Nanoparticles in Medicine: Therapeutic Applications and DevelopmentsNANOPARTICLE-BASED THERAPEUTICS APPROVED FOR CLINICAL USETable 1 Clinically approved nanoparticle-based therapeuticsNANOPARTICLE-BASED THERAPEUTICS IN CLINICAL TRIALSTable 2 Nanoparticle-based therapeutics in clinical trialsNANOPARTICLE-BASED THERAPEUTICS IN PRECLINICAL DEVELOPMENTFigure 1 Schematic illustration of therapeutic nanoparticle platforms in preclinical development: (a) liposome, (b) polymer-drug conjugate, (c) polymeric nanoparticle, (d) dendrimer, and (e) iron oxide nanoparticle.Table 3 Nanoparticle-based therapeutics in preclinical developmentCONCLUSIONOUTLOOKACKNOWLEDGMENTSCONFLICT OF INTERESTNanoparticles in Medicine: TherapeuticApplications and DevelopmentsL Zhang1,FXGu1, JM Chan2, AZ Wang3,4, RS Langer1and OC Farokhzad4Nanotechnology is the understanding and control of mattergenerally in the 1–100 nm dimension range. The applicationof nanotechnology to medicine, known as nanomedicine,concerns the use of precisely engineered materials at thislength scale to develop novel therapeutic and diagnosticmodalities.1,2Nanomaterials have unique physicochemicalproperties, such as ultra small size, large surface area tomass ratio, and high reactivity, which are different frombulk materials of the same composition. These propertiescan be used to overcome some of the limitations found intraditional therapeutic and diagnostic agents.The use of materials in nanoscale provides unparallelfreedom to modify fundamental properties such as solubility,diffusivity, blood circulation half-life, drug release character-istics, and immunogenicity. In the last two decades, a numberof nanoparticle-based therapeutic and diagnostic agents havebeen developed for the treatment of cancer, diabetes, pain,asthma, allergy, infections, and so on.3,4These nanoscaleagents may provide more effective and/or more convenientroutes of administration, lower therapeutic toxicity, extendthe product life cycle, and ultimately reduce health-care costs.As therapeutic delivery systems, nanoparticles allow targeteddelivery and controlled release. For diagnostic applications,nanoparticles allow detection on the molecular scale: theyhelp identify abnormalities such as fragments of viruses,precancerous cells, and disease markers that cannot bedetected w ith traditional diagnostics. Nanoparticle-basedimaging contrast agents have also been shown to improvethe sensitivity and specificity of magnetic resonance imaging.Given the vast scope of nanomedicine, we will focus on thetherapeutic applications, in particular, drug delive ry applica-tions, of nanoparticles.Many advantages of nanoparticle-based drug deliveryhave been recognized.5,6It improves the solubility of poorlywater-soluble drugs, prolongs the half-life of drug systemiccirculation by reducing immunogenicity, releases drugs at asustained rate or in an environmentally responsive mannerand thus lowe rs the frequency of administration, deliversdrugs in a target manner to minimize systemic side effects,and delivers two or more drugs simultaneously forcombination therapy to generate a synergistic effect andsuppress drug resistance. As a result, a few pione eringnanoparticle-base d therapeutic products have been intro-duced into the pharmaceutical market, and numerousensuing products are currently under clinical testing or areentering the pipeline.NANOPARTICLE-BASED THERAPEUTICS APPROVED FORCLINICAL USEIn the past two decades, there has been a progressive increasein the number of commercially available nanoparticle-basedtherapeutic produc ts. A global survey conducted by theEuropean Science and Technology Observatory in 2006showed that more than 150 companies are developingnanoscale ther apeutics. 7 So far, 24 nanotechn ology-ba sedtherapeutic products have been approved for clinical use,with total sales exceeding $5.4 billion.7Among theseproducts, liposomal drugs and polymer–drug conjugates aretwo dominant classes, accounting for more than 80% of thetotal amoun t (Tab le 1).Liposomes are spherical lipid vesicles with a bilayeredmembrane structure composed of natural or syntheticamphiphilic lipid molecules.8,9Liposomes have been widelyused as pharmaceutical carriers in the past decade because oftheir unique abilities to (a) encapsulate both hydrophilic andhydrophobic therapeutic agents with high efficiency, (b)protect the encapsulated drugs from undesired effects ofexternal conditions, (c) be functionalized with specificligands that can target specific cells, tissues, and organs ofinterest, (d) be coated with inert and biocompatible polymersnature publishing groupTRANSLATIONAL MEDICINE1Department of Chemical Engineering and Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;3Department of Radiation Oncology, Brigham and Women’sHospital, Harvard Medical School, Boston, Massachusetts, USA;4Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham Women’sHospital, Harv ard Medical School, Boston, Massachusett s, USA. Corre spondence: OC Farokhzad (ofaro [email protected] )Advance online publication 24 October 2007. doi:10.1038/sj.clp t.6100400CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 5 | MAY 2008 761such as polyethylene glycol (PEG), in turn prolonging theliposome circulation half-life in vivo, and (e) form desiredformulations with needed composition, size, surface charge,and other properties .9,10 Table 1 lists some liposom alproducts that have been approved in the past 15 years. Doxilwas the first liposomal drug formulation approved by theFood and Drug Administration, USA (FDA) for thetreatment of AIDS associated with Kaposi’s sarcoma in1995.11By encapsulating doxor ubicin (a widely used anti-cancer chemotherapeutic drug) into stealth liposome carrierscomprised of hydrogenated soy phosphatidylcholine, choles-terol, and PEGylated phosphoethanolamine, Doxil hasdramatically prolonged doxorubicin circulation half-life andenhanced drug deposition in the tumor tissue. OtherTable 1 Clinically approved nanoparticle-based therapeuticsComposition Trade name Company Indication AdministrationLiposomal platformsLiposomal amphotericin B Abelcet Enzon Fungal infections i.v.Liposomal amphotericin B AmBisome Gilead Sciences Fungal and protozoal infections i.v.Liposomal cytarabine DepoCyt SkyePharma Malignant