The State of the Art of Investigational and Approved Nanomedicine Products for Nucleic Acid Delivery

C H A P T E R

14 The State of the Art of Investigational and Approved Nanomedicine Products for Nucleic Acid Delivery Karina Ovejero Paredes*, Jesu´s Ruiz-Cabello†,‡,§,¶, David Izquierdo Alarco´n†, Marco Filice*,¶ *Nanobiotechnology for Life Sciences Group, Department of Chemistry in Pharmaceutical Sciences, Complutense University of Madrid (UCM), Madrid, Spain † Department of Chemistry in Pharmaceutical Sciences, Complutense University of Madrid (UCM), Madrid, Spain ‡ Molecular and Functional Biomarkers Group, CIC biomaGUNE, Donostia, Spain § IKERBASQUE, Basque Foundation for Science, Bilbao, Spain ¶ Spanish Biomedical Network of Research in Respiratory Diseases (CIBERES), Madrid, Spain

1 INTRODUCTION A nanomedicine is defined as a therapeutic or imaging agent that incorporates nanoparticles (1–100s nm) in order to control the biodistribution, enhance the efficacy, or reduce the toxicity of a drug or biologic agent.1, 2 Typically, nanoparticles are conjugated to existing drugs, changing their pharmacokinetic and/or pharmacodynamic properties. In the majority of cases, these nanoparticle/drug conjugates achieve their effects through passive targeting, which relies on nonspecific accumulation in diseased tissue (Enhanced Permeability and Retention (EPR) effect as in the case of tumors).3 Targeting specific

Nucleic Acid Nanotheranostics https://doi.org/10.1016/B978-0-12-814470-1.00015-0

cells that overexpress certain cell-surface receptors can also be achieved by immobilizing ligands (e.g., proteins, antibodies, small molecules) to the surface of the nanoparticle, leading to active targeting, which results in accumulation followed by specific uptake of the nanomedicines into the tissue of interest. They are usually administered orally or intravenously, but examples of topical, pulmonary and nasal delivery also exist (e.g., Estrasorb, an emulsion of estradiol used in hormone replacement therapy during menopause).4 The principal advantage of this direct administration is the selectivity in a determined tissue or organ. This effect reduces the drug blood concentration,

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Copyright # 2019 Elsevier Inc. All rights reserved.

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

reducing the adverse effects and enabling an increase of concentration levels in the tissue to be treated finally reducing cytotoxicity to the off-target tissues.5–9 These advantages have led to the development of new classes of therapeutic biomolecules, whose therapeutic efficacy rely directly on efficient nanoscale delivery systems (e.g., nucleic acids, proteins, and other biotherapeutics).10–12 These molecules present high therapeutic potential, by silencing a specific gene or triggering protein production, but they are sensitive to degradation and/or unable to cross the cell membrane alone on account of their hydrophilicity and/or negative charges (nucleic acids). Hence, nanoscale systems represent an ideal option for the delivery of this new class of biotherapeutics. In addition, immobilization within nanoparticles helps to stabilize and protect sensitive biomolecules from degradation, such as nucleic acids, that are highly sensitive to nucleases.13 The use of nanoformulations for the treatment of many diseases is rapidly increasing because they offer a number of advantages over conventional drug formulations. Especially for cancer, but also for other diseases, the utility of these materials has been proved with very good results, improving the selectivity when the carrier is biofunctionalized. Like traditional drugs, premarket authorization is regulated by the drug agencies (e.g., FDA and EMA) and hence nanomedicines are subject to the usual range of preclinical and clinical validation. The entire process of approval takes around 10–15 years and its cost is approximately $1 billion per new drug.14

1.1 From Bench to Market The approval of a new carrier or a new application for a carrier combines several challenges (e.g., toxicity, efficacy and efficiency of the drug and the carrier) that they must overcome.

In most cases this is only acceptable when both the well-described carrier and the drug are lowrisk substances. There are only a few products that justify the use of new excipients and they require expensive and time-consuming toxicity studies.15 One major issue in clinical applications and approval of nanoparticles is the safety of these formulations with regard to acute, but more importantly long-term toxicity. Therapeutically relevant nanoparticles are manufactured from biodegradable materials, and the physicochemical properties of the bulk materials and some specific characteristics of nanoformulations have to be assessed. Parameters such as the surface-to-volume ratio and some coating properties have a strong influence on biological interactions, pharmacokinetic, and pharmacological activity of the compound; small changes in these properties can have a major impact on drug safety.16 It is widely known that the particle size and shape have a strong influence on the cellular uptake of nanocarriers.17 Hence, particle size and size distribution represent an important aspect in the development of nanoformulations. The body distribution and elimination also depend on particle size, in addition to surface properties. If they are not eliminated by the kidney, biodistribution studies18 demonstrate that the major fraction of small particles accumulates in the liver.19 There is another mechanism with a strong influence on biodistribution: The EPR effect describes the enhanced accumulation of macromolecules in solid tumors.20–22 The inflammation and lesions of the vascular bed allow macromolecules and colloids to accumulate inside the interstitial space.22 This accumulation is different depending on tumors typology and patients. These are just few of the characteristics that must be taken into account to develop a nanocarrier, but there are many others, such as phase transition temperature, net charge, stability and

1 INTRODUCTION

release, etc.15 That is why all formulations must be tested in vitro and in vivo (preclinical research) before testing in humans. And, after that, these compounds go into clinical research to study the ways the drug will interact with the human body. Clinical trials have an established structure, so that the drug goes through several phases before being approved for release to the market.23 • Phase I: A small number of healthy volunteers and people with the desired disease (20–100) are needed to study the dosage and safety of the compound. This phase lasts a few months and is overcome by most drugs. • Phase II: Up to several hundred people with the disease are needed to check the efficacy and side effects of the compound. This phase can last up to 2 years and only 33% of the drugs pass through it. • Phase III: Between 300 and 3000 people with the desired disease are needed to demonstrate whether or not a product offers a treatment benefit. This phase is larger and longer in duration (1–4 years) so it shows long-term or rare side effects. Approximately 25%–30% of drugs move to the next phase. • Phase IV: These trials are carried out in thousands of volunteers who have the disease once the drug has been approved, during the Post-Market Safety Monitoring.

1.2 Types of Nanocarriers There are many types of nanoparticles and they can be organized in different ways based on different criteria. In this case, the classification will be made according to the material of which the nanocarrier is composed. 1.2.1 Polymeric Nanoparticles Polymeric nanoparticles (PNPs) are extensively employed as biomaterials because of their favorable characteristics: they are easily

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synthesized and applicable across almost all aspects of nanomedicine due to their biocompatibility.24 PNPs are able to bring drugs right into the desired place in the human body with excellent efficiency. They transport therapeutics to targeted tissues or organs and make them more stable and prolong the activity duration for volatile active ingredients.25 Polymer-based nanomedicines are mostly classified in two categories: polymer-drug conjugates for increased drug half-life and bioavailability, and degradable polymer architectures for controlled release applications. Besides, the high surface area (due to their nanosize) allows for a larger contact area between the nanoparticle and the biological target and leads to a rapid adsorption rate. 1.2.2 Polymeric Micelles Polymeric micelles can be used in controlled delivery of hydrophobic drugs due to their hydrophobic internal core and their polar exterior surface, which makes possible their dispersion in aqueous solution.26 Furthermore, the size and morphology of the assembled micelles can be controlled, among other factors, because of the hydrophobic/hydrophilic balance. In addition, these materials have higher stability in comparison with traditional surfactant-based micelles.27 1.2.3 Lipid-Based Nanoparticles The most used kind of lipid based nanoparticles are liposomes; they are the most easily synthesized type of nanoparticle that can integrate targeting ligands into liposome drug carriers, creating new potential combinations and finally improving therapeutic delivery. They have a phospholipid bilayer surrounding an aqueous core that chemically allows for the rapid integration of multiple molecules with different physical and chemical properties.28 Advances have facilitated active targeting by conjugating cell surface receptor ligands to the liposome surface. Approved drugs with high toxicity or low bioavailability benefit from the stabilizing nature

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and improved biodistribution of liposomes in circulation. The main advantages of liposomes include control over pharmacokinetics and pharmacodynamics properties, improved bioavailability and limited toxicity. Taken together, these enhanced properties confer to liposomes the ability to overcome the limitations of conventional therapy.29 There have been many improvements to the manufacturing and loading of these systems, allowing delivery of hydrophobic and hydrophilic compounds ranging from small weak bases to large macromolecules.28 1.2.4 Protein Nanoparticles Early protein nanoparticles used the natural properties of protein circulating in serum, allowing dissolution and transport of drug compounds in blood during circulation.30 Natural proteins were combined with known drugs in order to reduce toxicity. Furthermore, PEGylation of proteins was developed in the early 1970s as a strategy for extending their blood life and reducing their immunogenicity.31 At the moment, protein nanoparticles include different nanomedicine classes: drugs conjugated to protein carriers, engineered proteins where the active therapeutic is the protein itself and to combined complex platforms that rely on protein motifs for targeted therapeutic delivery. 1.2.5 Inorganic Nanoparticles Inorganic nanoparticles have an important role as drug or gene delivery carriers due to their high cellular uptake capacity, nonimmunogenic response and low toxicity.32 Some of the properties (e.g., electromagnetic, optical, and catalytic properties) of noble-metal nanoparticles, such as gold, silver, and platinum, are known to be strongly influenced by shape and size.33 Metalbased nanoconjugates have many biomedical applications: they are used as probes for electron microscopy to visualize cellular components, in drug delivery (proteins, peptides, plasmids, DNAs, miRNAs, etc.), detection, diagnosis, and therapy (targeted and nontargeted) of many diseases.34–38 Additionally, many of the inorganic

compounds that serve as the material for making nanoparticles have long been used in the clinic for various therapeutic applications.39, 40 1.2.6 Crystalline Nanoparticles This kind of nanoparticle is totally composed of drug, without any associated nanocarrier system.41 This leads to increased surface area for dissolution, which increases dissolution velocity and saturation solubility (due to a lower particle size). The production of crystalline nanoparticles has been applied to both organic drugs as well as inorganic materials.42 In fact, some of the solubility problems of a number of drugs have been solved by their conversion into nanocrystals. 1.2.7 Viral Nanoparticles Viruses are seen as good carriers for drug delivery as they naturally infect and deliver their genetic contents (DNA or RNA genome) to host cells.43 Virus-like particles usually consist of thousands of protein molecules that self-assemble to form a cover for the nucleic acids. Viral carriers derived from plants and bacteria are not only biocompatible and biodegradable, but they are also nontoxic and noninfectious in humans, and they have an easy functionalization due, among other things, to their symmetrical structure.44 The structure of viral carriers can be manipulated in such a way that their internal cavity contains drug molecules or imaging reagents, whereas the external surface can bear targeting ligands.45 Several clinical trials have failed due to the safety problem of viral vectors, so, ideally, the infection components should be transplanted from viruses to nanoparticles in order to avoid the toxicity.46

2 APPROVED NANOCARRIERS Based on the classification made previously, the nanoparticles that are currently on the market will be classified (see tables below).

2 APPROVED NANOCARRIERS

In addition, some of them will be explained in more detail in order to better understand their function.

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VIII deficiency is the cause of hemophilia A, so Adynovate, a recombinant antihemophilic factor, works by temporarily raising factor VIII levels in the blood to help clotting.

2.1 Polymeric Nanoparticles Polymer-based nanoformulations comprise a very heterogeneous group of nanosized therapeutics (Table 1).47, 48 The best example is Copaxone, a random copolymer composed of four amino acids (L-glutamic acid, L-alanine, L-lysine, and L-tyrosine).49 Glatiramer acetate (Copaxone) is a synthetic protein that simulates the basic myelin protein, a component of myelin that isolates nerve fibers in the brain and spinal cord. Initially approved in 1996, Copaxone was a revolutionary treatment that acted as an immunomodulator in the treatment of multiple sclerosis. Drugs are usually attached to a hydrophilic polymer to increase circulation or improve biocompatibility/solubility.50 The most wellestablished polymer is polyethyleneglycol (PEG). Such systems include the successful drug Neulasta (PEGylated granulocyte colony stimulating factor), which has been FDA-approved since 2002 for chemotherapy-induced neutropenia. In this case, PEGylation resulted in a significant increase in the biological half-life in plasma.51 More recently, the FDA approved new PEGylated biologic drugs. In 2014, Plegridy (PEGylated interferon gamma beta-1a) was approved for treatment of relapsing multiple sclerosis (MS). The addition of PEG to the therapeutic protein improved biological half-life and exposure in comparison with the protein alone.52 In comparison to Copaxone and other IFN-based MS treatments, which are often administered daily, Plegridy can be administered every 2–4 weeks. In 2015, Adynovate (PEGylated antihemophilic factor VIII) was approved for treatment of hemophilia A, both in terms of preventing bleeding episodes, or treating acute bleeding.53 Antihemophilic factor is a natural protein in the blood that helps the blood clot. Antihemophilic factor

2.2 Polymeric Micelles Among all the approved polymeric micelles (Table 2), conventional amphotericin B (Fungizone AMB deoxycholate) has been used and considered the “gold standard” of therapy to treat invasive systemic fungal infections since the early 1960s.55, 56 Fungizone is a preparation consisting of a dry powdery mixture of waterinsoluble AMB and sodium deoxycholate. Upon adding buffer, the deoxycholate solubilizes the drug by forming polydisperse micelles.57 Despite its broad-spectrum activity, the clinical use of Fungizone is limited by having high toxicity rates. This adverse effect becomes particularly important when used in patients for long periods of time (cumulative dose), if there is impaired renal function at baseline, and/or if it is used concomitantly with other nephrotoxic agents.58 One of the latest polymeric micelles that has been approved by the FDA is a traditional micellar formulation of estradiol (Estrasorb). It is indicated as a topical treatment for moderateto-severe vasomotor symptoms of menopause. Transdermal delivery avoids first pass metabolism and also gastrointestinal side effects, leading to stable serum levels for 8–14 days.59 Another application of polymeric micelles is the induction and maintenance of anesthesia or sedation. For this purpose, Diprivan was approved in 1989. It is an intravenous sedativehypnotic agent whose active component is propofol, a sterically hindered phenol.60

2.3 Lipid-Based Nanoparticles Lipid based nanoparticles are used in a vast set of clinical applications (Table 3). Within these, cancer therapy represents one of the most important fields of application. For example, Doxil/ Caelyx (PEGylated liposomal doxorubicin) was

426 TABLE 1

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

Approved Polymeric Nanoparticles Material Description

Application

Year Approved

Oncaspar/pegaspargase (Enzon Pharmaceuticals)54

PEGylated L-asparaginase

Acute lymphoblastic leukemia

1994

Eligard (Tolmar)54

Leuprolide acetate incorporated in nanoparticles composed of PLGH copolymer

Prostate cancer

2002

Polymer-protein conjugate

Hemophilia

2015

Adagen/pegademase bovine (Sigma-Tau Pharmaceuticals)23

PEGylated adenosine deaminase

Severe combined immunodeficiency 1990 disease (SCID)

Copaxone/Glatopa (Teva)49

Polypeptide composed of four amino acids

Multiple sclerosis (MS)

1996

Renagel [sevelamer hydrochloride]/Renagel [sevelamer carbonate] (Sanofi)23

Cross-linked poly allylamine hydro chloride

Chronic kidney disease, Hyperphosphatemia

2000

Peglntron (Merck)54

PEGylated interferon alfa-2b

Hepatitis C

2001

Pegasys (Genentech)

PEGylated interferon alfa-2b

Hepatitis B y C

2002

Neulasta/pegfilgrastim (Amgen)54

PEGylated filgrastim

Febrile neutropenia, chemotherapy induced

2002

Somavert/pegvisomant (Pfizer)23

PEGylated human growth hormone Acromegaly, second line therapy receptor antagonist

2003

Macugen/Pegaptanib (Bausch & Lomb)23

PEGylated anti-VEGF aptamer

Macular degeneration neovacular age-related

2004

Mircera/Methoxy polyethylene glycol-epoetin beta (Hoffman-La Roche)23

PEGylated epoetin beta (errythropoietin receptor activator)

Anemia associated with chronic kidney disease in adults

2007

Cimzia/certolizumab pegol (UCB)23

PEGylated antibody

Crohn’s disease, Rheumatoid arthritis, Psoriatic Arthritis, Ankylosing Spondylitis

2008

Krystexxa/pegloticase (Horizon)23

Polymer-protein conjugate

Chronic gout

2010

Plegridy (Biogen)52

Polymer-protein conjugate

Multiple sclerosis

2014

Name CANCER

CARDIOVASCULAR DISEASES Adynovate (Baxalta)53 OTHER DISEASES

54

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2 APPROVED NANOCARRIERS

TABLE 2

Approved Polymeric Micelles

Name

Material Description

Application

Year Approved

Polymeric micelle formulation of paclitaxel

Metastatic breast cancer, pancreatic cancer

2001

Fungizone (Bristol Meyers Squibb)55–58

Lyophilized powder of amphoterecin B with added sodium deoxycholate

Systemic fungal infections

1966

Diprivan (Astra-Zeneca)60

Oil-in-water emulsion of propofol in soybean oil/glycerol/egg lecithin

Sedative-hypnotic agent for induction and maintenance of anesthesia

1989

Estrasorb (Novavax)59

Emulsion of estradiol in soybean oil, polysorbate 80, ethanol, and water

Hormone replacement therapy during menopause

2003

CANCER Genexol-PM (Samyang Biopharmaceuticals)61 OTHER DISEASES

TABLE 3

Approved Lipid Based Nanoparticles

Name

Year Approved

Material Description

Application

Doxil/Caelyx (Sequus Pharmaceuticals)62

Doxcrubicin encapsulated into PEGylated liposomes

Karposis Sarcoma; Ovarian cancer; multiple mieloma; breast cancer

1995

DaunoXome (NeXstar Pharmaceuticals)66, 67

Liposomal daunorubicin

Karposis Sarcoma

1996

Myocet (Elan Pharmaceuticals)70

Doxorubicin encapsulated into cligolamellar liposomes

Metastatic breast cancer

2000

Mepact (Takeda Pharmaceutical Limited)71

Mifamurtide incorporated into a large multilamellar liposomes

Nonmetastasizing resectable osteosarcoma

2004

Marqibo (Talon Therapeutics. Inc.)68

Vincristine sulfate encapsulated into liposomes

Philadelphia chromosome-negative acute lymphoblastic leukemia

2012

Onivyde (Merrimack Pharmaceuticals Inc)69

Irinotecan encapsulated in a liposome

Metastatic pancreatic cancer

2015

VYEXOS, CPX-351 (Celator Pharmaceuticals)23

Liposomal formulation of cytarabine: daunorubicin

Leukemias

2017

Liposome-proteins SP-B and SP-C

Respiratory Distress Syndrome

1999

CANCER

RESPIRATORY DISEASES Curosurf/Poractant alpha (Chiesi)14, 23

Continued

428 TABLE 3

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

Approved Lipid Based Nanoparticles—cont’d

Name

Year Approved

Material Description

Application

Abelcet/Amphocil (Sigma-Tau Pharmaceuticals)82

Amphoterecin B complex 1:1 with DMPC and DMPG

Fungal infections Systemic fungal infections

1995

Amphotec (Ben Venue Laboratories Inc.)81

Amphotericin B complex with cholesteryl sulfate

Infectious diseases

1996

AmBisome (Astellas Pharma)80

Anphoterecin B liposomes

Infectious diseases

1997

Optison (GE Healthcare) (1997)86, 87

Human serum albumin stabilized perflutren microspheres

Ultrasound contrast agent

1997

Inflexal V (Crucell)78

Influenza virus antigens on surface of liposomes

Influenza vaccine

1997

DepoCyt (SkyPharma Inc.)14, 23

Cytarabine encapsulated in multivesicular liposomes

Lymphomatous meningitis

1999

Visudyne (Novartis)83–85

Verteporfin in liposomes

Photodynamic therapy of wet age-related macular degeneration. pathological myopia, ocular histoplasmosis syndrome

2000

Definity (Lantheus Medical Imaging)86, 87

Perflutren encapsulated in phospholipid microspheres

Ultrasound contrast agent

2001

SonoVue (Bracco Imaging)87

Phospholipid stabilized microbubble

Ultrasound contrast agent

2001

Restasis (Allergan)14,

Nanoemulsion of Cyclosporine A

Dry eye syndrome

2002

DepoDur (SkyPharma Inc.)

Morphine sulfate encapsulated in multivesicular liposomes

Analgesia (postoperative), chronic pain

2004

Durezel (Sirion Therapeutics)14, 23

Nanoemulsion of difluprednate

Eye infalammation, uveitis

2008

Bupivacaine in liposomes

Pain management

2011

Nanoemulsion of Cyclosporine A

Dry eye syndrome

2015

OTHER DISEASES

23 14, 23

Exparel (Pacira Pharmaceuticals, Inc.)14, Ikervis (Santen)14,

23

23

the first FDA-approved cancer nanomedicine; its major feature was the presence of polyethylene glycol (PEG) chains on the liposomal surface,62 which is a very successful strategy for increasing the longevity of liposomes in the circulatory system.63–65 Soon after, other liposomal formulations, such as liposomal daunorubicin liposomal vincristine (DaunoXome),66,67

(Marqibo), 68 and most recently liposomal irinotecan (Onivyde),69 were approved by the FDA, whereas non-PEGylated liposomal doxorubicin (Myocet)70 and liposomal mifamurtide (Mepact)71 were approved by the EMA. Onivyde is a topoisomerase I inhibitor for the treatment of metastatic pancreatic cancer. It is approved as a second-line treatment of

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2 APPROVED NANOCARRIERS

metastatic pancreatic cancer. Like all of the previously approved liposomal systems, Onivyde is based on passive targeting.72, 73 Myocet is a nonpegylated liposomal DOX that has been approved in combination with cyclophosphamide for first-line treatment of patients with breast cancer.74 Myocet was developed to reduce the cardiotoxicity of DOX while maintaining its antitumor efficacy.75, 76 Mepact is a mifamurtide (MFT) containing liposomes, and it was the first drug approved for the management of high-grade, resectable, nonmetastatic bone tumors combined with postoperative combination chemotherapy in children, adolescents, and young adults who have gone through full macroscopic surgical resection.71 Besides cancer therapy, liposomes have also been used as a nanocarrier for vaccines. Some of them have been approved in many European countries. For example, Epaxal for vaccination against hepatitis A (abolished at the moment)77 and Inflexal V for vaccination against influenza,78 which use their viral glycoproteinliposomal template as the primary adjuvant.79 In other applications, lipid-based nanoparticles have been approved for fungal and parasitic infections. For example, the highly toxic antifungal drug amphotericin B, used for treating systemic fungal infections, has been formulated in liposomes (AmBisome),80 reducing its toxicity and improving the pharmacokinetics and tissue distribution. Moreover, other FDA-approved lipid formulations of amphotericin B exist, such as Abelcet and Amphotec.81 Despite the fact that they are lipid formulations of amphotericin B, they have shown different behaviors: TABLE 4

AmBisome, the smallest (diameter of 60–70 nm) of the three nanoformulations, has been reported to have four- to seven-times higher concentrations in brain tissue than any of the other formulations, while Abelcet appears to have superior pulmonary perfusion compared with the other agents.82 Visudyne is a light-activated liposomal formulation of verteporfin for wet macular degeneration.83, 84 Liposomal encapsulation provides enhanced uptake in proliferating cells, which improves targeting and uptake by targeting neovascular areas, which, following light stimulation, damages the endothelium and blocks local blood vessels, finally preventing and treating neovascularization.85 Another use of lipid-based nanoparticles that is widely employed is as ultrasound contrast. Particles, such as Optison and SonoVue, have been approved for this purpose. In these cases, particles are microbubbles,86, 87 which provide a means to enhance contrast by stabilizing and encapsulating air bubbles (perfect reflectors of ultrasound).

2.4 Protein Nanoparticles Over the last years, albumin has gained significant attention as a carrier for therapeutic agents because it improves the pharmacokinetic and toxicological profile of the free drug (Table 4). Like other nanocarriers, albumin particles passively accumulate at the site of solid tumors. In addition, following the dissociation of the protein nanoparticle into individual drug-bearing albumin molecules, specific albumin-receptor

Approved Protein Nanoparticles

Name

Material Description

Application

Nanoparticles formed by albumin with conjugated paclitaxel

Metastatic breast cancer, non-small-cell lung cancer, metastatic pancreatic cancer

Year Approved

CANCER Abraxane(Celgene)91–93

2005

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mediated cellular uptake mechanisms have been discussed.88, 89 An increasing number of albumin-based therapeutics are currently in clinical trials,90 but the most representative albumin-based pharmaceutical is Abraxane, which consists of nanoparticles prepared from albumin with conjugated paclitaxel.91 It was approved by the FDA in 2005, and it was the first drug based on an albumin carrier. Abraxane has advantages over paclitaxel, including increased half-life in the circulation and lack TABLE 5

of hypersensitivity.92, 93 It has shown proteindrug nanoparticles to be excellent nanomaterials for improving toxicity and passive delivery to a desired target.

2.5 Inorganic Nanoparticles Inorganic nanoparticles are a well-studied field, with a large number of inorganic carriers being under investigation for therapeutic and imaging treatments (Table 5).

Approved Inorganic Nanoparticles

Name

Year Approved

Material Description

Application

Aminosilane-coated superparamagnetic iron oxyde

Local ablation in glioblastoma, prostate and pancreatic cancer

2010

CosmoFer/INFeD/Ferrisat (Sanofi Avertis)98–100

Iron(III)-hydroxide dextran complex

Iron deficiency in chronic kidney disease (CKD). Iron deficient anemia.

1957

Dexlron/Dexferrum (Sanofi Avertis)98–100

Iron dextran

Iron deficiency in chronic kidney disease (CKD)

1957

Feridex/Endorem (AMAG pharmaceuticals)96

Iron Oxide Nanoparticles (SPION) coated with dextran

Imaging of liver lesions

1996

Ferrlecit (Sanofi Avertis)98–100

Sodium ferric gluconate

Iron deficiency in chronic kidney disease (CKD)

1999

Venofer (Luitpold Pharmaceuticals)98–100

Iron sucrose

Iron deficiency in chronic kidney disease (CKD)

2000

GastroMARK; Lumirem (AMAG pharmaceuticals)94–96

SPION coated with silicone

Imaging agent

2001

Feraheme/Ferumoxytol (AMAG pharmaceuticals)102, 103

Super Paramagnetic Iron Oxide Nanoparticles (SPION) coated with dextran

Iron deficiency in patients with chronic kidney disease (CKD)

2009

Resovist (Bayer Schering Pharma)/ Cliavist94–96

Iron carboxydextran colloid

Imaging of liver lesions

2009

Monofer (Pharma cosmos)97

Iron isomaltose colloid

Iron deficiency anemia when iron delivery is required immediately

2010

Injectafter/Ferinject (Vifor)97

Iron carboxymaltose colloid

Iron deficient anemia

2013

CANCER Nanotherm (MagForce)107, 108 OTHER DISEASES

3 NANOCARRIERS IN STUDY

Due to their magnetic constituent materials, such as iron oxide, some inorganic particles are used for magnetic resonance imaging (MRI), generating contrast in cancers and other pathologies.94–96 However, the majority of FDAapproved materials are formulated as iron increase therapies.97 There are many approved compounds indicated to treat anemia related to chronic kidney disease (Venofer, Ferrlecit, etc.).98–100 They are composed of an iron oxide core, coated with hydrophilic polymers (e.g., sucrose, dextran), which provide slow dissolution of the iron. This allows a rapid administration of large doses without increasing free iron in the blood to a level that causes toxicity.101 There are also some particles (Feraheme)102, 103 under investigation for more than one application, such as MRI and anemia.104–106 On the other hand, NanoTherm was approved in 2010. NanoTherm is composed of aminosilanecoated SPIONs (superparamagnetic iron oxide nanoparticles) designed for tumor therapy (glioblastoma) using local tissue hyperthermia.107 Here, the nanoparticles are injected directly into the solid tumor mass, and then the exposure to an alternating magnetic field is used to selectively heat the particles, resulting in local heating of the tumor environment (temperatures reach 40–45°C), leading to programmed and nonprogrammed cell death.108 Depending on the length of exposure to the oscillating magnetic field, the achievable intratumoral temperatures vary and either directly destroy tumor cells (thermal ablation) or sensitize them for chemotherapy (hyperthermia). Because most of the nanoparticles remain at the treatment area, follow-up treatment is possible.

2.6 Crystalline Nanoparticles Crystalline nanoparticles approved by the FDA have different uses, such as graft substitutes and immunosuppressants (Table 6). Rapamune was the first nanocrystal approved by the FDA and marketed in 2000.109 It contains the

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active component rapamycin, an immunosuppressant.110 Rapamune is indicated to prevent organ rejection following transplantation, specifically for kidneys. The crystalline nature of the compound provides the poorly soluble drug a constant extended release profile well suited to ongoing indications.111 Tricor and Triglide are nanoparticle formulations of fenofibrate. Fenofibrate is a peroxisome proliferator receptor alpha activator and it is used as an adjunct to diet for the treatment of hypercholesterolemia and hypertriglyceridemia. Fenofibrate is an inactive prodrug that, once hydrolyzed, forms fenofibric acid.112 Fenofibric acid reduces total cholesterol (TC), low-density lipoprotein cholesterol (LDL), triglycerides (TG), and very-low-density lipoprotein concentrations; and it increases high density lipoprotein cholesterol (HDL).113, 114 Among others, inorganic nanoparticles are also used as bone substitutes. Some compounds, such as Vitoss, Ostim or EquivaBone, have been approved for this purpose. They are calcium phosphate systems (hydroxyapatite) that act on bone remodeling.115 In addition, crystalline nanoparticles are used for a less common purpose, Ryanodex is a skeletal muscle relaxant drug indicated for malignant hyperthermia.23

3 NANOCARRIERS IN STUDY Given the success of these nanocarriers and, as some of them were approved years ago, it is not surprising that these currently approved nanoparticles are being investigated in a large number of current clinical trials. These trials are built on the current indications of each individual nanoparticle by seeking approval for additional diseases, a combination therapy with other therapeutic agents, or by upgrading their use from a secondary therapy to a primary first-line therapy. But there are also new nanoparticle formulations for which approval is being sought.

432 TABLE 6

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

Approved Crystalline Nanoparticles

Name

Year Approved

Material Description

Application

Tricor (Lupin Atlantis)112–114

Fenofibrate as nanocrystals

Hypercholesterolemia, hyperglyceridemia

2004

Triglide (Casper Pharma)112–114

Fenofibrate as insoluble drug-delivery microparticles

Hypercholesterolemia, hyperglyceridemia

2005

Rapamune (Wyeth Pharmaceuticals)109–111

Rapamycin (sirolimus) as nanocrystals formulated in tablets

Immunosuppressant

2000

Megace ES (Par Pharmaceuticals)14

Megestrol acetate as nanocrystal

Anorexia, cachexia

2001

Morfine sulfate

Psychostimulant

2002

Metilphenidate HCl

Psychostimulant

2002

Tiazinidine HCl

Muscle relaxant

2002

Aprepitant as nanocrystals

Emesis, antiemetic

2003

Calcium phosphate

Bone substitute

2003

Hydroxyapatite

Bone substitute

2003

Hydroxyapatite

Bone substitute

2004

Dexamethyl-phenidate HCl

Psychostimulant

2005

Hydroxyapatite

Bone substitute

2005

CARDIOVASCULAR DISEASES

OTHER DISEASES

14

Avinza (Pfizer)

14

Ritalin LA (Novartis) 14

Zanaflex (Acorda) 14

Emend (Merk)

Vitoss (Stryker)

115

OsSatura (IsoTis Orthobiologics)

115

115

Ostim (Heraseus Kulzer) 14

Focalin XR (Novartis)

115

NanOss (Rti Surgical)

115

Hydroxyapatite

Bone substitutive

2009

14

Paliperidone palmitate

Schizoaffective disorder

2009

14

Dantrolene sodium

Malignant hyperthermia

2014

EquivaBone (Zimmer Biomet)

Invega Sustenna (Janssen Pharms)

Ryanodex (Eagle Pharmaceuticals)

3.1 Polymeric Nanoparticles Polymer efficacy in improving therapeutic and diagnostic advantage, over conventional medicines, is evident if looking at the polymeric approved nanocarriers for drug delivery. It is also shown by their continuing investigation in clinical trials (Table 7), especially for cancer. For example, etirinotecan pegol (NKTR-102) is a long-acting topoisomerase-I inhibitor from camptothecin (citotoxic drug). It consists of the topoisomerase-I inhibitor irinotecan bound to a

polyethylene glycol core by a biodegradable linker.116 The linker slowly hydrolyses in vivo to form SN38, the active moiety of NKTR102.117 The drug provides continuous exposure to SN38 while reducing the toxicities associated with excessively high irinotecan and SN38 plasma concentrations reported in patients who receive irinotecan directly.118, 119 Clinical studies in phases II and III of etirinotecan pegol showed promising activity,120 providing evidence of enhanced antitumor activity and less

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TABLE 7

Polymeric Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Phase

AZD2811 (AstraZeneca with BIND Therapeutics)62

Aurora B kinase inhibitor in BIND therapeutics polymer particle accurin platform

Small cell lung cancer, advanced solid tumors, acute myeloid leukemia, highrisk myelodysplastic syndrome

Phases I/II

BIND-014(BIND Therapeutics)134

Prostate-specific membrane antigen (PSMA) targeted (via ACUPA) docetaxel PEG-PLGA or PLA-PEG particle

Prostate, metastatic, non-small-cell lung (NSCLC), cervical, head and neck, or KRAS positive lung cancers

Phase II (Completed)

CRLX101 (Cerulean)128–130

Cyclodextrin based nanoparticle camptothecin conjugate

Ovarian, renal cell, small cell lung, or rectal cancers

Phases I/II

CRLX301 (Cerulean)62

Cyclodextrin based nanoparticle docetaxel conjugate

Dose escalation study in advanced solid tumors

Phases I/II

NKTR-102 (Nektar Therapeutics)116–127

PEGylated etirinotecan

Breast cancer

Phases II/III

PPX (CTI BioPharma)131–133

Polymer-drug conjugate of paclitaxel and polyglutamic acide

Non-small-cell lung cancer (NSCLC)

Phase III

CANCER

hematopoietic toxicity than the direct exposure to irinotecan.121–127 Using the same drug (camptothecin), cyclodextrin-based nanoparticles (CRLX101) are being tested with clinical results indicating good tolerability128 and tumor reduction in most patients.129 CRLX101 has achieved trials (phases I and II) in patients with rectal, ovarian, tubal, and peritoneal cancer, reducing the toxicity and increasing the efficacy of campothecin.130 Also for cancer treatment, a polymer-drug conjugate of paclitaxel and polyglutamic acid (paclitaxel poliglumex, PPX) is showing good results (trials in phase III) for patients who undergo paclitaxel therapy for non-small-cell lung cancer.131 PPX is a macromolecular polymer drug conjugate that links paclitaxel to a biodegradable polymeric structure consisting of 132 L-glutamic acid residues. Due to this structure, it reduces systemic exposure to peak concentrations of free paclitaxel.133

Another important targeted polymeric nanoparticle is BIND-014, which targets prostatespecific membrane antigen (PSMA). This antigen is expressed in many tumors, such as prostate cancer cells or lung cancer cells.134 These nanoparticles are composed of a hydrophobic polylactic acid polymeric core, encapsulating docetaxel (cytotoxic agent) and a hydrophilic polyethylene glycol corona decorated with small molecule PSMA-targeting ligands. The clinical results (phase II study) highlight the efficacy of BIND-014 in shrinking tumors, even in tumors that typically show minimal response to docetaxel.134

3.2 Polymeric Micelles Just like polymeric nanoparticles, there are many micelle nanocarriers under study for drug delivery (Table 8), especially for cancer treatment.

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

Polymeric Micelles in Clinical Trials

Name

Material Description

Investigated Application

Phase

Genexol-PM (Samyang Biopharmaceuticals)62

Paclitaxel polymeric micelle nanoparticle

Advanced solid tumors, lung, biliary or pancreatic cancers

Phases II/III

NC-6004 Nanoplatin (Nanocarrier)137–139

Polyamino acid, PEG, and cisplatin derivative micellar nanoparticle

Head and neck or breast cancer

Phase I

NC-4016 DACHPlatin micelle (Nanocarrier)136

Polyamino acid PEG, and oxaliplatin micellar nanoparticle

Advanced solid tumors or lymphomas

Phase I (Completed)

NK105 (Nippon Kayaku)62

Paclitaxel micelle

Breast cancer

Phase III (Completed)

Docetaxel-PM DOPNP201 (Samyang Biopharmaceuticals)62

Docetaxel micelle

Head and neck cancer and advanced solid tumors

Phase I (Completed)

CriPec (Cristal Therapeutics)135, 136

Docetaxel micelles

Solid tumors

Phase I

CANCER

Micellar nanoparticles have been used to deliver docetaxel (cancer drug) to various solid tumors using CriPec particles. Here, degradable lactate-based hydrophobic blocks were linked to PEG-based hydrophilic blocks and the resulting therapeutic was incorporated through a degradable linker into the micelle.135 Docetaxel is released and becomes active upon cleavage from various linkers at a predetermined and controlled rate. In turn, active, unconjugated docetaxel binds to the beta-subunit of tubulin, stabilizes microtubules, and inhibits microtubule disassembly, which prevents mitosis and results in tumor cell death. It has been shown, in a phase I study, that, compared with the administration of docetaxel alone, this formulation is able to increase docetaxel’s efficacy while avoiding systemic exposure, which minimizes its toxicity.136 NC-6004 is a polymeric micelle containing cisplatin as active moiety.137 The nanoparticle provides sustained release of the active moiety and it utilizes the enhanced permeability and retention effect to target the release of platinum to tumors.138 The currently available

data (phase I study) suggest that NC-6004 has the potential to be more active than cisplatin, with increased tolerability.139 DACH-platin (an antineoplastic metabolite of platinum) is highly hydrophobic and toxic when administered systemically. The use of polymeric micelles incorporating DACH-platin may both increase cell permeability and enhance the retention of the agent, which allows an extended half-life in the blood circulation and a selective and high accumulation of DACHplatin at tumor sites. A phase I study illustrated that this results in increased anticancer efficacy, while reducing side effects due to DACH-platin toxicity.136

3.3 Lipid-Based Nanoparticles Several lipid-based nanoparticles have been successfully translated into the clinic, while other liposomal formulations are in different phases of clinical investigation (Table 9). Furthermore, some of the FDA-approved lipidbased nanoparticles are currently in clinical trials for other diseases or to improve their

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TABLE 9

Lipid-Based Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Phase

Antigenic lipo-peptide (TCΜ)

Non-small-cell lung cancer (NSCLC) Phase II/III

Liposomal formulation of Cisplatin

Pleural malignancies

CANCER Stimuvax (Merck KgaA)145–147 Lipoplatin (Regulon lnc.)

148–150

Phase I

Promitil (Lipom edix Pharmaceuticals)62

Pegylated liposomal mitomycin-C Solid tumors metastatic colo rectal cancer

Phase I

ThermoDox (Celsion)151–153

Lyso-thermosensittve liposomal doxorubicin

Hepato cellular carcinoma

Phase III

VYEXOS, CPX-351 (Celator Pharmaceuticals)157, 158

Liposomal formulation of cytarabine: daunorubicin

Leukemias

Phase I/II/III

Oncoprex(Genprex)62

FUS1 (TUSC2) encapsulated liposome

Lung cancer

Phase II

Halaven E7389-LF (Eisai)62

Liposomal eribulin mesylate

Solid tumors

Phase I

Mitoxantrone Hydrochloride Liposome (CSPC ZhongQi Pharmaceutical Technology)62

Mitoxantrone liposome

Lymphoma and leukemia

Phases I/II

Lipocurc (Sign Path Pharma)62

Liposomal curcumin

Advanced cancer

Phases I/II

LiPlaCis (LiPlasome Pharma)161–163

Liposomal formulated cisplatin with specific degradationcontrolled drug release via phospholipase A 2 (PLA2)

Advanced or refractory solid tumors, Phases I/II metastatic breast cancer or skin cancer

MM-302 (Merrimack Pharmaceuticals)164

HER2-targeted liposomal doxorubicin (PEGylated)

Breast cancer

Phase I

LIPUSU (Nanjing Luye Sike Pharmaceutical Co., Ltd.)62

Paclitaxel Liposome

Lung squamous cell carcinoma

Phase IV

Arikace (Transave, Inc.)140–144

Amikacin (AMK) liposomal formulation

Bronchiectasis pseudomonas aeruginosa infection

Phases I/II/III (Completed)

CAL02 (Combioxin SA)165

Sphingomyelin and cholesterol Pneumonia liposomes for toxin neutralization

RESPIRATORY DISEASES

Phase I (Completed)

CARDIOVASCULAR DISEASES Sonazoid62

F-butane encapsulated in a lipid shell

Contrast-enhanced ultrasound for Phases I/II/IV estimating portal hypertension or for imaging hepatocellular carcinoma, skeletal muscle perfusion

Nanocort (Enceladus in Liposomal Prednisolone collaboration with Sun Pharma (PEGylated) Global)62

Renal dialysis, hemodynamics, vascular remodeling

Phase II

Liprostin (AngioSoma)154–156

Veno-occlusive disease. Arteriosclerosis, coronary microvascular perfusion in patients with ischemic heart disease

Phase II/III/IV

Prostaglandin E-1 (PGE-1)encapsulated liposomes

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

use as a combined therapy. For example, Visudyne was approved for treating neovascularization but it is currently being investigated in clinical trials by combining it with other antineovascularization therapies.72 AmBisome, also approved years ago, is still studied in the clinic for additional bacterial/fungal infections and in tolerability and efficacy in patients with other diseases or complications.72 Lipid nanocarriers are also employed in respiratory diseases: Arikace is a prolonged release amikacin (AMK) liposomal formulation for inhalation, developed using advanced pulmonary liposome technology. AMK acts by inhibiting the production of bacterial proteins, so Arikace is indicated in the treatment of certain serious bacterial infections,140 especially for site-specific treatment of serious lung infections. Arikace received orphan drug status for the treatment of Pseudomonas aeruginosa (PsA) infections in patients with Cystic Fibrosis (CF). It also received orphan drug status for Pseudomonas-associated non-CF bronchiectasis therapy and for other lung infections. The product, at present, is in phases I/II/III clinical trials for these indications,141 with very promising results.142–144 For the treatment of cancer, there are many liposome-based nanoparticles currently in clinical studies. Stimuvax, earlier known by the name BLP25 liposome vaccine, is a therapeutic vaccine indicated for certain types of cancer expressing Tumor-Specific Antigens (TSA).145 This vaccine incorporates an antigenic lipo-peptide, that is, Tecemotide (TCM), in a liposomal delivery system. TCM targets mucin 1 (MUC1), which is overexpressed in different cancer cells, including breast, prostate, non-small-cell lung cancer (NSCLC), and colorectal cancer. It was the first product belonging to the class of cancer vaccines that entered advanced clinical trial phases II/III.146,147 Another lipid-based nanocarrier for cancer is Lipoplatin, a proprietary liposomal formulation of Cisplatin (CPT), a cytotoxic agent widely used in cancer treatment. The product has been introduced as Lipoplatin for

the treatment of pancreatic cancer and Nanoplatin for lung cancer. Encapsulation of CPT into liposomes offer various advantages, such as high encapsulation efficiency, long-term circulation in vivo, ability to attain much higher concentration in tumors compared with CPT alone and the ability to penetrate the cell membrane.148 The product is presently in phase I clinical trials for malignant pleural effusion.149 Lipoplatin has considerably reduced the adverse effects associated with CPT, including toxicity and peripheral neuropathy.150 Another interesting drug under phase III study for the treatment of cancer is ThermoDox, which is a temperature-sensitive liposomal formulation of doxorubicin.151 ThermoDox is formulated with thermally sensitive lipids that degrade the bilayer when exposed to high heat, allowing for site-specific release of the drug.152 It is indicated in primary liver cancer (hepatocellular carcinoma) and also recurring chest wall breast cancer.153 Liprostin are prostaglandin E-1 (PGE-1)encapsulated liposomes formulated for the therapy of various cardiovascular diseases, such as restenosis subsequent to angioplasty. Restenosis is associated with re-blockage of blood vessels in the heart and legs following catheter intervention, which is a very expensive medical issue. PGE-1 acts as a potent vasodilator, platelet inhibitor, antiinflammatory and antithrombotic agent.154 Liprostin improved the drug dynamics and improved the therapeutic index of various ailments, including occlusive disease, limb salvage, claudication, and arthritis.155 This is the first clinical study in which a vasoactive hormone (PGE1) has been used as an adjunct treatment along with an angioplasty procedure,156 and it is in phase II/III/IV studies.

3.4 Protein Nanoparticles Several albumin-bound nanoparticles (NABs), have been entered into clinical trials (Table 10) with the goal of improving the therapeutic efficiency of other drugs.

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3 NANOCARRIERS IN STUDY

TABLE 10

Protein Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Phase

Albumin bound thiocolchicine analog (IDN 5405)

Neoplastic diseases

Phase I

Albumin bound rapamycin

Pulmonary hypertension

Phase I

CANCER ABI-011 (NantBioScience)166–170 RESPIRATORY DISEASES ABI-009 (Aadi with Celgene)171

In preclinical studies of phase I, nabrapamycin (ABI-009) has shown an excellent efficacy and safety profile; it reduced cell viability and decreased downstream signaling in various xenograft cancer models, including pancreatic, colorectal, multiple myeloma, and breast cancer.166–169 The binding of waterinsoluble rapamycin to nanoparticle albumin permits the albumin-mediated endocytosis of rapamycin by tumor cells and endothelial cells. Additionally, in human breast xenograft models, nab-rapamycin alone produced 75% tumor growth inhibition without weight loss and antitumor activity was further enhanced with the combination with other drugs.170 On the other hand, ABI-011 is a novel albuminbound formulation of IDN 5404 (a thiocolchicine analog). The active drug, IDN 5404, is related to the colchicine family of tubulin-binding compounds that have been found to have vasculardisrupting activity in vivo. Studies in phase I are trying to determine whether IDN 5404 has vascular-disrupting activity. As a dimer, IDN 5404 has an additional activity as an inhibitor of topoisomerase I, a critical enzyme in deoxyribonucleic acid (DNA) repair mechanisms.171

3.5 Inorganic Nanoparticles Some of the already approved inorganic particles are currently under study for other applications. This is the case of Ferumoxytol (Feraheme or Rienso), which was approved for iron-replacement therapies and, at the moment, is being widely investigated for

imaging applications in the clinic, with a special focus on imaging of cancers.172 In addition, there are also other new formulations under study for drug delivery (Table 11). AuroLase are silica-gold nanoshells coated with (poly)ethylene glycol (PEG) designed to thermally ablate solid tumors following stimulation with a near-infrared energy source.173 The silica core serves as the dielectric core, the gold shell grants thermal ablation ability following the intense absorption of near-infrared (NIR) light, and the PEG layer provides overall particle stability.174 AuroLase could be used to induce photothermal cell death following stimulation with a NIR energy source and to increase solid tumor temperatures to induce irreversible thermal damage.174 In studies of phase II, it was used for thermal ablation treatment of brain175 and prostate176 cancers. NBTXR3 is a novel radio enhancer utilizing a high electron density metal oxide (hafnium oxide) nanoparticle to increase radiotherapy efficacy without increasing the surrounding tissue dose.177 Incorporation of a high electron density material maximizes X-ray interactions, producing a larger number of excited electrons and, in turn, forming more reactive radical species.178 Uptake is increased by tuning the particle size and surface properties, maximizing the local cellular damage when particles are irradiated.177 NBTXR3 is under study (phases I/II/III) for use in soft tissue sarcoma, and in head, neck, and rectal cancer. Cornell dots (C-dots) are inorganic silica nanoparticles designed for fluorescence imaging

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

TABLE 11

Inorganic Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Phase

AuroLase (Nanospectra Biosciences)173–176

PEG-coated silica-gold nanoshells for near infrared light facilitated thermal ablation

Photothermal cell death, Neoplasms of the prostate

Phase II

NBTXR3 PEP503 (Nanobiotix)177, 178

Hafnium oxide nanoparticles stimulated with external radiation to enhance tumor cell death via electron production

Head and neck squamous cell carcinoma, adult soft tissue sarcoma or rectal cancer

Phases I/II/lII

Cornell Dots179

Silica nanoparticles with a NIR fluorophore, PEG coating, and a 1241 radiolabeled cRGDY targeting peptide

Imaging of melanoma and malignant brain tumors

Magnablate171

Iron nanoparticles

Thermal ablation for prostate cancer

Sienna+ (Endomag)171

Superparamagnetic iron oxide particles

Lymph node detection in rectal and breast cancer

CANCER

applications. Designed for lymph node mapping in cancer patients, these particles comprise a targeting moiety, an antifouling polymer layer, and an internal silica core labeled with a near-infrared (NIR) fluorescent dye, Cy5.5. Cyclic peptides were employed as the targeting agent that binds to tumor and tumor endothelial cells. The particle design leads to a nanoparticle that is brighter and more stable than the constituent dye in solution, so the trials indicate good results as a tumor imaging agent.179

4 NANOCARRIERS IN GENE THERAPY Gene therapy started in the early 1970s to restore the functionality of defective genes, and in a few years it became a potential powerful therapeutic approach for many different diseases, including diabetes,180 cancer,181 arthritis,182 hemophilia,183 neurological disorders,184 and retinal diseases,185 among others186–189 This therapy introduces new genes into cells, repairs or

Phase 0 (Completed)

replaces existing abnormal genes, or regulates the expression of particular genes.190 Usually, it is enough to introduce some nucleic acids into target cells; however, some of them are not able to cross the cellular membrane by simple passive diffusion methods because of the negative charge of the molecules and the negative nature of the cellular membrane.191 Due to their natural ability to transduce their own genetic material into host cells, viral vectors have been demonstrated to be a highly efficient delivery system in gene therapy192; nevertheless, they have also shown many signs of toxicity and side or off-target effects.193, 194 The use of genetic engineering and genedelivery systems in this therapy have been broadly studied195 and one of the major challenges is to engineer effective gene-delivery vectors with less cytotoxicity.196 In order to overcome the drawbacks of viral vectors (refer to Chapter 7 of this book, Viral Vectors for Treatment of Human Disease: Therapeutic and Manufacturing Challenges), nonviral vectors have been studied and developed with the same object.197 Nonviral

4 NANOCARRIERS IN GENE THERAPY

vectors are safer than viral ones as they are less likely to cause immune reactions and mutagenesis and are also more cost effective and easier to produce.198 Nanoparticles are a favorable nonviral option for gene delivery due to their nanometric size, high surface-volume ratio, and stability. Some nanoparticles are able to encapsulate nucleic acids and release them inside target cells, protecting these sensitive biomolecules from degradation. These characteristics, in addition to the lack of immunogenicity, make nanoparticles an ideal choice as nonviral vectors in gene therapy.199, 200 However, there are still several problems for the clinical application of nanoparticle-based gene therapy, including biodegradation and biocompatibility, aggregation in physiological fluids, nonspecific adsorption by undesired tissues, less efficient extravasation to reach target tissues, cellular internalization, and endosomal escape.201 There are many kinds of nanocarriers (organic and inorganic) used in gene therapy; for example, liposomes (refer to Chapter 9 of this book, Controlling Protein Expression by Delivery of RNA Therapeutics Using Lipid Nanoparticles) are one of the most widely used gene delivery systems in some types of cancer treatments. They can fuse with biological membranes, so they have been successfully employed to transfect nucleic acids.202, 203 As a vector in gene therapy, liposomes have been employed to tackle corneal diseases,204 cystic fibrosis,205 cardiovascular diseases,206 and cancer,207 among others. Cationic lipids are usually employed; they have a cationic polar head group that can form self-assembly interactions with DNA.208, 209 They have excellent gene-incorporation ability, high transfection efficiency, and are easy to prepare; these characteristics make them ideal nonviral gene carriers. But cationic lipids have some limitations, such as poor reproducibility and instability.208 Polymeric nanoparticles have received wide attention in gene delivery due to their outstand ing characteristics, including high stability and

439

biocompatibility.210 Among the polymers used in gene delivery carriers, the cationic polymer Polyethylenimine (PEI) is the most widely used for the delivery of DNA and RNA molecules.211, 212 Cationic polymers can bind DNA electrostatically.213 They are internalized into cells via adsorptive endocytosis or receptor-mediated endocytosis, and finally move into lysosomes.214 However, PEI is nonbiodegradable and has cytotoxicity induced by its high positive charge.215 To be used as an effective in vivo gene delivery carrier, PEI has been modified with other neutral or biodegradable polymers, such as polyethylene glycol (PEG), poly lactic-co-glycolic acid (PLGA), or biopolymers, to minimize its cytotoxicity.216 Polymeric micelles have been widely applied in gene delivery.217–219 The electrostatic interaction between the ionic segments of copolymer and the oppositely charged species, negatively charged nucleotides in gene delivery, lead to neutralization of ionic chains and change the ionic hydrophilic segment to hydrophobic. The DNA or RNA nucleotides are generally loaded or complexed inside the inner core, and the outer shell controls the pharmacokinetic behavior.220 Since the 1980s, self-assembled polymeric micelles have been developed as carrier systems for delivering various bioactive molecules, such as nucleotides, proteins, peptides and chemotherapeutic drugs.221 Micelles have also been widely applied in the codelivery of drugs and gene molecules. Alternatively, inorganic nanoparticles (refer to Chapters 10 and 12 of this book, Advanced Polymers for Non-viral Gene Delivery and Non-viral gene therapy: inorganic nanoplexes design and application) have lots of applications as gene delivery vectors due to their high surface-volume ratio, their optical and magnetic properties, and the convenience of functionalizing them.222 For example, advantageous properties of gold nanoparticles (AuNPs), such as nontoxicity and ease of preparation and functionalization, enable them to be ideal alternative delivery carriers in gene delivery systems.223 For the purpose of

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

efficient gene delivery, AuNPs have been conjugated with nucleotides, coated with polymer layers, or used as the core for dendrimers.224–228 In a pH-dependent gene delivery system, AuNPs were chemically modified with carboxylic acid chains and coated with PEI, the pH-dependent charge-reversal polyelectrolyte, for controlled release of small interfering RNA (siRNA) and plasmid DNA after pH change in the endosome.229 Among the viral vectors, those derived from retroviruses, lentiviruses, herpes simplex virus, pox viruses, adenovirus (Ad), and adenoassociated viruses have been in use.230 Ad-derived vectors (especially Ad type 5) are one of the most effective means of delivering genes in vivo and thus they are the most common vectors used in clinical trials.209 However, they have limitations that have been overcome by the electrostatic union of adenoviral vectors to lipid-based cationic particles, which has proven to be a good compromise to combine the advantages of viral and nonviral gene delivery vectors.231 Preclinical and early clinical studies of the Ad-based vectors for gene therapy have shown considerable promise for the future. Ad-mediated transgene expression is, however, hampered by the lack of adenoviral receptors in target cells and the systemic administration of Ad is limited by the host’s immune response, hepatotoxicity, short half-life of the vector and low accumulation at the target site.209 Depending on the disease to be treated, different types of nucleic acids (DNA, mRNA, siRNA, etc.) can be found.

4.1 Deoxyribonucleic Acid Delivery of DNA encoding a specific gene is a very promising tool in gene therapy, and great achievements are being made in this regard.232 There are some DNA delivery strategies under clinical evaluation for several diseases, including clinical trials for cancer therapy. For example, in a

phase I clinical trial, a tumor suppressor gene was delivered to lung cancer patients using liposomes, resulting in transgene expression and activation of apoptotic pathways.233 There are also some trials with a codelivery of two tumor suppressor genes fused to PEI.234 This therapy is also under evaluation in other diseases and has demonstrated good safety profiles and antitumor efficacy.235–238 One application of exogenous DNA delivery is the overexpression of genes that can suppress or kill tumor cells. These genes can be human in origin, viral proteins, bacterial toxins, or proteins designed for desired functions. Whereas many barriers to gene delivery are universal to all oligonucleotides (stability, cellular uptake, endosomal escape), DNA must additionally be delivered to the nuclear compartment to permit access to transcriptional machinery,239 which means an extra challenge to be met.

4.2 Messenger RNA The purpose of messenger RNA (mRNA) delivery is the same as in the DNA case: to supply a therapeutic gene that will be translated into protein within target cells.232 But unlike DNA, mRNA needs to reach the cytosol and be recognized by ribosomes, which makes transfection efficiency with mRNA higher than for DNA.240 Although mRNA does not have much stability, its protection against nucleases through nanoparticles can increase its stability. There are some clinical trials using mRNA for vaccines, adjuvants, or to express antigens either in dendritic cells ex vivo or by direct injection. However, gene replacement therapy is still under preclinical development.241

4.3 microRNAs microRNAs (miRNAs) are a class of noncoding, regulatory RNAs that have critical roles in nearly all biological processes, including diseases such as cancer, being able to serve as both

5 APPROVED NANOCARRIERS FOR GENE THERAPY

oncogenes and tumor suppressors.242 Each miRNA can target lots of mRNAs, and thus can regulate transcriptome-wide changes.243 Additionally, miRNAs are essential for immune cell development and immune activation244 as well as crosstalk between cancer cells and the tumor microenvironment.245 Therapeutic strategies with miRNAs are already in clinical trials, and there are some studies about this topic.246 For example, delivery of miR-16 with EGFRtargeted EnGeneIC Delivery Vehicle nanocells completed phase I clinical trials in mesothelioma with an acceptable safety profile and signs of efficacy.247 However, there have also been some trials that were terminated for showing severe immune-related and bone marrow suppressive adverse events.171

4.4 Small Interfering RNA Once inside the cells, siRNAs are incorporated into RNA-induced silencing complexes to bind to the target mRNA and induce mRNA degradation.248 They interact in the cytoplasm to degrade target mRNAs, so they do not have to transfer through the nuclear membrane, providing greater safety than plasmid DNAs.249 In structure, siRNAs are the same as miRNAs, and can be modified and encapsulated in the same way. Both the pathways, siRNAs and miRNAs, result in the inhibition of protein synthesis inside the cell.250–252 The main advantages of siRNAs are that the sequences can be rapidly designed for specific inhibition of the target of interest and also their synthesis is relatively simple.253 The broad therapeutic applicability of siRNA is evident by many clinical trials for the treatment of different types of cancer, liver fibrosis, and hypercholesterolemia, among others.254, 255 Even though the delivery of siRNA for biomedical applications is very promising, there are some drawbacks to be overcome for it application.256 Among them, the possibility for an ‘off-target’ effect, that is, the inhibition of a gene

441

sharing partial homology with the siRNA.257 Besides, a siRNA duplex can be recognized by the innate immune system (immune stimulation).258 In addition to these problems, delivery of siRNA during the therapy is an important challenge itself. Due to the large molecular weight, and the polycationic and hydrophilic nature of these products, they are unable to enter cells by passive diffusion mechanisms.259

4.5 Aptamers Aptamers are single-stranded oligonucleotides (DNA or RNA) with specific sequences that can form unique three-dimensional structures, which in turn can bind to the target molecules with selectivity.260 A number of aptamers with the capability of binding targets, such as metal ions, small molecules, proteins, viruses, and cells, have been identified.261 Due to the simplicity of nucleic acid composition, aptamers can be reversibly denatured and refolded without loss of activity.262 Moreover, aptamers can be chemically synthesized in large quantities with high reproducibility263 and can be sitespecifically modified.264

4.6 Other Noncoding RNAs Several classes of noncoding RNAs have been identified, including piwi-interacting RNAs, endogenous siRNAs, long-noncoding RNAs, and circular RNAs. The function of these species and their role in disease biology are being actively investigated.265

5 APPROVED NANOCARRIERS FOR GENE THERAPY After years of research and development, gene therapies are now becoming a commercial reality, although their beginnings have not been easy.

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

The first gene therapy medicinal product approved in Europe (2012) was Glybera (Alipogene tiparvovec). It is an adenoassociated virus serotype 1-based gene therapy approved for the treatment of lipoprotein lipase deficiency, a rare disease leading to abdominal pain, pancreatitis, and xanthomas. Glybera has been formally evaluated through Health Technology Assessment in Germany266 and France267 but failed to achieve recognition of benefit in either country. As a result, the actual benefit of Glybera is insufficient to justify reimbursement by their national health insurance, so the product is not commercialized in France. In addition, Glybera missed approval in the United States, so these facts contributed to it being withdrawn. Another gene therapy medicinal product that has been approved is Imlygic (Talimogene laherparepvec), a modified form of the herpes simplex virus type 1 for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.268 It was approved by both the EMA and the FDA in 2015, but the only European country in which an evaluation of Imlygic has been completed is the United Kingdom.268 While Imlygic may achieve coverage in several European countries, it will clearly face challenges and this final coverage may either be limited or may require a price discount (or both). While gene therapies are recognized as innovative and cutting-edge medicines, European health systems mainly focus on clinically significant and relevant patient outcomes compared with existing standard-of-care therapies, rather than on the mechanism of action used to generate these benefits. Moreover, European health systems are also unlikely to accept the long-term benefits of gene therapies without clear proof of sustainability. Another example of gene therapy that has recently been approved is Luxturna (Spark Therapeutics), approved in December 2017.269 It is an adeno-associated virus vector-based gene

therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutationassociated retinal dystrophy. One of the requirements for using Luxturna is having viable retinal cells.269 The approval of this therapy to treat children and adult patients with an inherited type of vision loss that can cause blindness involves the first directly administered gene therapy approved in the United States that targets a disease caused by mutations in a specific gene.

6 NANOCARRIERS IN CLINICAL TRIALS FOR GENE THERAPY Although currently few gene therapy drugs have been approved, there are many clinical trials in which these products are being studied. Below are some of these clinical trials, focusing on the most common or relevant ones. In this section, the different medicines will be grouped according to their genetic payload to check the development of each one.

6.1 siRNA One of the first siRNA nanoparticles in clinical trials was CALAA-01. It is a cationic cyclodextrin-based PEGylated polymer with a human transferrin protein ligand to target cancer cells.270 The siRNA of CALAA-01 targets the M2 subunit of ribonucleotide reductase (RRM2), which is overexpressed in several cancers and is involved in nucleic acid metabolism.270 Clinical trials confirmed CALAA-01 accumulation in tumors and not in adjacent normal tissues, and this uptake coincided with the knockdown of RRM2 at the transcript and protein levels.270, 271 Even though CALAA-01 demonstrated encouraging results in a phase I trial, some patients stopped treatment due to toxicities,272 such as hypersensitivity reaction, fever, lymphopenia, and diarrhea,270 in addition to inducing the production of cytokines.

6 NANOCARRIERS IN CLINICAL TRIALS FOR GENE THERAPY

Due to these severe adverse events and toxicities, further clinical development of CALAA01 was not pursued. Despite these negative results, many siRNA therapies are currently in clinical trials (Table 12); an example is ALN-VSP, a 100-nm lipid-based nanoformulation encapsulating two different chemically modified siRNAs that target vascular growth factor A (VEGFA) and kinesin spindle protein (KSP).270, 273 The treatment normalizes the tumor vasculature and decreases the tumor blood flow. A decrease in KSP mRNA levels, which impacts the mitotic cell cycle, was also observed.273 Another anticancer gene therapy-based formulation under clinical study is NU-0129.274 This is a spherical nucleic acid (SNA) gold nanoparticle formulation composed of small interfering RNAs (siRNAs) targeting the Bcl-2-like protein 12 (BCL2L12) sequence and conjugated to gold nanoparticles, with potential antineoplastic activity.274 When SNA NU-0129 is administered, the siRNA prevents the translation of the BCL2L12 gene, which induces tumor cell apoptosis. Bcl2L12, a protein belonging to the Bcl-2 protein family, is overexpressed in glioblastoma multiforme (GBM) and plays an important role in tumor cell progression and tumor cell resistance to apoptosis. In addition, NU-0129 is able to cross the blood brain barrier (BBB).274 In addition to anticancer applications, siRNA nanoparticles are studied for the treatment of other diseases. For example, TP705 is formulated for cardiovascular diseases.274 It is composed of two siRNAs targeting TGF-β1 and COX-2 mRNA, and formulated in nanoparticles with Histidine-Lysine Co-Polymer (HKP) peptide. Each individual siRNA inhibits the expression of its target mRNAs and combining the two siRNAs diminishes pro-fibrogenic and proinflammatory factors. Besides, the inhibition of these targets has effects on downstream gene products associated with fibrosis (α-SMA, Col1A1, Col3A1).274 These results suggest that

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STP705 has the potential for broad application in many inflammatory and fibrotic driven disease states.

6.2 mRNAs As with siRNAs, there are many medical nanoparticles based on mRNAs which are under clinical study for the treatment of different diseases (Table 13). There are a large number of these nanoformulations that focus on the treatment of various viruses. This is the case of mRNA-1647 (Moderna Therapeutics), which is being studied to combat the cytomegalovirus (CMV) infection.275 It is a vaccine that consists of six mRNAs, including five proteins designed to express the Pentamer complex, and another CMV antigen, the herpes virus glycoprotein protein.275 Another example, in which several mRNAs are combined, in this case for the treatment of cancer, is the Lipo-MERIT vaccine.276 It consists of a fixed set of RNA (LIP) products that encode the shared antigens associated with NY-ESO-1 melanoma, tyrosinase, MAGE-A3, and TPTE, which are administered successively within each treatment cycle.276

6.3 miRNAs Another type of nanoparticle studied in gene therapy contains miRNAs. Although the use of this type of particle is booming among preclinical experiments, there are still not many miRNA nanoparticles in clinical studies (Table 14). Within this field, the development of TargomiRs (miRNA mimics delivered by targeted bacterial minicells) stands out.277 As an alternative to the liposomal or nanoparticle-based methods frequently used to deliver miRNAs, EDVTMnanocells (EDVs) are employed. This bacterially derived delivery system developed by EnGeneIC Ltd278 comprises nonviable minicells produced by de-repressing polar sites of cell division in bacteria. Once loaded, EDVs

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14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

TABLE 12

siRNA Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Status

ALN-VSP02 (Alnylam Pharmaceuticals)171

Liposomal siRNA nanoparticles against VSP/VEGF-A

Solid tumors

Phase I

TKM-080301,TKM PLK1 (Arbutus Biopharma)171

Liposomal siRNA nanoparticles against PLK1

Hepatocellular carcinoma and other cancers with hepatic metastases

Phase I/II

siRNA-EphA2-DOPC (M.D. Anderson Cancer Center)171

Liposomal siRNA nanoparticles against EphA2

Advanced cancers

Phase I

Atu027 (Silence Therapeutics)171

Liposomal siRNA formulation targeting human PKN3

Advanced or metastatic pancreatic cancer

Phase I/II

NU-0129 (Northwestern University)171

siRNA targeting BCL2L12 conjugated Glioblastoma to gold nanoparticles

Phase I

siG12DLODER (Silenseed Ltd)171

Polymeric matrix containing siRNA for mutant KRAS

Pancreatic cancer

Phase II

Liposomal siRNA nanoparticles against HSP47

Pulmonary or hepatic fibrosis

Phase I/II

Phase I/II/III

CANCER

RESPIRATORY DISEASES ND-L02-S0201/BMS-986263 (Nitto Denko/Bristol-Myers Squibb)171

CARDIOVASCULAR DISEASES Inclisiran. ALN –PCSSC (Alnylam Pharmaceuticals)171

Liposomal siRNA nanoparticles against PCSK9

Hypercholesterolemia, renal impairment, atherosclerotic cardiovascular disease, type 2 diabetes

ALN-PCS02 (Alnylam Pharmaceuticals)171

Liposomal siRNA nanoparticles against PCSK9

Elevated LDL Cholesterol (LDL-C) Phase I

STP705(Simaomics)171

Polymer nanopartide containing siRNA against TGF-1β and Cox-2

Hypertrophic scarring

Phase I/II

OTHER DISEASES Patisiran, ALN-TTR02 (Alnylam Pharmaceuticals)171

siRNAs directed against transthyretin Transthyretin-induced amyloidosis Phase III (TTR) encapsulated in lipids

ALN-TTR01 (Alnylam Pharmaceuticals)171

siRNAs directed against transthyretin Transthyretin-induced amyloidosis Phase I (TTR) encapsulated in lipids

ARB-001467 (Arbutus Biopharma)171

Three siRNAs against all four Hepatitis B Virus (HBV) transcripts into lipid nanoparticles

Hepatitis B

Phase II

6 NANOCARRIERS IN CLINICAL TRIALS FOR GENE THERAPY

TABLE 13

445

mRNA Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Phase

TNBC-MERIT(BioNTech AG)171

Lipid nanoparticles mRNAs encoding TAAs and/or personalized neoantigens

Triple negative breast cancer

Phase I

Lipo-MERIT (BioNTech AG)171

Lipid nanoparticles with four mRNAs encoding MAAs

Melanoma

Phase I/II

mRNA-4157 (Moderna Therapeutics)171

Lipid nanoparticles containing mRNA encoding for personalized Neoantigens

Solid tumors

Phase I

mRNA-2416 (Moderna Therapeutics)171

Lipid nanoparticles encapsulated mRNA encoding human OX40L

Relapsed/Refractory solid tumors or lymphoma

Phase I

mRNA-1647 (Moderna Therapeutics)171

Lipid nanoparticles combining 6 mRNAs encoding 6 CMV proteins

Cytomegalovirus (CMV) infection

Phase I

mRNA-1653 (Moderna Therapeutics)171

HMPV/PIV3 vaccine combining mRNAs encoding for a viral antigenic protein associated with HMPV and other associated with PIV3

Human Metapneumovirus (HMPV) and Parainfluenza Virus 3 (PIV3)

Phase I

VAL-506440, mRNA-1440 (Moderna Therapeutics)171

Lipid nanoparticles containing mRNA which encodes for the membranebound hemagglutinin 10 (H10) protein

Influenza A virus subtype H10N8

Phase I

VAL-339851, mRNA-1851 (Moderna Therapeutics)171

mRNA encoding H7

Influenza infection

Phase I

VAL-181388, mRNA 1388 (Moderna Therapeutics/ DARPA)171

Lipid nanoparticles containing mRNA encoding viral antigenic proteins associated with CHIKV

Chikungunya virus infection

Phase I

mRNA-1325 (Moderna Therapeutics/DARPA)171

Lipid nanoparticles containing mRNA encoding antigenic proteins associated with the Zika virus

Zika virus infection

Phase I/II

CANCER

OTHER DISEASES

TABLE 14 Name

miRNA Nanoparticles in Clinical Trials Material Description

Investigated Application

Phase

CANCER Targeted TargomiR (EnGeneIC)171 minicells containing a microRNA mimic

Malignant pleural mesothelioma, non-small-cell lung cancer (NSCLC)

Phase II

are coated with bispecific antibody (BsAB) in which one arm is available for binding to a receptor expressed on the surface of cancer cells.277 Following i.v. administration, EDVs tend to accumulate in the tumor vasculature then bind to overexpressed target receptors on tumor cells and are thought to become involved in the endocytosis process. The EDV technology has been used in multiple preclinical studies to deliver chemotherapeutic agents,278 siRNAs,279 and miRNAs280–283 to tumors in vivo.

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6.4 DNA

6.5 Others

Another of the molecules being studied for gene therapy treatments is DNA (Table 15). One of these particles is SGT 53, a cationic liposomal, tumor-targeting p53 (TP53) gene delivery system with potential antitumor activity.171 Transferrin receptor-targeted liposomal p53 cDNA contains plasmid DNA encoding the tumor suppressor protein p53 packaged in membrane-like liposome capsules that are complexed with antitransferrin receptor single-chain antibody (TfRscFv). Upon systemic administration, the anti-TfRscFv selectively binds to tumor cells expressing transferrin receptors. The p53 plasmid is delivered into the nucleus and as a result, p53 protein is produced in tumor cells that have altered p53 function. This results in the restoration of normal cell growth control mechanisms as well as normal response mechanisms to DNA damage.171 The other formulation under clinical study, JVRS-100, is a cationic liposome-DNA complex (CLDC) and was developed as an adjuvant for vaccines against infectious diseases and as an immunomodulator for cancer therapy.171

In addition to particles containing DNA, mRNA, miRNA, and siRNA, there are some particles that are being studied as gene therapy drugs and that contain other nucleic acids (Table 16). For example, MTL-CEBPA consists of liposomes encapsulating a small oligonucleotide encoding a small activating RNA (saRNA) with potential antineoplastic activity.171 Although the exact mechanism of action through which saRNAs exert their effect is still largely being investigated, it appears that the CEBPA-targeting saRNA MTL-CEBPA liposome targets and binds to a specific DNA regulatory target region, most likely the promoter region, for the CEBPA gene. This restores CEBPA gene transcription and increases both CEBPA mRNA levels and protein expression. This in turn activates the expression of tumor suppressor genes and may halt proliferation of susceptible tumor cells.171 Specifically, upregulation of CEBPA in

TABLE 15

Name

DNA Nanoparticles in Clinical Trials

Name

Material Description

Investigated Application

Cationic Leukemia liposome incorporating plasmid DNA complex for immune system stimulation

Cationic SGT liposome 53 (SynerGene Therapeutics)171 containing plasmid DNA encoding the tumor suppressor protein p53

Recurrent glioblastoma

Material Description

Investigated Application

Status

Advanced cancer

Phase I

Myeloid leukemia

Phase I/II

CANCER Status

CANCER JVRS-100 (Colby Pharma)159, 160

TABLE 16 Others Gene Therapy Nanoparticles in Clinical Trials

Phase I

Phase II

LErafAON-ETU Lipid nanoparticle (INSYS Therapeutics)171 containing antisense oligonucleotides (ASOs) Prexigebersen, BP1001 (BioPath Holdings)171

Lipid nanoparticle containing antisense oligonucleotides (ASOs)

saRNA MTL-CEBPA Hepatocellular Phase formulated into a carcinoma, (MiNA I Therapeutics)171 SMARTICLES liver cancer liposomal nanoparticle

REFERENCES

liver cells abrogates liver cancer cell proliferation, prevents liver failure and normalizes liver function. CEBPA, a transcription factor that plays a key role in the regulation of the expression of genes with many functions, including those involved in cellular proliferation, metastasis, and normal hepatocyte function, is found in many tissues, including liver cells, adipose tissue, and myeloid cells. It is downregulated in certain types of cancer cells, such as liver cancer cells. saRNA is a short, double-stranded RNA that is structurally related to small interfering RNAs (siRNAs); saRNA is most likely to bind to a target site on the promoter of the CEBPA gene and upregulates its gene expression.171

7 CONCLUSIONS In this chapter, the practical importance of the application of novel nanoformulations in the treatment of a wide set of diseases has been highlighted. A large number of nanopharmaceuticals—a pharmaceutical formulation in which the unique physicochemical properties of the nanosized material generated via nanoengineering play the pivotal therapeutic role—are actually under study and are proving their effectiveness in therapeutic application against various diseases. In the majority of cases, the nanocarrier structure is based on previously known and approved formulations (e.g., PEGylated liposomes), thereby facilitating their release into the market. Fueled by the tremendous advances in nanotechnology, an evolution and expansion in terms of type and complexity of nanovectors is promptly envisioned, especially for gene therapy. Considering that the number of registered clinical trials has increased considerably in recent years, it is therefore reasonable to assume that this trend will continue. As a consequence, the number of overall approvals resulting in available nanoformulations will increase considerably. Unfortunately, a still challenging road must be crossed before

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the definitive demonstration of the translational usefulness of the nanoformulations. Nevertheless, considering the overall state-of-the-art snapshot that we have detailed here, we are totally convinced that in the not too distant future the theranostic use of nanopharmaceuticals will have become a common clinical practice.

Acknowledgments MF and KOP would like to thank the Comunidad Autonoma de Madrid and the Universidad Complutense de Madrid (Spain) for supporting this work through the research project no. 2017-T1/BIO-4992 (“Atraccio´n de Talento” Action). MF and JRC also gratefully acknowledge the Comunidad Autonoma de Madrid for supporting this research with the I + D collaborative Programme in Biomedicine NIETO-CM (Project reference B2017-BMD3731). This study was also supported by SAF2017-84494-C2-1-R and Programa Red Guipuzcoana de Ciencia, Tecnologı´a e Informacio´n 2018CIEN-000058-01 to JRC. This work was performed under the Maria de Maeztu Units of Excellence Programme – Grant No. MDM-2017-0720.

References 1. Pillai G. Nanomedicines for cancer therapy: an update of FDA approved and those under various stages of development. SOJ Pharm Sci. 2014;1(2):13–21. 2. Kakkar A, Traverso G, Farokhzad OC, Weissleder R, Langer R. Evolution of macromolecular complexity in drug delivery systems. Nat Rev Chem. 2017;1:0063. 3. Duncan R, Sat YN. Tumour targeting by enhanced permeability and retention (EPR) effect. Ann Oncol. 1998;9:39. 4. Lu H, Wang J, Wang T, Zhong J, Bao Y, Hao H. Recent progress on nanostructures for drug delivery applications. J Nanomater. 2016;2016(3). 5. Anselmo AC, Mitragotri S. An overview of clinical and commercial impact of drug delivery systems. J Control Release. 2014;190:15–28. 6. Babu A, Templeton AK, Munshi A, Ramesh R. Nanodrug delivery systems: a promising technology for detection, diagnosis, and treatment of cancer. AAPS PharmSciTech. 2014;15(3):709–721. 7. BCC Research. Nanotechnology in Medical Applications: The Global Market. BCC Research; 2015. 8. Choi KY, Liu G, Lee S, Chen XY. Theranostic nanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives. Nanoscale. 2012;4(2):330–342.

448

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

9. Blanco E, Hsiao A, Mann AP, Landry MG, MericBernstam F, Ferrari M. Nanomedicine in cancer therapy: innovative trends and prospects. Cancer Sci. 2011; 102:1247–1252. 10. Tibbitt MW, Dahlman JE, Langer R. Emerging frontiers in drug delivery. J Am Chem Soc. 2016;138:704–717. 11. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15:541–555. 12. Colombo S, Zeng X, Ragelle H, Foged C. Complexity in the therapeutic delivery of RNAi medicines: an analytical challenge. Expert Opin Drug Deliv. 2014;11 (9):1481–1495. 13. Ragelle H, Danhier F, Preat V, Langer R, Anderson DG. Nanoparticle-based drug delivery systems a commercial and regulatory outlook as the field matures. Expert Opin Drug Deliv. 2017;14(7):851–864. 14. Bobo D, Robinson K, Islam J, Thurecht K, Corrie S. Nanoparticle-based medicines: a review of FDAapproved materials and clinical trials to date. Pharm Res. 2016;33(10):2373–2387. 15. Wacker M. Nanocarriers for intravenous injection—the long hard road to the market. Int J Pharm. 2013;457 (1):50–62. 16. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9:615–627. 17. Albanese A, Tang PS, Chan WCW. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng. 2012;14:1–16. 18. Owens 3rd DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102. 19. Hirn S, Semmler-Behnke M, Schleh C, et al. Particle size dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur J Pharm Biopharm. 2010;77:407–416. 20. Maeda H, Sawa T, Konno T. Mechanism of tumortargeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release. 2001;74:47–61. 21. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46: 6387–6392. 22. Torchilin V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev. 2011;63: 131–135. 23. Food and Drug Administration. https://www.fda. gov/, 2018 (Accessed 6 September 2018). 24. El-Say KM, El-Sawy HS. Polymeric nanoparticles: promising platform for drug delivery. Int J Pharm. 2017;528(1–2):675–691.

25. Kayser O, Lemke A, Herna´ndez-Trejo N. The impact of nanobiotechnology on the development of new drug delivery systems. Curr Pharm Biotechnol. 2005;6:3–5. 26. Xu W, Ling P, Zhang T. Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. J Drug Deliv. 2013;2013. 27. Oerlemans C, Bult W, Bos M, Storm G, Nijsen JFW, Hennink WE. Polymeric micelles in anticancer therapy: targeting, imaging and triggered release. Pharm Res. 2010;27(12):2569–2589. 28. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across lamellae of swollen phospholipids. J Mol Biol. 1965;13(1):238–252. 29. Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics. 2017;9(2):12. 30. Date AA, Joshi MD, Patravale VB. Parasitic diseases: liposomes and polymeric nanoparticles versus lipid nanoparticles. Adv Drug Deliv Rev. 2007;59:505–521. 31. He C, Yin L, Tang C, Yin C. Multifunctional polymeric nanoparticles for oral delivery of TNFa siRNA to macrophages. Biomaterials. 2013;34:2843–2854. 32. Paul W, Sharma CP. Inorganic nanoparticles for targeted drug delivery. In: Biointegration of Medical Implant Materials: Science and Design; 2010:204–235. 33. Anselmo AC, Mitragotri S. A review of clinical translation of inorganic nanoparticles. AAPS J. 2015;17 (5):1041–1054. 34. Huang H-C, Barua S, Sharma G, Dey SK, Rege K. Inorganic nanoparticles for cancer imaging and therapy. J Control Release. 2011;155(3):344–357. 35. Na HB, Song IC, Hyeon T. Inorganic nanoparticles for MRI contrast agents. Adv Mater. 2009;21(21):2133–2148. 36. Li Z, Barnes JC, Bosoy A, Stoddart JF, Zink JI. Mesoporous silica nanoparticles in biomedical applications. Chem Soc Rev. 2012;41(7):2590–2605. 37. Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC, Mirkin CA. Gold nanoparticles for biology and medicine. Angew Chem Int Ed. 2010;49(19): 3280–3294. 38. Marciello M, Pellico J, Fernandez-Barahona I, Herranz F, Ruiz-Cabello J, Filice M. Recent advances in the preparation and application of multifunctional iron oxide and liposome-based nanosystems for multimodal diagnosis and therapy. Interface Focus. 2016;6 (6):20160055. 39. Harper BW, Krause-Heuer AM, Grant MP, Manohar M, Garbutcheon-Singh KB, Aldrich-Wright JR. Advances in platinum chemotherapeutics. Chemistry. 2010;16(24): 7064–7077. 40. Zhang CX, Lippard SJ. New metal complexes as potential therapeutics. Curr Opin Chem Biol. 2003;7(4):481–489. 41. Junghanns JU, Muller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3(3):295–309.

REFERENCES

42. Weissig V, Pettinger TK, Murdock N. Nanopharmaceuticals (part I): products on the market. Int J Nanomedicine. 2014;9:4357–4373. 43. Ma Y, Nolte RJM, Cornelissen JJLM. Virus-based nanocarriers for drug delivery. Adv Drug Deliv Rev. 2012;64 (9):811–825. 44. Khodabandehloo H, Zahednasab H, Hafez AA. Nanocarriers usage for drug delivery in cancer therapy. Iran J Cancer Prev. 2016;9(2):e3966. 45. Zhang W, Xu C, Yin G-Q, Zhang X-E, Wang Q, Li F. Encapsulation of inorganic nanomaterials inside virus-based nanoparticles for bioimaging. Nanotheranostics. 2017;1(4):358–368. 46. Somiya M, Liu Q, Kuroda S. Current progress of virusmimicking nanocarriers for drug delivery. Nanotheranostics. 2017;1(4):415–429. 47. Chaudhuri RG, Paria S. Core/shell nanoparticles: classes, properties, synthesis mechanisms, characterization, and applications. Chem Rev. 2012;112(4):2373–2433. 48. Cimalla P, Werner T, Gaertner M, et al. Magnetomotive imaging of iron oxide nanoparticles as cellular contrast agents for optical coherence tomography. Proc SPIE. 2013;8802. 49. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology. 1998;50(3):701–708. 50. Alconcel SNS, Baas AS, Maynard HD. FDA-approved poly(ethylene glycol)-protein conjugate drugs. Polym Chem. 2011;2(7):1442–1448. 51. Benbrook DM. Biotechnology and biopharmaceuticals: transforming proteins and genes into drugs, 2nd edition. Clin Infect Dis. 2015;60(2):331–332. 52. Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798–808. 53. Dunn AL, Ahuja SP, Mullins ES. Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A. Haemophilia. 2018;24(3):e84–e92. 54. Alphand
ery E, Grand-Dewyse P, Lefe`vre R, Mandawala C, Durand-Dubief M. Cancer therapy using nanoformulated substances: scientific, regulatory and financial aspects. Expert Rev Anticancer Ther. 2015;15(10):1233–1255. 55. Howard DH. Effect of mycostatin and fungizone on the growth of Histoplasma capsulatum in tissue culture. J Bacteriol. 1960;79:442–449. 56. Perlman D, Giuffre NA, Brindle SA. Use of Fungizone in control of fungi and yeasts in tissue culture. Proc Soc Exp Biol Med. 1961;106:880–883. 57. Lamy-Freund MT, Ferreira VF, Schreier S. Polydispersity of aggregates formed by the polyene antibiotic amphotericin B and deoxycholate. A spin label study. Biochim Biophys Acta. 1989;981(2):207–212.

449

58. Wingard JR, Kubilis P, Lee L, et al. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis. 1999;29(6):1402–1407. 59. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110(1):13–21. 60. Thompson KA, Goodale DB. The recent development of propofol (DIPRIVAN). Intensive Care Med. 2000;26(4): S400–S404. 61. Aliabadi HM, Lavasanifar A. Polymeric micelles for drug delivery. Expert Opin Drug Deliv. 2006;3 (1):139–162. 62. Anselmo AC, Mitragotri S. Nanoparticles in the clinic. Bioeng Transl Med. 2016;1(1):10–29. 63. Barenholz YC. Doxil®—the first FDA-approved nanodrug: lessons learned. J Control Release. 2012;160(2): 117–134. 64. Sanchez-Moreno P, Ortega-Vinuesa JL, PeulaGarcia JM, et al. Smart drug-delivery systems for cancer nanotherapy. Curr Drug Targets. 2018;19(4):339–359. 65. Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 1990;268 (1):235–237. 66. Petre CE, Dittmer DP. Liposomal daunorubicin as treatment for Kaposi’s sarcoma. Int J Nanomedicine. 2007;2 (3):277–288. 67. Fox JL. FDA advisors okay NeXstar’s DaunoXome. Nat Biotechnol. 1995;13(7):635–636. 68. Silverman JA, Deitcher SR. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol. 2013;71(3):555–564. 69. Carnevale J, Ko AH. MM-398 (nanoliposomal irinotecan): emergence of a novel therapy for the treatment of advanced pancreatic cancer. Future Oncol. 2016;12:453–464. 70. Leonard R, Williams S, Tulpule A, Levine A, Oliveros S. Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (MyocetTM). Breast. 2009;18(4):218–224. 71. Ando K, Mori K, Corradini N, Redini F, Heymann D. Mifamurtide for the treatment of nonmetastatic osteosarcoma. Expert Opin Pharmacother. 2011;12 (2):285–292. 72. Ur Rehman SS, Lim K, Wang-Gillam A. Nanoliposomal irinotecan plus fluorouracil and folinic acid: a new treatment option in metastatic pancreatic cancer. Expert Rev Anticancer Ther. 2016;16(5):485–492. 73. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabinebased therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387 (10018):545–557.

450

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

74. Yu X, Trase I, Ren M, Duval K, Guo X, Chen Z. Design of nanoparticle-based carriers for targeted drug delivery. J Nanomater. 2016;2016. 75. Balazsovits J, Mayer L, Bally M, et al. Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemother Pharmacol. 1989;23:81–86. 76. Kanter P, Bullard G, Pilkiewicz F, Mayer L, Cullis P, Pavelic Z. Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99): comparison with doxorubicin and empty liposomes in mice and dogs. In Vivo. 1992;7:85–95. 77. Bovier PA. Epaxal®: a virosomal vaccine to prevent hepatitis A infection. Expert Rev Vaccines. 2008;7:1141–1150. 78. Herzog C, Hartmann K, Kunzi V, et al. Eleven years of Inflexal® V—a virosomal adjuvanted influenza vaccine. Vaccine. 2009;27(33):4381–4387. 79. Lee S, Nguyen MT. Recent advances of vaccine adjuvants for infectious diseases. Immune Netw. 2015;15(2): 51–57. 80. Boswell G, Buell D, Bekersky I. AmBisome (liposomal amphotericin B): a comparative review. J Clin Pharmacol. 1998;38(7):583–592. 81. Rust DM, Jameson G. The novel lipid delivery system of amphotericin B: drug profile and relevance to clinical practice. Oncol Nurs Forum. 1998;25:35–48. 82. Groll A, Giri N, Gonzalez C. Penetration of lipid formulations of amphotericin B into cerebrospinal fluid and brain tissue. In: 37th International Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario; 1997. A90 p. 83. Hann IM, Prentice HG. Lipid-based amphotericin B: a review of the last 10 years of use. Int J Antimicrob Agents. 2001;17(3):161–169. 84. Arnold J, Kilmartin D, Olson J, et al. Verteporfin therapy of subfoveal choroidal neovascularization in agerelated macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131(5):541–560. 85. Schmidt-Erfurth U, Hasan T. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv Ophthalmol. 2000;45(3):195–214. 86. Schutt EG, Klein DH, Mattrey RM, Riess JG. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals. Angew Chem Int Ed. 2003;42(28):3218–3235. 87. Klibanov AL. Microbubble contrast agents: targeted ultrasound imaging and ultrasound-assisted drugdelivery applications. Investig Radiol. 2006;41(3):354–362. 88. Foote M. Using nanotechnology to improve the characteristics of antineoplastic drugs: improved

89.

90.

91.

92.

93.

94.

95.

96.

97.

98. 99.

100.

101.

102.

characteristics of nab-paclitaxel compared with solvent-based paclitaxel. Biotechnol Annu Rev. 2007;13:345–357. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albuminbound paclitaxel, ABI-007, compared with cremophorbased paclitaxel. Clin Cancer Res. 2006;12(4):1317–1324. Elsadek B, Kratz F. Impact of albumin on drug delivery—new applications on the horizon. J Control Release. 2012;157(1):4–28. Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev. 2008;60(8):876–885. Nyman DW, Campbell KJ, Hersh E, et al. Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J Clin Oncol. 2005;23 (31):7785–7793. Lohcharoenkal W, Wang L, Chen Y, Rojanasakul Y. Protein nanoparticles as drug delivery carriers for cancer therapy. Biomed Res Int. 2014. Ni D, Bu W, Ehlerding EB, Cai W, Shi J. Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents. Chem Soc Rev. 2017;46(23):7438–7468. Laurent S, Forge D, Port M, et al. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev. 2008;108(6):2064–2110. Sa´nchez A, Ovejero Paredes K, Ruiz-Cabello J, et al. Hybrid decorated Core@Shell Janus nanoparticles as flexible platform for targeted multimodal molecular bioimaging of cancer. ACS Appl Mater Interfaces. 2018;10(37):31032–31043. Coyne DW, Auerbach M. Anemia management in chronic kidney disease: intravenous iron steps forward. Am J Hematol. 2010;85(5):311–312. Macdougall IC. Evolution of IV iron compounds over the last century. J Renal Care. 2009;35(Suppl 2):8–13. Borchard G, Fl€ uhmann B, M€ uhlebach S. Nanoparticle iron medicinal products—requirements for approval of intended copies of nonbiological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol. 2012;64(2):324–328. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol. 2004;15(Suppl 2):S93–S98. Salah EDTA, Bakr MM, Kamel HM, Abdel KM. Magnetite Nanoparticles as a Single Dose Treatment for Iron Deficiency Anemia. Google Patents, 2010. Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol. 2010;85 (5):315–319.

REFERENCES

103. Prince MR, Zhang HL, Chabra SG, Jacobs P, Wang Y. A pilot investigation of new superparamagnetic iron oxide (ferumoxytol) as a contrast agent for cardiovascular MRI. J Xray Sci Technol. 2003;11(4):231–240. 104. Bashir MR, Bhatti L, Marin D, Nelson RC. Emerging applications for ferumoxytol as a contrast agent in MRI. J Magn Reson Imaging. 2015;41(4):884–898. 105. Gupta AK, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials. 2005;26(18):3995–4021. 106. Wang Y-XJ, Hussain SM, Krestin GP. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol. 2001;11(11):2319–2331. 107. Thiesen B, Jordan A. Clinical applications of magnetic nanoparticles for hyperthermia. Int J Hyperth. 2008;24 (6):467–474. 108. Maier-Hauff K, Ulrich F, Nestler D, et al. Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J Neuro-Oncol. 2011;103(2):317–324. 109. Lu Y, Li Y, Wu W. Injected nanocrystals for targeted drug delivery. Acta Pharm Sin B. 2016;6(2):106–113. 110. Sirolimus: AY 22989, NSC 226080, NSC 606698, Rapamycin, Rapamune. Drugs R D. 1999;1(1):100–107. 111. Shegokar R, M€ uller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm. 2010;399(1):129–139. 112. Ling H, Luoma JT, Hilleman D. A review of currently available fenofibrate and fenofibric acid formulations. Cardiol Res. 2013;4(2):47–55. 113. Downing NS, Ross JS, Jackevicius CA, Krumholz HM. Avoidance of generic competition by Abbott Laboratories’ fenofibrate franchise. Arch Intern Med. 2012;172 (9):724–730. 114. Sauron R, Wilkins M, Jessent V, Dubois A, Maillot C, Weil A. Absence of a food effect with a 145 mg nanoparticle fenofibrate tablet formulation. Int J Clin Pharmacol Ther. 2006;44(2):64–70. 115. Sokolova V, Epple M. Bioceramic nanoparticles for tissue engineering and drug delivery. In: Tissue Engineering Using Ceramics and Polymers. Elsevier; 2014:633–647. vol. 2. 116. Awada A, Garcia AA, Chan S, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. Lancet Oncol. 2013;14(12):1216–1225. 117. Cort
es J, Rugo HS, Twelves C, et al. Safety and tolerability of etirinotecan pegol in advanced breast cancer: analysis of the randomized, phase 3 BEACON trial. Springerplus. 2016;5(1):1033. 118. Von Hoff DD, Jameson GS, Borad MJ, et al. First phase I trial of NKTR-102 (PEG irinotecan) reveals early

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

451 evidence of broad antitumor activity in three schedules. Eur J Cancer. 2008;6(12):186. Jameson GS, Hamm JT, Weiss GJ, et al. A multicenter, phase 1, open-label, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of NKTR-102 in patients with refractory solid tumors. Clin Cancer Res. 2013;19:268–278. Perez E, Hillman DW, Mailliard JA, et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol. 2004;22:2849–2855. Antonian L, Burton K, Goodin R, Bentley M, Eldon MA. PEGylation governs the disposition and metabolism of irinotecan following administration of a novel PEGirinotecan conjugate. Eur J Cancer. 2007;5(4):115. Eldon MA, Antonian L, Staschen CM, et al. Anti-tumor activity and pharmacokinetics of a novel PEGylatedirinotecan, in irinotecan resistant colorectal tumors implanted in mice. Eur J Cancer. 2007;5(4):114. Eldon MA, Staschen CM, Viegas T, Bentley M. NKTR102, a novel PEGylated irinotecan conjugate, results in sustained tumor growth suppression in mouse models of human colorectal and lung tumors that is associated with increased and sustained tumor SN38 exposure. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, USA, 22–26 Oct; 2007. Abstract C157. Persson H, Antonian L, Staschen CM, Viegas T, Bentley M. Polyethylene glycol conjugation of irinotecan improves its anti-tumor activity in three mouse xenograft models. In: Proceedings of the AACR-NCIEORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, USA, 22–26 Oct; 2007. Abstract C10. Persson H, Barker T, Eldon M, Wolff R. NKTR-102, a novel PEGylated-irinotecan, has a superior acute safety, tolerability, and pharmacokinetic profile compared to irinotecan in rats and dogs. In: Proceedings of AACR Annual Meeting. San Diego, CA, USA; April 12–16; 2008. Abstract 5742. Persson H, Barker T, Eldon M, et al. NKTR-102, a novel PEGylated-irinotecan, has an enhanced pharmacokinetic profile with reduced gastrointestinal and hematopoietic toxicity compared to irinotecan with repeat dosing in dogs. In: Proceedings of AACR Annual Meeting, San Diego, CA, USA, April 12–16; 2008. Abstract 5741. Hoch U, Masuoka L, Maslyar D, et al. NKTR-102 demonstrates nonclinical and phase 1 clinical anti-tumor activity in ovarian cancer. Eur J Cancer. 2009;7(2):454. Weiss GJ, Chao J, Neidhart JD, et al. First-in-human phase 1/2ª trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients

452

129.

130.

131.

132. 133.

134.

135.

136.

137.

138. 139. 140.

141.

142.

143.

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

with advanced solid tumor malignancies. Investig New Drugs. 2013;31(4):986–1000. Pham E, Birrer MJ, Eliasof S, et al. Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer. Clin Cancer Res. 2015;21(4):808–818. Svenson S, Wolfgang M, Hwang J, Ryan J, Eliasof S. Preclinical to clinical development of the novel camptothecin nanopharmaceuticals CRLX101. J Control Release. 2011;153(1):49–55. Paz-Ares L, Ross H, O’Brien M, et al. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br J Cancer. 2008;98(10):1608–1613. Zhang Z, Mei L, Feng SS. Paclitaxel drug delivery system. Expert Opin Drug Deliv. 2013;10(3):325–340. Singer JW, Shaffer S, Baker B, et al. Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane. Anti-Cancer Drugs. 2005;16:243–254. Hrkach J, Von Hoff D, Mukkaram Ali M, et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med. 2012;4:(128):128–139. Rijcken CJF, Veldhuis TFJ, Ramzi A, Meeldijk JD, van Nostrum CF, Hennink WE. Novel fast degradable thermosensitive polymeric micelles based on PEG-blockpoly(N-(2-hydroxyethyl)methacrylamideoligolactates). Biomacromolecules. 2005;6(4):2343–2351. NCI Drug Dictionary. https://www.cancer.gov/ publications/dictionaries/cancer-drug, 2018 (Accessed 6 September 2018). Plummer R, Wilson RH, Calvert H, et al. A phase I clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours. Br J Cancer. 2011;104(4):593–598. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7(8):573–584. Madias NE, Harrington JT. Platinum nephrotoxicity. Am J Med. 1978;65(2):307–314. Li Z, Zhang Y, Wurtz W, et al. Characterization of nebulized liposomal amikacin (Arikace™) as a function of droplet size. J Aerosol Med Pulm Drug Deliv. 2008;21: 245–254. Clancy JP. Clinical trials of lipid-associated aerosolized amikacin: the arikace™ story. Pediatr Pulmonol. 2009;44:186–188. Bilton D, Pressler T, Fajac I, et al. Phase 3 efficacy and safety data from randomized, multicenter study of liposomal amikacin for inhalation (ARIKACE) compared with TOBI in cystic fibrosis patients with chronic infection due to Pseudomonas Aeruginosa. Pediatr Pulmonol. 2013;48:207–453. Clancy J, Dupont L, Konstan MW, et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax. 2013;68:818–825.

144. Gupta R, Daley CL, Winthrop KL, et al. A randomized, double-blind, placebo-controlled study of liposomal amikacin for inhalation (Arikace®) in patients with recalcitrant nontuberculous mycobacterial lung disease. In: Diagnosis and Treatment of Nontuberculous Mycobacteria Infections; 2014:4126. 145. Timmerman L. Oncothyreon Marches on with ‘Son of Stimuvax’ Cancer Vaccine. https://www.xconomy. com/seattle/2012/04/10/oncothyreon-marches-onwith-son-of-stimuvax-cancer-vaccine/, 2018 (Accessed 6 September 2018). 146. Kroemer G, Zitvogel L, Galluzzi L. Victories and deceptions in tumor immunology: Stimuvax®. Oncoimmunology. 2013;2(1):23687. 147. Cart S, Alert NPR. Merck KGaA Starts Stimuvax Phase III Study INSPIRE in Asian Patients With Advanced NSCLC. http://www.businesswire.com/news/home/ 20091210005488/en/Merck-KGaAStarts-, 2018 (Accessed 6 September 2018). 148. Sotiriosrigatos ED, Viliotou V, Stathopoulos JG. Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): phase I study. Oncol Rep. 2005;13:589–595. 149. Mylonakis N, Athanasiou A, Ziras N, et al. Phase II study of liposomal cisplatin (Lipoplatin™) plus gemcitabine versus cisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small cell lung cancer. Lung Cancer. 2010;68:240–247. 150. Boulikas T, Stathopoulos GP, Volakakis N, Vougiouka M. Systemic Lipoplatin infusion results in preferential tumor uptake in human studies. Anticancer Res. 2005;25: 3031–3039. 151. Chen J, He C-Q, Lin A-H, et al. Thermosensitive liposomes with higher phase transition temperature for targeted drug delivery to tumor. Int J Pharm. 2014;475: 408–415. 152. May JP, Li S-D. Hyperthermia-induced drug targeting. Expert Opin Drug Deliv. 2013;10(4):511–527. 153. Palazzi M, Maluta S, Dall’Oglio S, Romano M. The role of hyperthermia in the battle against cancer. Tumori. 2010;96(6):902–910. 154. Chang H-I, Yeh M-K. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomedicine. 2012;7: 49–60. 155. Summers D, Ruff D, Smalling R, Cardoza D, Dottavio D, Lasic D. Administration of liprostin (TM) for the treatment of critical limb ischemia (CLI) and peripheral arterial disease (PAD). J Liposome Res. 2003;13. 156. Li J, Wang B, Wang Y, et al. Therapeutic effect of liposomal prostaglandin E1 in acute lower limb ischemia as an adjuvant to hybrid procedures. Exp Ther Med. 2013;5:1760–1764. 157. Feldman EJ, Lancet JE, Kolitz JE, et al. First-in-man study of CPX-351: a liposomal carrier containing

REFERENCES

158.

159.

160.

161.

162.

163. 164.

165.

166.

167.

168.

169.

170.

cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29(8):979–985. Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015;121(2):234–242. Chang S, Warner J, Liang L, Fairman J. A novel vaccine adjuvant for recombinant flu antigens. Biologicals. 2009;37(3):141–147. Keasey N, Herse Z, Chang S, et al. A non-coding cationic lipid DNA complex produces lasting antileukemic effects. Cancer Biol Ther. 2010;10(6):625–631. de Jonge MJ, Slingerland M, Loos WJ, et al. Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation. Eur J Cancer. 2010;46(16):3016–3021. Larsen JE, Henriksen JR, Bæksted M, Andresen TL, Jacobsen GK, Ju`rgensen K. Liposome-based drug delivery using secretory phospholipase A2 as a tumorspecific release mechanism: preclinical evaluation of efficacy, pharmacokinetics, and individual patient expression profiles. Clin Cancer Res. 2006;12(19). B24–B24. Kaiser E, Chiba P, Zaky K. Phospholipases in biology and medicine. Clin Biochem. 1990;23(5):349–370. Wickham T, Futch K. Abstract P5-18-09: a phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive breast cancer. Cancer Res. 2012;72(24):P5–18-09. Henry BD, Neill DR, Becker KA, et al. Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice. Nat Biotechnol. 2015;33(1):81–88. Kennecke H, Rahman M, Yip S, Woods R, Schaeffer D, Tai I. Effect of nab-rapamycin versus rapamycin in colorectal cancer cell lines and associations with KRAS and PI3K mutations. J Clin Oncol. 2011;e13532. Trieu V, Ran S, Volk L, Stutzman A, D’Cruz O, Desai N. CNS safety, antitumor activity, and antiangiogenic activity of nab-rapamycin (ABI-009). In: Proceedings of the 100th American Association for Cancer Research Annual Meeting (AACR); 2009. Abstract 136. De T, Trieu V, Yim Z, et al. Nanoparticle albuminbound (nab) rapamycin as an anticancer agent. In: Proceedings of the 98th American Association for Cancer Research Annual Meeting (AACR); 2007. Abstract 4719. Cirstea D, Hideshima T, Rodig S, et al. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010;9:963–975. Gonzalez-Angulo AM, Meric-Bernstam F, Chawla S, et al. Weekly nab-rapamycin in patients with advanced nonhematologic malignancies: final results of a phase 1 trial. Clin Cancer Res. 2013;19(19):5474–5484.

453

171. Clinical trials.gov. https://clinicaltrials.gov/, 2018 (Accessed 6 September 2018). 172. Vasanawala SS, Nguyen K-L, Hope MD, et al. Safety and technique of ferumoxytol administration for MRI. Magn Reson Med. 2016;75(5):2107–2111. 173. Nanospectra. AuroLase® Therapy. http://www. nanospectra.com/, 2011 (Accessed 6 September 2018). 174. Hirsch LR, Stafford RJ, Bankson JA, et al. Nanoshellmediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc Natl Acad Sci. 2003;100(23):13549–13554. 175. Schwartz JA, Shetty AM, Price RE, et al. Feasibility study of particle-assisted laser ablation of brain tumors in orthotopic canine model. Cancer Res. 2009;69(4): 1659–1667. 176. Stern JM, Stanfield J, Kabbani W, Hsieh JT, Cadeddu JA. Selective prostate cancer thermal ablation with laser activated gold nanoshells. J Urol. 2008;179(2):748–753. 177. Marill J, Anesary NM, Zhang P, et al. Hafnium oxide nanoparticles: toward an in vitro predictive biological effect? Radiat Oncol. 2014;9(1):150. 178. Pottier A, Borghi E, Levy L. New use of metals as nanosized radioenhancers. Anticancer Res. 2014;34 (1B):443–453. 179. Phillips E, Penate-Medina O, Zanzonico PB, et al. Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe. Sci Transl Med. 2014;6(260). 180. Niu L, Xu Y-C, Dai Z, Tang H-Q. Gene therapy for type 1 diabetes mellitus in rats by gastrointestinal administration of chitosan nanoparticles containing human insulin gene. World J Gastroenterol. 2008;14:4209–4215. 181. Trepel M, K€ orbelin J, Spies E, et al. Treatment of multifocal breast cancer by systemic delivery of dualtargeted adeno-associated viral vectors. Gene Ther. 2015;22:840–847. 182. Goater J, M€ uller R, Kollias G, et al. Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis. J Rheumatol. 2000;27:983–989. 183. High KA, Anguela XM. Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet. 2015;25 (R1):R36–R41. 184. Choong C-J, Baba K, Mochizuki H. Gene therapy for 34 neurological disorders. Expert Opin Biol Ther. 2015;16: 143–159. 185. Ye G-J, Budzynski E, Sonnentag P, et al. Cone-specific promoters for gene therapy of achromatopsia and other retinal diseases. Hum Gene Ther. 2015;27:72–82. 186. Wong MS, Hawthorne WJ, Manolios N. Gene therapy in diabetes. Self Nonself. 2010;1(3):165–175. 187. Choi YS, Lee MY, David AE, Park YS. Nanoparticles for gene delivery: therapeutic and toxic effects. Mol Cell Toxicol. 2014;10:1–8. 188. Chen J, Jiao ZX, Lin L, et al. Polylysine modified polyethylenimines as siRNA carriers for effective tumor treatment. Chin J Polym Sci. 2015;33:830–837.

454

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

189. Dizaj SM, Jafari S, Khosroushahi AY. A sight on the current nanoparticlebased gene delivery vectors. Nanoscale Res Lett. 2014;9:252. 190. Liu Y, Kim YJ, Ji M, et al. Enhancing gene delivery ofadeno-associated viruses by cell-permeable peptides. Mol Ther Methods Clin Dev. 2014;1:12. 191. Matar R, Soleimani M, Merheb M. Human gene therapy—the future of health care. Hamdan Med J. 2015;8:101–110. 192. Bouard D, Alazard-Dany N, Cosset FL. Viral vectors: from virology to transgene expression. Br J Pharmacol. 2009;157:153–165. 193. Soleimani M, Majid Al Zaabi A, Merheb M, Matar R. Nanoparticles in gene therapy. Int J Integr Biol. 2016;17:7–16. 194. Touchefeu Y, Harrington K, Galmiche JP, Vassaux G. Review article: gene therapy, recent developments and future prospects in gastrointestinal oncology. Aliment Pharmacol Ther. 2010;32:953–968. 195. Alemzadeh E, Dehshahri A, Izadpanah K, Ahmadi F. Plant virus nanoparticles: novel and robust nanocarriers for drug delivery and imaging. Colloids Surf B: Biointerfaces. 2018;167:20–27. 196. Daamen WF, Veerkamp J, Van Hest J, Van Kuppevelt T. Elastin as a biomaterial for tissue engineering. Biomaterials. 2007;28:4378–4398. 197. Gawande MB, Goswami A, Asefa T, et al. Core-shell nanoparticles: synthesis and applications in catalysis and electrocatalysis. Chem Soc Rev. 2015;44:7540–7590. 198. Ramamoorth M, Narvekar A. Non viral vectors in gene therapy—an overview. J Clin Diagn Res. 2015; 9:GE01. 199. Liu D, Yang F, Xiong F, Gu N. The smart drug delivery system and its clinical potential. Theranostics. 2016;6 (9):1306–1323. 200. Jin S, Ye K. Nanoparticle-mediated drug delivery and gene therapy. Biotechnol Prog. 2007;23(1):32–41. 201. Miele E, Spinelli GP, Miele E, et al. Nanoparticlebased delivery of small interfering RNA: challenges for cancer therapy. Int J Nanomedicine. 2012;7:3637–3657. 202. Chen J, Guo Z, Tian H, Chen X. Production and clinical development of nanoparticles for gene delivery. Mol Ther Methods Clin Dev. 2016;3. 203. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. 2013;8(1):102. 204. Sharma U, Badyal PN, Gupta S. Polymeric nanoparticles drug delivery to brain: a review. Int J Pharmacol. 2015;2:60–69. 205. Jun A, Larkin D. Prospects for gene therapy in corneal disease. Eye. 2003;17:906–911. 206. Caplen N, Gao X, Hayes P, et al. Gene therapy for cystic fibrosis in humans by liposome-mediated DNA transfer: the production of resources and the regulatory process. Gene Ther. 1994;1:139–147.

207. DzAu VJ, Mann MJ, Morishita R, Kaneda Y. Fusigenic viral liposome for gene therapy in cardiovascular diseases. Proc Natl Acad Sci. 1996;93:11421–11425. 208. Balazs DA, Godbey W. Liposomes for use in gene delivery. J Drug Deliv. 2011;2011:326497. 209. Kim S-Y, Lee M-K, Lim S-J. Current advances in developing cationic lipid-based nanoparticles as a vehicle for improving adenoviral gene delivery. J Pharm Investig. 2016;46:393–402. 210. Zhi D, Zhang S, Wang B, Zhao Y, Yang B, Yu S. Transfection efficiency of cationic lipids with different hydrophobic domains in gene delivery. Bioconjug Chem. 2010;21:563–577. 211. Lee H-Y, Mohammed KA, Nasreen N. Nanoparticlebased targeted gene therapy for lung cancer. Am J Cancer Res. 2016;6(5):1118–1134. 212. Nimesh S. Polyethylenimine as a promising vector for targeted siRNA delivery. Curr Clin Pharmacol. 2012;7:121–130. 213. Patnaik S, Gupta KC. Novel polyethylenimine-derived nanoparticles for in vivo gene delivery. Expert Opin Drug Deliv. 2013;10:215–228. 214. Eliyahu H, Barenholz Y, Domb A. Polymers for DNA delivery. Molecules. 2005;10:34–64. 215. Li S, Wang Y, Wang S, et al. Biodegradable cyclen-based linear and cross-linked polymers as non-viral gene vectors. Bioorg Med Chem. 2012;20:1380–1387. 216. Kafil V, Omidi Y. Cytotoxic impacts of linear and branched polyethylenimine nanostructures in a431 cells. BioImpacts. 2011;1:23–30. 217. Su WP, Cheng FY, Shieh DB, Yeh CS, Su WC. PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells. Int J Nanomedicine. 2012;7:4269–4283. 218. Lu Y, Park P. Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs. Int J Pharm. 2013;453(1):198–214. 219. Jones MC, Leroux JC. Polymeric micelles—a new generation of colloidal drug carriers. Eur J Pharm Biopharm. 1999;48(2):101–111. 220. Yin T, Wang P, Li J, et al. Ultrasound-sensitive siRNA loaded nanobubbles formed by hetero-assembly of polymeric micelles and liposomes and their therapeutic effect in gliomas. Biomaterials. 2013;34 (18):4532–4543. 221. Gong J, Chen MW, Zheng Y, Wang SP, Wang YT. Polymeric micelles drug delivery system in oncology. J Control Release. 2012;159:312–323. 222. Cabral H, Kataoka K. Progress of drug-loaded polymeric micelles into clinical studies. J Control Release. 2014;190:465–476. 223. Ojea-Jim
enez I, Urba´n P, Barahona F, et al. A highly flexible platform for tuning surface properties of silica nanoparticles and monitoring their biological interaction. ACS Appl Mater Interfaces. 2016;8:4838–4850.

REFERENCES

224. Mieszawska AJ, Mulder WJ, Fayad ZA, Cormode DP. Multifunctional gold nanoparticles for diagnosis and therapy of disease. Mol Pharm. 2013;10:831–847. 225. Ding Y, Jiang Z, Saha K, et al. Gold nanoparticles for nucleic acid delivery. Mol Ther. 2014;22:1075–1083. 226. Tiwari PK, Lee YS. Gene delivery in conjunction with gold nanoparticle and tumor treating electric field. J Appl Phys. 2013;114. 227. Ryou SM, Kim S, Jang HH, et al. Delivery of shRNA using gold nanoparticle-DNA oligonucleotide conjugates as a universal carrier. Biochem Biophys Res Commun. 2010;398:542–546. 228. Bishop CJ, Tzeng SY, Green JJ. Degradable polymercoated gold nanoparticles for co-delivery of DNA and siRNA. Acta Biomater. 2015;11:393–403. 229. Shan Y, Luo T, Peng C, et al. Gene delivery using dendrimer-entrapped gold nanoparticles as nonviral vectors. Biomaterials. 2012;33:3025–3035. 230. Appaiahgari MB, Vrati S. Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. Expert Opin Biol Ther. 2015;15:337–351. 231. Selot R, Marepally S, Vemula P, GR J. Nanoparticle coated viral vectors for gene therapy. Curr Biotechnol. 2015;5:44–53. 232. Harrison EB, Azam SH, Pecot CV. Targeting accessories to the crime: nanoparticle nucleic acid delivery to the tumor microenvironment. Front Pharmacol. 2018;9:307. 233. Lu C, Stewart DJ, Lee JJ, et al. Phase I clinical trial of systemically administered TUSC2 (FUS1)-nanoparticles mediating functional gene transfer in humans. PLoS One. 2012;7. 234. Buscail L, Bournet B, Vernejoul F, et al. First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings. Mol Ther. 2015;23:779–789. 235. Sidi AA, Ohana P, Benjamin S, et al. Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin. J Urol. 2008;180: 2379–2383. 236. Smaldone MC, Davies BJ. BC-819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers. Curr Opin Mol Ther. 2010;12:607–616. 237. Hanna N, Ohana P, Konikoff F, et al. Phase 1/2a, doseescalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer. Cancer Gene Ther. 2012;19:374–382. 238. Gofrit ON, Benjamin S, Halachmi S, et al. DNA based therapy with diphtheria toxin-A BC-819: a phase 2b marker lesion trial in patients with intermediate risk

239.

240.

241.

242. 243. 244. 245.

246.

247.

248. 249.

250.

251.

252.

253. 254.

255.

256.

455 nonmuscle invasive bladder cancer. J Urol. 2014;191: 1697–1702. Capecchi MR. High efficiency transformation by direct microinjection of DNA into cultured mammalian cells. Cell. 1980;22:479–488. Yamamoto A, Kormann M, Rosenecker J, Rudolph C. Current prospects for mRNA gene delivery. Eur J Pharm Biopharm. 2009;71:484–489. Kaczmarek JC, Kowalski PS, Anderson DG. Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med. 2017;9(1):60. Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. Adv Exp Med Biol. 2013;774:1–20. Kosik KS. MicroRNAs and cellular phenotypy. Cell. 2010;143:21–26. Xiao C, Rajewsky K. MicroRNA control in the immune system: basic principles. Cell. 2009;136:26–36. Chou J, Shahi P, Werb Z. microRNA-mediated regulation of the tumor microenvironment. Cell Cycle. 2013;12:3262–3271. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–222. van Zandwijk N, Pavlakis N, Kao SC, et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-inman, phase 1, openlabel, dose-escalation study. Lancet Oncol. 2017;18:1386–1396. Mcmanus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs. Nat Rev Genet. 2002;3(3):737–747. Xie Z, Zeng X. DNA/RNA-based formulations for treatment of breast cancer. Expert Opin Drug Deliv. 2017;14(12):1379–1393. Aigner A. Applications of RNA interference: current state and prospects for siRNA-based strategies in vivo. Appl Microbiol Biotechnol. 2007;76:9–21. Lu PY, Woodle MC. Delivering small interfering RNA for novel therapeutics. Methods Mol Biol. 2008; 437:93–107. De Paula D, Bentley MV, Mahato RI. Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting. RNA. 2007;13:431–456. Sah DWY. Therapeutic potential of RNA interference for neurological disorders. Life Sci. 2006;79:1773–1780. Reischl D, Zimmer A. Drug delivery of siRNA therapeutics: potentials and limits of nanosystems. Nanomedicine. 2009;5:8–20. Chou S-T, Mixson AJ. siRNA nanoparticles: the future of RNAi therapeutics for oncology? Nanomedicine. 2014;9(15):2251–2254. Kesharwani P, Gajbhiye V, Jain N. A review of nanocarriers for the delivery of small interfering RNA. Biomaterials. 2012;33:7138–7150.

456

14. THE STATE OF THE ART OF INVESTIGATIONAL AND APPROVED NANOMEDICINE PRODUCTS

257. Oh YK, Park TG. SiRNA delivery systems for cancer treatment. Adv Drug Deliv Rev. 2009;61:850–862. 258. Fougerolles AD, Vornlocher HP, Maraganore J, Lieberman J. Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov. 2007;6:443–453. 259. Bumcrot D, Manoharan M, Koteliansky V, Sah DW. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol. 2006;2:711–719. 260. Wang CC, Wu SM, Li HW, Chang HT. Biomedical applications of DNA-conjugated gold nanoparticles. Chembiochem. 2016;17(12):1052–1062. 261. Bunka DH, Platonova O, Stockley PG. Development of aptamer therapeutics. Curr Opin Pharmacol. 2010;10: 557–562. 262. Song S, Wang L, Li J, Fan C, Zhao J. Aptamer-based biosensors. Trends Anal Chem. 2008;27(2):108–117. 263. Cox JC, Ellington AD. Automated selection of anti-protein aptamers. Bioorg Med Chem. 2001;9(10): 2525–2531. 264. O’Sullivan CK. Aptasensors—the future of biosensing? Anal Bioanal Chem. 2002;372(1):44–48. 265. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12:861–874. 266. Federal Joint Committee. http://www.english.g-ba.de/ downloads/91-1028146/Alipogene%20tiparvovec_ ENG_2015-05-21.pdf, 2018 (Accessed 6 September 2018). 267. HAS-Sante. http://www.has-sante.fr/portail/upload/ docs/evamed/CT-14224_GLYBERA_PIC_INS_Avis3_ CT14224.pdf, 2018 (Accessed 6 September 2018). 268. National Institute of Clinical Excellence. https://www. nice.org.uk/guidance/indevelopment/gid-tag509, 2018 (Accessed 6 September 2018). 269. Touchot N, Flume M. Early insights from commercialization of gene therapies in Europe. Barry M, ed.Genes. 2017;8(2):78 270. Zuckerman JE, Davis ME. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat Rev Drug Discov. 2015;14 (12):843–856. 271. Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010;464 (7291):1067–1070. 272. Zuckerman JE, Gritli I, Tolcher A, et al. Correlating animal and human phase Ia/Ib clinical data with

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

CALAA-01, a targeted, polymer-based nanoparticle containing siRNA. Proc Natl Acad Sci U S A. 2014;111 (31):11449–11454. Tabernero J, Shapiro GI, LoRusso PM, et al. First-inhumans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov. 2013;3(4):406–417. Sharma B, Crist RM, Adiseshaiah PP. Nanotechnology as a delivery tool for precision cancer therapies. AAPS J. 2017;19(6):1632–1642. Schleiss MR, Permar SR, Plotkin SA. Progress toward development of a vaccine against congenital cytomegalovirus infection. Clin Vaccine Immunol. 2017;24(12). e00268–17. Grabbe S, Haas H, Diken M, M Kranz L, Langguth P, Sahin U. Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma. Nanomedicine. 2016;11:2723–2734. Reid G, C Kao S, Pavlakis N, et al. Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer. Epigenomics. 2016;8(8):1079–1085. MacDiarmid JA, Mugridge NB, Weiss JC, et al. Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics. Cancer Cell. 2007;11(5):431–445. MacDiarmid JA, Amaro-Mugridge NB, MadridWeiss J, et al. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol. 2009;27(7):643–651. Reid G, Pel ME, Kirschner MB, et al. Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. Ann Oncol. 2013;24 (12):3128–3135. Williams M, Kirschner MB, Cheng YY, et al. miR193a-3p is a potential tumor suppressor in malignant pleural mesothelioma. Oncotarget. 2015;6(27): 23480–23495. Reid GWM, Kirschner MB, Mugridge N, et al. Targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy. Cancer Res. 2015;75(15). Abstract 3976. Glover AR, Zhao JT, Gill AJ, et al. microRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma. Oncotarget. 2015;6(34):36675–36688.