Liposome–Nanoparticle Hybrids for Multimodal Diagnostic and Therapeutic Applications

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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

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.

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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 have been studied thoroughly with attempts to delivery system by applying magnetic forces. improve the resulting MRI resolution and They achieve a high drug concentration at the reduce toxicity. Most commonly, they have specific site without associated toxicity to been embedded in stabilizing polymers, such neighboring tissues [19,23,26]. Also, the magne- as dextran or PEG to improve their biocom- toliposome’s surface can be modified chemi- patibility and reduce their aggregation in cally by specific targeting ligands [19,20,27–30] or physiological environments. PEG-grafted lipids [22,31] to reduce the non- SPIO nanoparticles have been encapsulated specific adsorption and avoid macrophage within the phospholipid vesicles (Figure 1) using uptake. Functionalized PEG ligands have also techniques, such as reverse phase evaporation been incorporated to improve the blood [18–21], extrusion [22], freeze-thawing [21,23] or circulation time and target recognition [21,32]. sonication [24,25]. Liposomes containing nano- Hyperthermia is a promising tool for cancer meter-sized superparamagnetic particles have therapy as it has fewer side effects than chemo- been prepared to improve SPIO biocompati- therapy or radiotherapy. Hyperthermia bility as the lipid bilayer is biocompatible with involves raising the temperature of the tissue to the biological membrane and enhances SPIO 42–44°C, which causes physical damage. utilization by the cells [22]. Lipid bilayer coat- Many procedures have been followed to induce ing of the magnetic nanoparticles preserved the hyperthermia but they all cause damage to the magnetic characteristics of SPIOs, reduced normal tissues as well as to the tumor [33].

Figure 1. Diagram showing the incorporation of superparamagnetic iron oxide nanoparticles within a liposome bilayer (left) or a liposome aqueous core (right).

Target ligand (e.g., antibody, protein)

Hydrophilic polymer (e.g., PEG)

Targeting ligand coupled to the SPIOs terminus of the surface-grafted polymer

Encapsulation of hydrophobic SPIOs in Encapsulation of hydrophilic SPIOs a liposome bilayer in a liposome aqueous core

PEG: Polyethylene glycol; SPIO: Superparamagnetic iron oxide particle.

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Figure 2. Incorporation of hydrophobic quantum dot nanoparticles within a liposome bilayer (left) and electrostatic complexation of negatively charged hydrophilic quantum dots with commercially available cationic liposomes (right).

CdSe/ZnS core/shell QDs

COOH functionalized Hydrophobic QDs Negatively charged QDs Cationic liposomes hydrophilic QDs

Cationic liposomes

Nanomedicine

QD: Quantum dot.

Magnetoliposomes can act as heat mediators increases in local temperature can induce drug within the tumor when an alternating mag- release from thermosensitive liposomes netic field is applied, resulting in antitumor [18,38,39] or, more interestingly, may activate an activity without heating of the surrounding encapsulated prodrug molecule prior to its healthy tissues [25,27–29,34]. Magnetoliposomes release [40]. More complex fullerene–liposome induce selective hyperthermia if they accumu- hybrid nanoparticles and magneto-fuller- late only within the tumor. Such accumulation ene–liposomes have been constructed where has been achieved by direct intratumoral injec- fullerenes incorporated into the phosphatidyl- tion [24,25,33,34] or by antibody conjugation for choline liposome bilayer, which, on near-infra- inaccessible tumors [27,28,30], which makes red (NIR) laser pulse, can trigger drug release them more convenient for intravenous admin- from such nanocarriers [41]. Magneto- istration. Interestingly, cationic magnetolipo- liposomes, directed by a magnetic field to the somes (CMLs) have shown higher tumor site, can be used for targeting, imaging, accumulation and affinity for the cell mem- therapeutic hyperthermia, gene transfection, brane after intratumoral injection than neutral prodrug activation and controlled drug release liposomes [29,35]. Thus, CMLs induced effi- [42], all of which provide multiple options for cient and selective intracellular hyperthermia cancer therapy. in different tumor models without raising the whole body temperature, resulting in tumor Liposome–QD hybrids necrosis and complete tumor regression after Semiconductor nanocrystals, known as QDs, multiple exposures to an alternating magnetic are fluorescent nanoparticles of 1–10 nm in field [25,29,34]. Furthermore, CMLs have poten- diameter [43–45] that offer distinct spectrofluor- tial applications in gene delivery as their posi- ometric advantages over traditional fluorescent tive charge can condense negatively charged organic molecules. QDs exhibit fluorescence DNA, which will facilitate cell association and characteristics that are 10–20-times brighter transfection [36,37]. than conventional dyes, greater photostability, In addition to their antitumor activity, broad excitation wavelength range, size-tunea- magnetoliposomes can be developed as trig- ble spectrum and narrow and symmetric emis- gerable systems since magnetically induced sion spectrum, ranging from 400 to 2000 nm,

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depending on their size and chemical compo- approach has been to functionalize QDs with sition. Owing to these photophysical charac- polar moieties and ligands with specific recep- teristics they are being explored as potential tor recognition signals (e.g., peptides and mon- imaging agents primarily in fluorescence- oclonal antibodies or their fragments) [44,54–56]. based diagnostic applications [45–47]. Recent However, this surface modification leads to reports have shown that QDs can also be decreases in QD fluorescence intensity and linked to SPIO nanoparticles to develop a dual photostability [57–59]. Preformed liposomes of modality contrast agent for cell tracking cationic surface character have been electro- in vivo via MRI and optical imaging [48,49]. statically complexed with functionalized QDs Samia and colleagues and others have reported (Figure 2) to enhance the cellular binding and using QDs in photodynamic therapy (PDT) internalization of QDs for cell labeling and [50–52], since QD emission wavelength can tracking purposes [60–62]. However, these stud- excite a photosensitiser and QDs alone also ies simply mixed commercially available, lipo- have the potential to produce the reactive sin- some-based transfection agents with QDs in glet oxygen, which can be used as a order to translocate enough QD particles intra- cytotoxic agent against tumor cells [50]. cellularly to achieve efficient levels of mamma- QDs are prepared originally in organic sol- lian cell fluorescent labeling. More recently, vents [53], therefore their hydrophobic shells Feng and colleagues have reported the encap- compromise their water solubility and conse- sulation of organic CdSe QDs within PEG- quently their compatibility with the biological conjugated phosphatidylcholine liposomes milieu. In addition, their hydrophobic surface (Figure 2). Gopalakrishnan and colleagues have results in an unfavorable toxicity profile, intro- reported the incorporation of hydrophobic ducing serious limitations in potential bio- QDs within fusogenic liposome bilayers that medical and clinical applications of QDs. were able to translocate and stain the plasma Many strategies are being developed to over- membrane of cell cultures upon fusion [63]. come this limitation. The most succsessful Incorporation of the organic QDs within

Figure 3. Multicompartment liposome encapsulating SUVs within an outer bilayer membrane where different therapeutic molecules (cocktail therapies) can be loaded into SUVs.

SUV

Lipid bilayer

SUV: Small unilamellar vesicle.

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phospholipid bilayers renders QDs compatible Multivesicular systems were first described in with the aqueous environment and allows fluo- 1982 [69], prepared by the double emulsification rescent labeling of the lipid bilayers for in vivo technique. Cytarabine-containing multivesicu- and in vitro imaging. lar liposomes in the micrometer scale (average In an alternative approach, ultrasmall, diameter 6–30 µm) have been introduced to the uncapped QDs have been prepared using uni- market for cancer therapy (DepoCyt®, Enzon lamellar phosphatidylcholine vesicles and electro- Pharmaceuticals, NJ, USA) (Table 1). These are poration. Schelly and colleagues have synthesised large clusters of smaller lipid bilayers seemingly PbS [64] and AgBr subnanometer crystals [65] by ‘glued’ to each other by triolein-rich hydropho- encapsulating the metal ions within unilamellar bic regions. Multivesicular structures consisting liposomes and dispersing anionic ions in the sur- of lipid bilayers encapsulating intact liposomes rounding aqueous phase. The application of high of smaller mean diameters (multicompartment voltage induced the formation of reversible pores liposome [MCL]) have been further developed within the membrane, followed by adsorption of by various laboratories [70], however, the mini- QD monomers on the external surface of the mum average diameter described for any MCL liposomes. With time, self-aggregation took place, system is in the range of a few micrometers [7,71]. resulting in crystals less than 10 Å in diameter. This inhibits the use of multivesicular systems for systemic indications, such as cancer, whereby Liposomes-in-liposomes blood circulation of the delivery systems is Doxil® (Ortho Biotech Products, NJ, USA), required. Micrometer-sized multivesicular sys- Caelyx® (Schering-Plough, NJ, USA) and tems have been reported recently as oral (for hor- Myocet® (Zeneus Pharma, Oxford, UK) are mones, proteins and vaccine) [13,14,72] and local nanometer-sized liposome systems (encapsulat- (intratumoral and intramuscular) [15,16] drug- ing doxorubicin in their aqueous core) that have delivery systems, providing a sustained drug- been used in cancer clinics for over a decade. release profile, inner liposome protection and a Administration of combination chemotherapy higher drug-encapsulation efficiency. treatment regimens using a single delivery system An alternative MCL system, called vesosome, is thought to significantly enhance therapeutic has been developed by Zasadzinski and coworkers efficacy [66–68]. Therefore, the engineering of new using the self-assembly properties between strepta- types of multicompartment liposomes is needed vidin-coated cochleate cylinders [14,71–75] or etha- to allow adoption of such novel modalities in a nol interdigitated phospholipid bilayer sheets [73] single liposome carrier system [68] (Figure 3). and biotin-coated smaller liposomes. Such

Figure 4. Mechanism of interaction between polystyrene nanospheres and SUVs.

Lipid bilayer deposition

Lipid monolayer-covered polystyrene nanosphere first + formed

B Polystyrene Polystyrene SUVs nanosphere–SUV nanospheres interaction

Lipid bilayer-covered polystyrene nanosphere

(A) A lipid monolayer-covered nanosphere can be formed if the lipid and nanosphere are similarly charged. If a neutral lipid is used, a lipid bilayer can be adsorbed on the lipid monolayer-covered nanosphere by further lipid deposition. (B) A lipid bilayer is formed on the surface of an oppositely charged nanosphere. SUV: Small unilamellar vesicle.

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micrometer-sized vesosome systems were reported towards the aqueous phase [79]. Unstable adsorp- recently as vaccine-delivery systems following topi- tion of neutral liposomes occurred on charged cal (skin) immunization [76]. We have constructed polystyrene nanosphere surfaces and depends on a novel MCL system of nanometer dimensions the hydrophobic attractions between the phos- (200 nm average diameter) recently that can pholipid bilayer(s) and the monolayer-covered potentially be a tool for systemic administration of nanospheres [82]. The self-assembled lipid on solid combinatory therapeutic/imaging modalities [77]. particles combines the intrinsic properties of both the solid core and the surface bilayer, which can be Liposome–polystyrene used as a model of the cell membrane. As such, it nanosphere hybrids can act as a host for transmembrane proteins or Adsorption of a lipid bilayer around the surface of receptors [83] and be of benefit in designing polystyrene nanospheres [78–82] leads to the forma- biosensors for optical or electrical detection [84,85]. tion of hybrid systems consisting of nanoparticles within liposomes. The mechanism of interaction Liposome–silica nanoparticle hybrids between liposome vesicles and the solid polysty- Formation of a solid particle-supported bilayer rene particles is not yet well understood. Different has also been described by deposition of small lipids and types of nanoparticles have been studied unilmellar vesicles (SUVs), composed of either and lipid deposition at the solid surface has been synthetic amphiphiles or natural phospholipids shown to depend on the lipid concentration, the onto hydrophilic silica nanospheres [86–88]. Dep- surface charge and the hydrophilic/hydrophobic osition is followed by vesicle distortion and rup- nature of the solid nanoparticles (Figure 4) [78,79,82]. ture to form a continuous fluid bilayer Positively charged synthetic dioctadecyldimeth- membrane (Figure 5) [82,86–88]. The bilayer adsorp- ylammonium bromide (DODAB) amphiphiles tion is as a result of electrostatic attractions formed bilayers and had a high adsorption affinity between the silica surface and the vesicle polar for the negatively charged polystyrene nanosphere groups. The adsorption stability of neutral phos- surface owing to electrostatic attraction [78]. How- pholipid bilayer on a silica surface depends on ever, negatively charged liposomes formed a lipid the H-bridges formed between the deprotonated monolayer on the surface of sulphated polystyrene silanol groups (Si-OH) and the phosphate nanospheres with their polar heads directed groups (O=P-) of the phospholipids. Therefore,

Figure 5. (A) The chemical composition of a silica nanoparticle and (B) the mechanism of interaction between silica nanoparticles and SUVs.

H H – A –

H Si Si H – Si Si – H O Si Si 2 Si Si

Si Si Si Si Si H Si H – Si Si –

H H – – Silica Deprotonated silica

Lipid bilayer-coated Silica nanoparticles SUVs Silica–SUV electrostatic interaction silica nanoparticles

SUV: Small unilamellar vesicle.

futurefuture sciencescience groupgroup www.futuremedicine.com 91 REVIEW – Al-Jamal & Kostarelos [37] [26] [27] [19] [18] [22] [63] [91] Ref. [24,25,34] MRI Application Cell imaging Could be usedas labels for fluorescent applications biological Gene delivery therapy Cancer drug delivery Targeted hyperthermia Local human of treatment cell carcinoma renal for drug delivery Active cerebrovascular diseases Can be used in cancer used in cancer be Can providing treatment and targeting magnetic response in drug release hyperthermia to local : Not available; PC: Phosphatidylcholine; SA: Stearylamine; SPIO: SA: Stearylamine; particle; oxide iron Superparamagnatic DSPE: Distearoylphosphatidylethanolamine; g on the method of liposome preparation. avoiding particles aggregation and aggregation particles avoiding dilution blood Advantages of liposome liposome of Advantages encapsulation of separation Magnetic transfected cell provides magnetoliposome Cationic hyperthermia intracellular selective induction response and immune upon applying Drug targeting field magnetic antibody-conjugated Tumor-specific magnetoliposome Monocyte/neutrophil-mediated to of drug delivery active inflammatory sites cell solubilization and QD water membrane labeling solubilization QD water liposomes in response to response in liposomes hyperthermia induced magnetically * * * * * Nanoscale Final product size 20 –100 nm 20 nm Nanoscale Nanoscale Nanoscale Nanoscale -dimethylammonium chloride; DOPE: Dioleoylphosphatidylethanolamine; DOPS: Dioleoylphosphatidylserine; nce; MRI: Magnetic resonance imaging; NA imaging; nce; resonance Magnetic MRI: N , N -dioleoyl- N - N itoylphosphatidylcholine;Dipalmitoylphosphatidylglycerol; DPPG: phatidylserine; QD: Reverse-phase evaporation; Quantum dot; REV: assumed that this will be in the range of 100–200 dependin be 100–200 the range nm, of will in this that assumed Lipid Lipid film hydration and extrusion 200 nm by MR contrast agent efficient Highly SPIOs were encapsulated within a within encapsulated were SPIOs film by lipid liposome cationic and sonication, hydration magnetoliposomes by followed to DNA complexation Method of nanoparticle encapsulation sonication and hydration film Lipid by followed hydration film Lipid and extrusion sonication Lipid film hydration and sonication and hydration film Lipid Egg phosphatidylcholine; MR: Magnetic resona -(trimethylammonio-acetyl)-didodecyl-D-glutamate chloride. -(trimethylammonio-acetyl)-didodecyl-D-glutamate

α PEG2000 (95:5mol %) (95:5mol PEG2000 Vesicle lipid type lipid Vesicle DMPC:DOTAP:DPPE- PEG2000 (47.5:25:0.5 mol %) PC:PE:chol:PEG (1:2:2 ratio) molar (1:2:2 ratio) molar ) EPC, EPC:DSPE- 3 )TMAG:DLPC:DOPE O 4 2 O 3 Fe γ Table 2. Different liposome–nanoparticle hybrid systems 2. Different Table Nanoparticle composition particles oxide iron Superparamagnetic (Fe Magnetite MagnetiteMagnetiteMagnetite TMAG:DLPC:DOPE Dextran–magnetite Lecithin:chol PC:PEDextran–magnetite Soy PC:chol:PS sonication and hydration film Lipid DPPC sonication REV and ( Maghemite sonication and hydration film Lipid Quantum dots QD CdSe Hydrophobic REV QD CdSe Hydrophobic 1 µm thermosensitive from release Drug *The mean size of these systems was not mentioned, but it can be it but not mentioned, was systems of these size *The mean DHP: Dihexadecylphosphate; DLPC: Dilauroylphosphatidylcholine; DODAC: DOTAP: 1, 2-dioleoyl-3-trimethylammoniumDOTAP: propane; DPPC: Dipalm PE: PS: glycol); Poly(ethylene PEG: Phosphatidylethanolamine; Phos EDTA: EPC: acid; Ethylenediaminetetraacetic SUV: Small unilamellar vesicle; TMAG: N-

92 Nanomedicine (2007) 2(1) futurefuture sciencescience ggrouproup Liposome–nanoparticle hybrids for multimodal diagnostic and therapeutic applications – REVIEW [47] [72] [76] [75] [92] [73] Ref. [60,61] [64,65]

in vitro and and imaging Application Oral vaccine immunization Topical drug a as used be Could for delivery system therapy combinatory synergistic providing for therapeutic effect diagnostic and purposes In vivo : Not available; PC: Phosphatidylcholine; SA: Stearylamine; SPIO: SA: Stearylamine; particle; oxide iron Superparamagnatic DSPE: Distearoylphosphatidylethanolamine; g on the method of liposome preparation. Advantages of liposome liposome of Advantages encapsulation pepsin against the antigen Protect release the antigen and prolonged the deliver vesosomes Fusogenic topical via systemically antigen application Formation of multicompartment vesicle encapsulating liposomes a within bilayer aggregates Formation of multicompartment or of composed anionic liposomes neutral liposomesencapsulated within an anionic bilayer liposomes Multicompartment solubilization and increase increase and solubilization colloidal stability Final product size µm 1–10 3–5 µm µm 0.5–5 µm 0.3–2 0.3–2 µm NA QD delivery intracellular High trafficking Intracellular -dimethylammonium chloride; DOPE: Dioleoylphosphatidylethanolamine; DOPS: Dioleoylphosphatidylserine; nce; MRI: Magnetic resonance imaging; NA imaging; nce; resonance Magnetic MRI: trusion 100–200 nm QDs of Angstrom-sized Preparation N/A N , N -dioleoyl- electrostatic electrostatic N - N itoylphosphatidylcholine;Dipalmitoylphosphatidylglycerol; DPPG: phatidylserine; QD: Reverse-phase evaporation; Quantum dot; REV: assumed that this will be in the range of 100–200 dependin be 100–200 the range nm, of will in this that assumed Method of nanoparticle encapsulation and REV, Glass bead method and by sonication followed extrusion Ethanol interdigitation formation Cylinder-aggregate biotin–streptavidin using by unrolling followed interaction, the vesicle around of PS bilayer aggregates from the cochleate cylinder by addingEDTA the around of PS bilayer Unrolling from nanoparticles colloidal EDTA adding by cylinder cochleate Ethanol interdigitation QDs–liposome complexation Egg phosphatidylcholine; MR: Magnetic resona -(trimethylammonio-acetyl)-didodecyl-D-glutamate chloride. -(trimethylammonio-acetyl)-didodecyl-D-glutamate

ions with ions α +2 anionic SUVs) anionic Vesicle lipid type lipid Vesicle DMPC:DMPG (10:1 ratio) molar DPPC:chol (97.5:2.5 ratio) molar DOPS cochleates formed (a cylinder interaction the upon of Ca DOPS cochleate DSPC, DPPC, DPPG, chol DPPC: ( 97.5:2.5 molar ratio), DPPC-DPPE- PEG2000 Lipofectamine 2000 Lipofectamine liposomes) (cationic PC:PEG–PE sonication and hydration film Lipid 20–100 nm QD water individualization, Table 2. Different liposome–nanoparticle hybrid systems (cont.). systems hybrid liposome–nanoparticle 2. Different Table Nanoparticle composition Quantum dots PEG-coated QD (CdSe/ZnS) QD DHLA-capped QD Hydrophobic (CdSe/ZnS) ionsQD cationic Phospholipid vesicles PC:chol:SA DPPC:Soya (7:7:5:4) DOPC(200 nm) ) (2:1:0.5 DOTAP:PC:DOPE aggregates Large vesicle DLPC of unilamellar and ex hydration film Lipid (vesosomes) liposomes liposomes 200-nm composed of DSPC:chol or (2:1) (2:1:1). DSPC:chol:SA 100 of nm liposomes DOPS 50 nm or 200 nm vesicles or (2:1) chol of DSPC: DPPC: chol:SA (50:25:25 %). mol can be it but not mentioned, was systems of these size *The mean DHP: Dihexadecylphosphate; DLPC: Dilauroylphosphatidylcholine; DODAC: DOTAP: 1, 2-dioleoyl-3-trimethylammoniumDOTAP: propane; DPPC: Dipalm PE: PS: glycol); Poly(ethylene PEG: Phosphatidylethanolamine; Phos EDTA: EPC: acid; Ethylenediaminetetraacetic SUV: Small unilamellar vesicle; TMAG: N-

futurefuture sciencescience groupgroup www.futuremedicine.com 93 REVIEW – Al-Jamal & Kostarelos [71] [93] [78] Ref. [13,70] [88,89] [81,83] Application useful in the Can be of development sensors aqueous-based model providing and study systems to nanoparticle/ cell interaction used in be Can biosensors designing Oral administration of Oral administration drugs peptide or Defloculating of oppositely stabilizing latex charged of cholera Development biosensors toxin : Not available; PC: Phosphatidylcholine; SA: Stearylamine; SPIO: SA: Stearylamine; particle; oxide iron Superparamagnatic DSPE: Distearoylphosphatidylethanolamine; g on the method of liposome preparation. Advantages of liposome liposome of Advantages encapsulation solubilization of Water hydrophobic photoluminescent silicon bilayer lipid supported of Preparation the combine nanoparticles on silica and of silica properties intrinsic the bilayer insulin release retardation and inner inner and retardation release insulin against protection liposome degradation enzymatic nanosphere smooth bilayer into bilayer-covered receptors nanospheres which retard the drug release retard which µm liposomes, double of Preparation Final product size 60 nm, 150 nm, 300 nm 100–150 nm 100–200 nmand monodispersed of Production -dimethylammonium chloride; DOPE: Dioleoylphosphatidylethanolamine; DOPS: Dioleoylphosphatidylserine; nce; MRI: Magnetic resonance imaging; NA imaging; nce; resonance Magnetic MRI: N , N -dioleoyl- N - N itoylphosphatidylcholine;Dipalmitoylphosphatidylglycerol; DPPG: phatidylserine; QD: Reverse-phase evaporation; Quantum dot; REV: assumed that this will be in the range of 100–200 dependin be 100–200 the range nm, of will in this that assumed Method of nanoparticle encapsulation by followed hydration film Lipid and extrusion sonication Adsorption of SUVs on the silica by surface, followed nanoparticles forming a lipid SUV rupture, or bilayer(s) monolayer Glass filter methodGlass filter µm 2–10 owing to effect Better hypoglycemic Adsorption of SUV on the surface, nanoparticles polystyrene forming by SUV rupture followed or bilayer(s) monolayer a lipid Egg phosphatidylcholine; MR: Magnetic resona -(trimethylammonio-acetyl)-didodecyl-D-glutamate chloride. -(trimethylammonio-acetyl)-didodecyl-D-glutamate

α Vesicle lipid type lipid Vesicle EYPC, 16-DOXYL, 5-DOXYL DOPS, DOPC, DOTAP, DOPC:DOPS DODAB DHP, PC, HSPC, HSPC:SA, HSPC, HSPC:PS and DODAC DODAB, DHP HSPC, DMPC, EPCHSPC, Glass bead method 0.25–10 , ® Table 2. Different liposome–nanoparticle hybrid systems (cont.). systems hybrid liposome–nanoparticle 2. Different Table Nanoparticle composition Phospholipid vesicles Coatsome EL series vesicles Liposome composed of HSPC:SA, HSPC:PS HSPC, nanoparticles Silicon-based silicon Organic-capped silica Hydrophilic Polystyrene nanospheres and amidine Sulphate nanorosphere polystyrene nanorosphereAmidine PC can be it but not mentioned, was systems of these size *The mean 170–200 nm toxin of cholera Incorporation DHP: Dihexadecylphosphate; DLPC: Dilauroylphosphatidylcholine; DODAC: which are 200-nm are which of composed liposomes DMPC:chol:SA:DMPG (52:40:8:0) (54:40:0:6) DOTAP: 1, 2-dioleoyl-3-trimethylammoniumDOTAP: propane; DPPC: Dipalm PE: PS: glycol); Poly(ethylene PEG: Phosphatidylethanolamine; Phos EDTA: EPC: acid; Ethylenediaminetetraacetic SUV: Small unilamellar vesicle; TMAG: N-

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adsorption of the lipid bilayer on the solid silica present in biological fluids. Combinatory imag- nanoparticle depends on the buffer used, the ing–therapeutic applications will include lipo- amphiphile’s polar headgroup and the physical some–SPIO hybrid nanoparticles that have been state of the bilayer [86,87]. shown to be nontoxic and highly stable, offering Liposome vesicles composed of the synthetic multimodal capacities. Within the next few years, DODAB amphiphile demonstrated a high affinity we expect the development of liposomal SPIO for silica surface. By contrast, negatively charged products encapsulating different drug molecules liposomes composed of dihexadecylphosphate for cancer therapy. Another hybrid system at ear- (DHP) amphiphile did not form a continuous lier development stages is based on QD–liposome layer on the hydrophilic silica, presumably owing to hybrid nanoparticles. We speculate that incorpora- electrostatic repulsive forces. However, neutral tion of QDs with the liposomal structure can dra- phospholipid bilayer deposition can be driven by matically improve QDs biocompatibility under stabilizing the H-bridges between the interacting physiological conditions and can help bring QD particles [86,87]. These liposome–silica nanoparti- technologies to the clinic faster by reducing QD cle hybrid systems can be used in designing biosen- dose and their associated toxicity. Furthermore, sors whereby the physical (e.g., semiconductors) liposomes that are combined with NIR nano- characteristics of silica can be matched with the particles, which can be imaged within the NIR biocompatibility and pharmaceutical and light ‘transparency window’ deeper within human pharmacodynamicproperties of liposomes [89,90]. tissue, can have a tremendous impact in imaging and therapeutic combined modality agents. Future perspective Several liposomal products are licensed for clinical Conclusion use in cancer therapy and for vaccination. Encapsu- In this review, we have shown that liposomes, lation of amphotericin B and anthracyline cyto- apart from being clinically used delivery systems toxic drugs into liposome carriers significantly of anticancer agents and vaccines, can also be con- increased the drug therapeutic index and reduced sidered as carriers for different types of nanoparti- associated cytotoxicity. Most importantly, they cles. The variety of novel, usually biologically have established clinically nanoscale liposome incompatible, nanoparticles developed as a result delivery systems. One future direction in liposome of advances in nanotechnology represents a rich research will be in combination with other nano- source of materials that liposomes can transform particulate systems for the construction of multiple into clinically relevant diagnostic or therapeutic modality systems. In the diagnostic field, bilayer- agents. Different strategies to achieve encapsula- coated nanoparticles have already been described tion of solid or semi-solid nanoparticles within for the design of multifunctional biosensors. These liposomes have been reported. All such strategies types of biosensors can increase the detection sensi- offer improvements in the nanoparticle aqueous tivity and save time and effort, as protein receptors solubilization and offer a viable platform (the can be anchored into lipid membranes to detect liposome surface) for further bioconjugation. the presence of several antigens and antibodies Moreover, liposome–nanoparticle hybrids can increase blood circulation times on systemic Executive summary administration and thus improve accumulation • Liposomes are the most clinically established nanomedicines today, with a within sites of leaky vasculature (tumor or inflam- decade-long clinical history as nanoscale delivery systems of anticancer mation) and offer opportunities for the develop- drug molecules. ment of combinatory imaging and therapeutic modalities at those sites. • Intensive research in nanotechnology has led to the development of many types of nanoparticles not compatible with the biological milieu. Acknowledgement • Liposome–nanoparticle hybrid constructs improve the biocompatibility of The authors would like to acknowledge The School of novel nanoparticles. Pharmacy for funding this research. WAJ is the recipient • Liposome–nanoparticle hybrids are structurally diverse nanosystems of an Overseas Research Student (ORS) Award from the offering a wide variety of opportunities for engineering to achieve specific University of London, UK. biological functions (e.g., tissue targeting and triggerable release). Financial disclosure • Liposome–nanoparticle hybrids constitute candidates for clinically viable The authors would like to declare that they have no and easily translational combinatory therapeutic–diagnostic modalities. competing financial interests with the work described.

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