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Liposome–Nanoparticle Hybrids for Multimodal Diagnostic and Therapeutic Applications

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Liposome–Nanoparticle Hybrids for Multimodal Diagnostic and Therapeutic Applications For reprint orders, please contact: EVIEW [email protected] R Liposome–nanoparticle hybrids for multimodal diagnostic and therapeutic applications Wafa’ T Al-Jamal & Liposomes have a decade-long clinical presence as nanoscale delivery systems of Kostas Kostarelos† encapsulated anthracycline molecules. However, their use as delivery systems of †Author for correspondence nanoparticles is still in the preclinical development stages. Liposome–nanoparticle hybrid Nanomedicine Laboratory, Centre for Drug Delivery constructs present great opportunities in terms of nanoscale delivery system engineering Research, The School of for combinatory therapeutic–imaging modalities. Moreover, many novel materials are Pharmacy, University of being developed in nanotechnology laboratories that often require methodologies to London, 29–39 Brunswick Square, London enhance their compatibility with the biological milieu in vitro and in vivo. Liposomes are WC1N 1AX, UK structurally suitable to make nanoparticles biocompatible and offer a clinically proven, Tel.: +44 207 753 5861; versatile platform for the further enhancement of pharmacological efficacy. Small iron Fax: +44 207 753 5942; E-mail: kostas.kostarelos@ oxide nanoparticles, quantum dots, liposomes, silica and polystyrene nanoparticles have pharmacy.ac.uk been incorporated into liposomes for a variety of different applications. In this review, all such liposome–nanoparticle hybrid systems are described, both in terms of their structural characteristics and the potential they offer as diagnostic and therapeutic multimodality agents. Liposomes are the most clinically established liposome carriers can alter a drug’s in vivo phar- nanometer-scale systems that are used to deliver macokinetic and pharmacodynamic profile, cytotoxic and antifungal drugs, genes and vac- leading to an increase in the therapeutic index, cines, and are also being used as imaging agents [1]. reduction in tissue toxicity and other side Liposomes consist of a single or multiple concen- effects [9–12], an increase in drug stability [13,14] tric lipid bilayers (called lamellae) that encapsulate or the emergence of a sustained-release profile an aqueous compartment. Biocompatibility, bio- formulation [7,15,16]. New-generation systems degradability, reduced toxicity and capacity for include liposomes responsive to external or envi- size and surface manipulations comprise the out- ronmental stimuli (e.g., pH, temperature or standing profile that liposomes offer compared enzymes) that trigger drug release at specific and with other delivery systems. Hydrophilic poly- controlled sites [17]. mers, such as polyethylene glycol (PEG), can be The versatility of the liposomal structure lies in attached onto the liposome surface to sterically its capacity to cargo drug molecules and biological stabilize and increase liposome blood circulation macromolecules that are hydrophilic (therefore residence time; targeting ligands (e.g., antibodies entrapped in the liposome inner aqueous core) or or peptides) can also be attached to increase lipo- hydrophobic (therefore incorporated within the some specificity toward target tissues [2]. Lipo- lipid bilayer). In recent years, with the advent of somes constitute the most established nanoscale nanotechnology, there has been a dramatic delivery system already in clinical use for over a increase in the development of novel particulate decade and provide a leading example of how systems that are of nanoscale dimensions. nanomedicines can be developed and have a valu- Nanometer-sized particles, such as superparamag- able clinical history. Some of the commercially netic iron oxides (SPIOs) and semiconducting available liposome-based products in clinical use nanocrystals (quantum dots [QDs]), possess novel currently are listed in Table 1 and many more are magnetic and optical properties that can be used still undergoing clinical trials [2–7]. as imaging probes. However, their hydrophobicity Keywords: double liposomes, Most clinically used liposomes encapsulate a or poor colloidal stability at physiological condi- liposome, polystyrene hydrophilic therapeutic agent (e.g., anthracy- tions frequently renders them inappropriate for nanospheres, quantum dot, silica, superparamagnetic iron clines) in their aqueous compartment, which is clinical use. Our proposal is to take advantage of oxides, vesosomes surrounded by a lipid bilayer that may contain the much more developed and sophisticated lipo- polymers or targeting ligands on its surface. The some technology as a platform for the delivery of part of pharmacokinetics of such systems have been novel nanoparticles. Encapsulation of these nano- studied thoroughly [8]. Drug encapsulation into particles within liposomes can lead to enhanced 10.2217/17435889.2.1.85 © 2007 Future Medicine Ltd ISSN 1743-5889 Nanomedicine (2007) 2(1), 85–98 85 REVIEW – Al-Jamal & Kostarelos Table 1. Commercially available liposomal preparations. Category Trade name Manufacturer Liposome system details Therapeutic target Cytotoxic Doxil®/Caelyx® Ortho Biotech (Doxil) 80–100-nm sterically stabilized Kaposi sarcoma, Schering Plough liposomes (HSPC:chol:DSPE- ovarian cancer (Caelyx) PEG2000) suspension encapsulating doxorubicin DaunoXome® Gilead Small rigid (DSPC:chol) liposomes Kaposi sarcoma encapsulating daunorubicin Myocet® Zeneus Pharma Liposomal formulation (EPC:chol) Combinational therapy with encapsulating doxorubicin cyclophosphamide for citrate complex advanced stage or metastatic breast cancer DepoCyt® Enzon Cytarabine liposome injection Lymphomatous meningitis Pharmaceuticals (DOPC:chol:DPPG multivesicular (cancer of the lymph system liposome) that has spread to the brain) Fungicide AmBisome® Gilead Small negatively charged liposomal Systemic fungal infections suspension (HSPC:chol:DSPG) (visceral leishmaniasis) encapsulating amphotericin B Vaccine Epaxal® Berna Biotech Formalin-inactivated hepatitis A virus Hepatitis A virus infections attached to phospholipid vesicles together with influenza virus hemagglutinin AVAXIM® Sanofi Pasteur MSD Liposome suspension contains Hepatitis A virus infections inactivated hepatitis A virus Bio-Hep-B ® Biotechnology HBs antigen vaccine Hepatitis B virus infections General Inflexal®V Berna Berna Biotech AG Purified influenza hemagglutinin Influenza prophylaxis glycoprotein and neuraminidase inserted into the liposomal membrane (lecithin) FluMist® MedImmune Nasal liposomal preparation contains Influenza prophylaxis Vaccines weakened live influenza viruses Newcastle Schering-Plough Novasome is nonphospholipid Newcastle disease (a highly disease vaccine Animal Health liposomes containing killed Newcastle infectious viral disease of (vet) Corporation disease virus domestic and wild birds) Avian Rheovirus Schering-Plough Nonphospholipid vesicle containing Passive protection of vaccine (vet) Animal Health killed avian rheovirus chickens against rheovirus Corporation infections Others Visudyne® Novartis Liposomal suspension encapsulating Photodynamic therapy for verteporfin drug macular degeneration (ophthalmic preparation) *The dates of clinical approval for some of the products listed: Doxil®/Caelyx®: 1995 (USA), 1996 (Europe); DaunoXome®: 1996 (USA & Europe); Myocet®:: 2005 (Europe & Canada); DepoCyt®: 1999 (USA); AmBisome®: 1990 (Europe), 1997 (USA); Epaxal®: 1994 (Switzerland); Inflexal®V Berna: 1997 (USA); FluMist®: 2003 (USA); Avian Rheovirus vaccine: 2006 (USA); Visudyne®: 2000 (USA). Chol: Cholesterol; DOPC: Dioleoyl phosphatidylcholine; DPPG: Dipalmitoylphosphatidylglycerol; DSPE: Distearoylphosphatidylethanolamine; EPC: Egg phosphatidylcholine; HBs: Hepatitis B surface; HSPC: Hydrogenated soy phosphatidylcholine; PEG: Polyethylene glycol. nanoparticle hydrophilicity, stability in plasma In this review, we highlight various types of and an overall improvement in their biocompati- nanometer-sized particles that have been bility. Furthermore, by taking advantage of the encapsulated within phospholipid bilayers and capability offered by liposomes to carry their applications in the biomedical field, par- hydrophilic and hydrophobic moieties, combina- ticularly in designing novel biosensor devices. tory therapy/imaging modalities can be achieved Following is a more detailed description of by incorporating therapeutics and diagnostic most such types of liposome–nanoparticle agents in a single liposome-delivery system. hybrids. 86 Nanomedicine (2007) 2(1) futurefuture sciencescience groupgroup Liposome–nanoparticle hybrids for multimodal diagnostic and therapeutic applications – REVIEW Liposome–SPIO particle hybrids SPIO aggregation in the blood stream, The unique properties of magnetic particles, reduced the cytotoxicity of the free iron oxide such as gadolinium, magnetite and maghemite particles [22] and, most importantly, provided a (γ-Fe2O3), when placed in magnetic fields, more effective MRI contrast agent. Encapsula- have attracted great attention with regards to tion of SPIOs within liposomes (known as their potential for magnetic resonance imag- magnetoliposomes) provides a promising ing (MRI). Their applications in the biomedi- delivery system with combinatory capacity, cal field, including noninvasive imaging, drug whereby therapeutic agents can also be incor- targeting, gene therapy, tissue engineering porated either in the aqueous core or in the and, more recently, as heat mediators for can- lipid bilayer. Drug-loaded magnetoliposomes cer treatments, have been investigated. They provide a specific targeting and therapeutic
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