Table 1.

Approved drugs commonly referred to as “nanopharmaceuticals”

Name	Description	Mechanism of action	Approval/indication
1) Liposomes
AmBisome®	Amphotericin B encapsulated in liposomes (60–70 nm) composed of hydrogenated soy phosphatidylcholine, cholesterol, and distearoyl phosphatidylglycerol (2/0.8/1 molar)15	MPS targeting: Liposomes preferentially accumulate in organs of the MPS. Negative charge contributes to MPS targeting. Selective transfer of the drug from lipid complex to target fungal cell with minimal uptake into human cells has been postulated16,17	FDA 1997 Systemic fungal infections (IV)
DaunoXome®	Daunorubicin citrate encapsulated in liposomes (45 nm) composed of distearoyl phosphatidylcholine and cholesterol (2/1 molar)18,19	Passive targeting via EPR effect: Concentration of available liposomal drug in tumors exceeds that of free drug. Liposomal daunorubicin persists at high levels for several days20	FDA 1996 HIV-related KS (IV)
DepoCyt®	Cytarabine encapsulated in multivesicular liposomes (20 μm; classified as nanopharmaceutical based on its individual drug containing “chambers”) made from dioleoyl lecithin, dipalmitoyl phosphatidylglycerol, cholesterol, and triolein21	Sustained release: This formulation of cytarabine maintains cytotoxic concentrations of the drug in the cerebrospinal fluid for more than 14 days after a single 50 mg injection22	FDA 1999/2007 Lymphomatous malignant meningitis (IV)
DepoDur®	Morphine sulfate encapsulated in multivesicular liposomes (17–23 μm; per se not a nanopharmaceutical – classified as such based only on its individual drug containing “nano-sized chambers”) made from dioleoyl lecithin cholesterol, dipalmitoyl phosphatidylglycerol, tricaprylin, and triolein	Sustained release: After the administration into the epidural space, morphine sulfate is released from the multivesicular liposomes over an extended period of time23,24	FDA 2004 For treatment of chronic pain in patients requiring a long-term daily around-the-clock opioid analgesic (administered into the epidural space)
Doxil®	Doxorubicin hydrochloride encapsulated in Stealth® liposomes (100 nm) composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero3-phosphoethanolamine sodium, fully hydrogenated soy phosphatidylcholine, and cholesterol9	Passive targeting via EPR effect: Extravasation of liposomes by passage of the vesicles through endothelial cell gaps present in solid tumors. Enhanced accumulation of doxorubicin in lesions of AIDS-associated KS after administration of PEG-liposomal doxorubicin25	FDA 1995 AIDS-related KS, multiple myeloma, ovarian cancer (IV)
Inflexal® V	Influenza virus antigens (hemagglutinin, neuraminidase) on surface of 150 nm Liposomes	Mimicking native antigen presentation: Liposomes mimic the native virus structure, thus allowing for cellular entry and membrane fusion.26 Retention of the natural presentation of antigens on liposomal surface provides for high immunogenicity27,28	Switzerland 1997 Influenza vaccine
Marqibo®	Vincristine sulfate encapsulated in sphingomyelin/cholesterol (60/40, molar) 100 nm liposomes	Passive targeting via EPR effect: Extravasation of liposomes through fenestra in bone marrow endothelium	FDA 2012 Acute lymphoid leukemia, Philadelphia chromosome-negative, relapsed or progressed (IV)
Mepact™	Mifamurtide (synthetic muramyl tripeptide-phosphatidylethanolamine) incorporated into large multilamellar liposomes composed of 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine and 1,2-dioleoyl-sn-glycero-3-phospho-L-serine29	MPS targeting: The drug, an immune stimulant, is anchored in negatively charged liposomal bilayer membrane	Europe 2009 Non-metastasizing resectable osteosarcoma (IV)
Myocet®	Doxorubicin encapsulated 180 nm oligolamellar liposomes composed of egg phosphatidylcholine/cholesterol (1/1, molar)	MPS targeting: Forms “MPS depot”, slow release into blood circulation resembles prolonged infusion30	Europe 2000 Metastatic breast cancer (IV)
Visudyne®	Verteporfin in liposomes made of dimyristoyl-phosphatidylcholine and egg phosphatidylglycerol (negatively charged); lyophilized cake for reconstitution	Drug solubilization: Rendering drug biocompatible and enhancing ease of IV administration. No other apparent function of liposomes. Liposomal formulation instable in the presence of serum. Fast transfer of verteporfin from Visudyne® to lipoproteins31	FDA 2000 Photodynamic therapy of wet age-related macular degeneration, pathological myopia, ocular histoplasmosis syndrome (IV)
2) Lipid-based (non-liposomal) formulations
Abelcet®	Amphotericin B complex 1:1 with DMPC and DMPG (7:3), >250 nm, ribbon like structures of a bilayered membrane15	MPS targeting: Selective transfer of drug from lipid complex to fungal cell with minimal uptake into human cells has been postulated32,33	FDA 1995 and 1996 Marketed outside USA as Amphocil® Systemic fungal infections (IV)
Amphotec®	Amphotericin B complex with cholesteryl sulfate (1:1). Colloidal dispersion of disc-like particles, 122 nm ×4 nm15	MPS targeting
3) PEGylated proteins, polypeptides, aptamers
Adagen®	PEGylated adenosine deaminase34 One enzyme molecule is modified with up to 17 strands of PEG, MW 5,000, 114 oxymethylene groups per strand	Increased circulation time and reduced immunogenicity PEGylation generally increases hydrodynamic radius, prolongs circulation and retention time, decreases proteolysis, decreases renal excretion, and shields antigenic determinants from immune detection without obstructing the substrate-interaction site35,36	FDA 1990 Adenosine deaminase deficiency – severe combined immunodeficiency disease
Cimzia®	PEGylated antibody (Fab’ fragment of a humanized anti-TNF-alpha antibody)		FDA 2008 Crohn’s disease, rheumatoid arthritis
Neulasta®	PEGylated filgrastim (granulocyte colony-stimulating factor)		FDA 2002 Febrile neutropenia, In patients with nonmyeloid malignancies; prophylaxis (SC)
Oncaspar®	PEGylated L-asparaginase		FDA 1994 Acute lymphoblastic leukemia
Pegasys®	PEGylated interferon alfa-2b		FDA 2002 Hepatitis B and C
PegIntron®	PEGylated interferon alfa-2b		FDA 2001 Hepatitis C
Somavert®	PEGylated human growth hormone receptor antagonist		FDA 2003 Acromegaly, second-line therapy
Macugen®	PEGylated anti-VEGF aptamer		FDA 2004 Intravitreal Neovascular age-related macular degeneration
Mircera®	PEGylated epoetin beta (erythropoietin receptor activator)		FDA 2007 Anemia associated with chronic renal failure in adults
4) Nanocrystals
Emend®	Aprepitant as nanocrystal	Increased bioavailability due to increased dissolution rate: Below 1,000 nm, the saturation solubility becomes a function of the particle size leading to an increased saturation solubility of nanocrystals, which in turn increases the concentration gradient between gut lumen and blood, and consequently the absorption by passive diffusion37	FDA 2003 Emesis, antiemetic (oral)
Megace ES®	Megestrol acetate as nanocrystal		FDA 2005 Anorexia, cachexia (oral)
Rapamune®	Rapamycin (sirolimus) as nanocrystals formulated in tablets		FDA 2002 Immunosuppressant (oral)
Tricor® Triglide®	Fenofibrate as nanocrystals		FDA 2004
Triglide®	Fenofibrate as insoluble drug-delivery microparticles		Hypercholesterolemia, hypertriglyceridemia (oral)
5) Polymer-based nanoformulations
Copaxone®	Polypeptide (average MW 6.4 kDa) composed of four amino acids (glatiramer)	No mechanism attributable to nanosize. Based on its resemblance to myelin basic protein, glatiramer is thought to divert as a “decoy” an autoimmune response against myelin	FDA 1996/2014 Multiple sclerosis (SC)
Eligard®	Leuprolide acetate (synthetic GnRH or LH-RH analog) incorporated in nanoparticles composed of PLGH copolymer (DL-lactide/glycolide; 1/1, molar)	Sustained release38	FDA 2002 Advanced prostate cancer (SC)
Genexol®	Paclitaxel in 20–50 nm micelles39 composed of block copolymer poly(ethylene glycol)- poly(D,L-lactide)	Passive targeting via EPR effect	South Korea 2001 Metastatic breast cancer, pancreatic cancer (IV)
Opaxio®	Paclitaxel covalently linked to solid nanoparticles composed of polyglutamate	Passive targeting via EPR effect: Drug release inside solid tumor via enzymatic hydrolysis of polyglutamate	FDA 2012 Glioblastoma
Renagel®	Cross-linked poly allylamine hydrochloride,40 MW variable	No mechanism attributable to nano size. Phosphate binder	FDA 2000 Hyperphosphatemia (oral)
Zinostatin stimalamer®	Conjugate protein or copolymer of styrene-maleic acid and an antitumor protein NCS.41 Synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid)42	Passive targeting via EPR effect43	Japan 1994 Primary unresectable hepatocellular carcinoma
6) Protein–drug conjugates
Abraxane®	Nanoparticles (130 nm) formed by albumin with conjugated paclitaxel44,45	Passive targeting via EPR effect: Dissociation into individual drug-bound albumin molecules, which may mediate endothelial transcytosis of paclitaxel via albumin-receptor mediated pathway46,47	FDA 2005 Metastatic breast cancer, non-small-cell lung cancer (IV)
Kadcyla®	Immunoconjugate. Monoclonal antibody (against human epidermal growth factor receptor-2)–drug (DM1, a cytotoxin acting on microtubule) conjugate, linked via thioether	No mechanism attributable to nano size	FDA 2013 Metastatic breast cancer
Ontak®	Recombinant fusion protein of fragment A of diphtheria toxin and subunit binding to interleukin-2 receptor	Fusion protein binds to interleukin-2 receptor, followed by receptor-mediated endocytosis; fragment A of diphtheria toxin then released into cytosol where it inhibits protein synthesis48	FDA 1994/2006 Primary cutaneous T-cell lymphoma, CD25-positive, persistent or recurrent disease
7) Surfactant-based nanoformulations
Fungizone® (also referred to as “conventional AMB”)	Lyophilized powder of amphotericin B with added sodium deoxycholate. Forms upon reconstitution colloidal (micellar) dispersion	Drug solubilization: Rendering drug biocompatible and enhancing ease of administration after IV injection No other apparent function of micelles, which dissociate into monomers following dilution in circulation	FDA 1966 Systemic fungal infections (IV)
Diprivan®	Oil-in-water emulsion of propofol in soybean oil/glycerol/egg lecithin	Drug solubilization: Rendering drug biocompatible and enhancing ease of administration after IV injection	FDA 1989 Sedative–hypnotic agent for induction and maintenance of anesthesia (IV)
Estrasorb™	Emulsion of estradiol in soybean oil, polysorbate 80, ethanol, and water	Drug solubilization	FDA 2003 Hormone replacement therapy during menopause (transdermal)
8) Metal-based nanoformulations
Feridex®	Superparamagnetic iron oxide nanoparticles coated with dextran. Iron oxide core 4.8–5.6 nm, hydrodynamic diameter 80–150 nm	MPS targeting: 80% taken up by liver and up to 10% by spleen within minutes of administration. Tumor tissues do not take up these particles and thus retain their native signal intensity36	FDA 1996 Liver/spleen lesion MRI (IV) Manufacturing discontinued in 2008
Feraheme™ (Ferumoxytol)	Superparamagnetic iron oxide nanoparticles coated with dextran. Hydrodynamic diameter >50 nm	MPS targeting: Iron released inside macrophages, subsequently enters into intracellular storage iron pool, or is transferred to plasma transferrin	FDA 2009 Treatment of iron deficiency anemia in adults with chronic kidney disease
NanoTherm®	Aminosilane-coated superparamagnetic iron oxide 15 nm nanoparticles	Thermal ablation: Injecting iron oxide nanoparticles exposed to alternating magnetic field causing the nanoparticles to oscillate, generating heat directly within the tumor tissue	Europe 2013 Local ablation in glioblastoma, prostate, and pancreatic cancer (intratumoral)
9) Virosomes
Gendicine®	Recombinant adenovirus expressing wildtype-p53 (rAd-p53)	“[…] the adenoviral particle infects tumor target cells and delivers the adenovirus genome carrying the therapeutic p53 gene to the […] nucleus […] The expressed p53 gene appears to exert its antitumor activities”49	People’s Republic of China 2003 Head and neck squamous cell carcinoma
Rexin-G®	Gene for dominant-negative mutant form of human cycline G1, which blocks endogenous cyclin-G1 protein and thus stops cell cycle, inserted into retroviral core (replication-incompetent retrovirus) devoid of viral genes. About 100 nm particle	Targeted gene therapy: This retrovirus-derived particle targets specifically exposed collagen, which is a common histopathological property of metastatic tumor formation50,51	Philippines 2007 For all solid tumors

Abbreviations: DMPC, dimyristoylphosphatidylcholine; DMPG, dimyristoyl phosphatidylglycerol; EPR, enhanced permeability and retention; FDA, US Food and Drug Administration; GnRH, Gonadotropin-releasing hormone; IV, intravenous; KS, Kaposi’s sarcoma; LH-RH, Luteinizing hormone-releasing hormone; MPS, Mononuclear phagocyte system; MRI, magnetic resonance imaging; MW, molecular weight; NCS, neocarzinostatin; PEG, polyethylene glycol; PLGH, poly-(D,L-lactide-co-glycolide); SC, subcutaneous.