by mouse peritoneal macrophages.
Biochim. Biophys. Acta
Interactions of liposomes with the reticuloendothelial system. Effects of reticuloendothelial blockade on the clearance of large unilamellar vesicles
Biochim. Biophys. Acta
Uptake of small liposomes by non-reticuloendothelial tissues
Biochim. Biophys. Acta
Effect of fetal calf serum and serum protein fractions on the uptake of liposomal phosphatidylcholine by rat hepatocytes in primary monolayer culture
Biochim. Biophys. Acta
Association of blood proteins with large unilamellar liposomes in vivo. Relation to circulation lifetimes
J. Biol. Chem.
Large unilamellar liposomes with low uptake into the reticuloendothelial system
FEBS Lett.
Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase
J. Biol. Chem.
Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes
FEBS Lett.
Liposomes for the sustained drug release in vivo
Biochim. Biophys. Acta
Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo
Biochim. Biophys. Acta
Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: studies with the poly(ethylene glycol)-coated vesicles
Biochim. Biophys. Acta
Pharmacokinetics of Stealth versus conventional liposomes: effect of dose
Biochim. Biophys. Acta
Accelerated clearance of PEGylated liposomes in rats after repeated injections
J. Control. Release
Enhanced localization of liposomes with prolonged blood circulation time in infected lung tissue
Biochim. Biophys. Acta
Liposomal doxorubicin (Doxil): an effective new treatment for Kaposi's sarcoma in AIDS
Clin. Oncol. (R. Coll. Radiol.)
The preparation of cell fusion-inducing proteoliposomes from purified glycoproteins of HVJ (Sendai virus) and chemically defined lipids
J. Biol. Chem.
pH-dependent fusion of phosphatidylcholine small vesicles. Induction by a synthetic amphipathic peptide
J. Biol. Chem.
pH-induced destabilization of lipid bilayers by a lipopeptide derived from influenza hemagglutinin
Biochim. Biophys. Acta
Antibody-mediated targeting of liposomes. Binding to lymphocytes does not ensure incorporation of vesicle contents into the cells
Biochim. Biophys. Acta
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This review is part of the Advanced Drug Delivery Reviews theme issue on “25th Anniversary issue — Advanced Drug Delivery: Perspectives and Prospects”.