Received: 23 January 2016
`
`DOI 10.1002/btm2.10003
`
`| Accepted: 25 February 2016
`
`R E V I E W
`
`Nanoparticles in the clinic
`
`Aaron C. Anselmo1
`
`| Samir Mitragotri2
`
`1David H. Koch Institute for Integrative
`Cancer Research, Massachusetts Institute of
`Technology, Cambridge, MA 02139
`
`2Dept. of Chemical Engineering, Center for
`Bioengineering, University of California,
`Santa Barbara, CA 93106
`
`Correspondence
`Samir Mitragotri, Dept. of Chemical
`Engineering, University of California, Santa
`Barbara, CA 93106.
`Email: samir@engineering.ucsb.edu
`
`Funding information
`SM acknowledges support from the
`National Institute of Health
`(1R01HL129179-01).
`
`Abstract
`Nanoparticle/microparticle-based drug delivery systems for systemic (i.e., intravenous) applications
`have significant advantages over their nonformulated and free drug counterparts. For example,
`nanoparticle systems are capable of delivering therapeutics and treating areas of the body that
`other delivery systems cannot reach. As such, nanoparticle drug delivery and imaging systems are
`one of the most investigated systems in preclinical and clinical settings. Here, we will highlight the
`diversity of nanoparticle types, the key advantages these systems have over their free drug coun-
`terparts, and discuss their overall potential in influencing clinical care. In particular, we will focus
`on current clinical trials for nanoparticle formulations that have yet to be clinically approved. Addi-
`tional emphasis will be on clinically approved nanoparticle systems, both for their currently
`approved indications and their use in active clinical trials. Finally, we will discuss many of the often
`overlooked biological, technological, and study design challenges that impact the clinical success of
`nanoparticle delivery systems.
`
`K E Y W O R D S
`clinic, translational medicine, clinical translation, clinical trials, drug delivery, nanomedicine,
`nanoparticles
`
`1 |
`
`INTRODUCTION
`
`Nanoparticle/microparticle delivery systems are widely investigated pre-
`clinically with many particle-based formulations and technologies having
`already been introduced in the clinic.1–5 Oral, local, topical, and systemic
`(e.g., intravenous) administration are all proven methods that have been
`Food and Drug Administration (FDA)-approved for the delivery of nano-
`particles/microparticles, depending on the desired application or tar-
`geted site. For example: (a) oral delivery of particles has been approved
`clinically for imaging applications (e.g., Gastromark),6 (b) local delivery of
`particles has been widely used in the clinic as depot delivery systems for
`the extended delivery of a variety of biologics including peptides and
`other small molecules (e.g., DepoCyt),4 (c) topical application of particles
`has been approved clinically to increase penetration of biologics across
`the skin barrier (e.g., Estrasorb),7 and (d) systemic delivery of particles
`has been approved clinically for treating a variety of cancers (e.g., Doxil)8
`and other diseases. Given the utility and success of these clinical exam-
`ples, preclinical research efforts for each of these delivery methods con-
`tinue to increase with particular attention placed on developing new
`applications and further improving their delivery and efficacy.
`
`Of these delivery methods, intravenously administered nanoparticles
`receive the most attention, both preclinically and clinically. The increased
`interest for intravenous delivery is not surprising given that nanoparticles
`delivered systemically have direct access to nearly all parts of the body and
`thus have the most potential to influence clinical care. For this same reason,
`systemically delivered nanoparticles also face exceedingly difficult chal-
`lenges with regards to both the delivery aspect (e.g., biological challenges)9,10
`and the regulatory aspect (e.g., study design and approval challenges).11,12
`This review focuses on the clinical translation of intravenously administered
`nanoparticles, with additional emphasis on the challenges faced by nanopar-
`ticles from a clinical and translational point of view. Specifically, the biologi-
`cal, technological, and study design challenges facing the clinical translation
`of nanoparticles will be discussed. Comprehensive lists of intravenous nano-
`particle technologies that are either approved or currently in clinical trials
`will be provided to highlight the current clinical landscape.
`
`2 | NANOPARTICLE TYPES, APPLICATIONS,
`ADVANTAGES, AND POTENTIAL
`
`Therapeutic and diagnostic nanoparticles typically fall into two catego-
`ries: (a) inorganic nanoparticles (e.g., gold, silica, iron oxide, etc.) and (b)
`
`VC 2016 The Authors. Bioengineering & Translational Medicine is published by Wiley Periodicals, Inc. on behalf of The American Institute of Chemical Engineers. This is an
`open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
`work is properly cited.
`
`10 |
`
`wileyonlinelibrary.com/btm2
`
`Bioengineering & Translational Medicine 2016; 1: 10-29
`
`

`

`ANSELMO AND MITRAGOTRI
`
`| 11
`
`FIG URE 1 Clinically relevant nanoparticles. Organic and inorganic nanoparticles have been approved for a variety of clinical indications (black text)
`and are being investigated in current clinical studies for additional indications (red text). Examples included (a) Doxil (200 nm scale bar), (b) Abraxane
`(200 nm scale bar), (c) CRLX101 (50 nm scale bar), (d) Feraheme (20 nm scale bar), (e) early iteration of Cornell Dots (50 nm scale bar), and (f) gold
`nanoshells (inset: 100 nm scale bar, main figure: 1,000 nm scale bar) from Nanospectra, makers of AuroLase. (a) Reprinted from ref. 16. Copyright
`(2016), with permission from Elsevier. (b) Adapted by permission from Macmillan Publishers Ltd: Nature Communications,17 copyright (2015). (c)
`Reprinted from ref. 18 (d) Reprinted from refs. 16 and 19. Copyright (2016), with permission from Elsevier. (e) Adapted with permissions from ref.
`20. Copyright (2012) American Chemical Society. (f) Reprinted from ref. 21
`
`organic nanoparticles (e.g., polymeric, liposomes, micelles, etc.). Inor-
`ganic nanoparticles have been successful
`in preclinical studies, are
`being developed in the clinic for a variety of applications including
`intraoperative sentinel lymph node imaging and thermal ablation of
`tumors, and have already been approved for imaging applications and
`anemia treatment (Figure 1).13–15 Alongside this, organic nanoparticles
`have also exhibited substantial success in the clinic where they are
`currently being developed for broad applications ranging from vaccina-
`tion, to hemostasis, to long-lasting depot delivery systems, to topical
`agents for systemic delivery through the skin.1–5 More relevant to this
`review are nanoparticle formulations that are delivered intravenously,
`
`and in this realm, organic nanoparticles predominantly fall into two
`categories: (a) nanoparticles for gene therapy applications22,23 or (b)
`nanoparticles for delivery of small molecule drugs for cancer treatment
`(e.g., head and neck, melanoma, breast, metastatic, etc.).24,25 Organic
`nanoparticle formulations for other applications (e.g., vaccines, fungal
`treatments, etc.) are also in development and will be highlighted here
`(Figure 1).
`The main reasons behind the interest in nanoparticle technologies
`
`are that: (a) in the case of organic nanoparticles, they possess distinct
`
`advantages over many intravenously administered pharmaceuticals
`
`and biologics, and (b) in the case of inorganic nanoparticles, many
`
`

`

`12 |
`
`stimuli responsive functions are possible based on specific colloidal
`
`assemblies. Organic nanoparticles can be designed and formulated to
`
`offer enhanced drug protection, controlled release, extended circula-
`
`tion, and improved targeting to diseased tissues as compared to their
`free drug counterparts.25,26 Likewise, inorganic nanoparticles benefit
`from these same advantages, and additionally from stimuli-responsive
`
`functions arising from their surface plasmon resonance (e.g., thermal
`
`heating or imaging) or magnetic responsiveness (e.g., magnetic reso-
`
`nance imaging [MRI] imaging or magnetic targeting) that individual
`drugs or other molecules (e.g., noncolloidal) do not offer.2,27 Given
`these advantages, it has been a long-held idea that nanoparticles have
`
`the potential to dramatically change clinical care by introducing new,
`
`or improving upon current, therapies. A large portion of the interest in
`
`nanoparticles stems from their potential as a platform delivery system,
`
`with the capability of exchanging specific design features (e.g., target-
`
`ing antibodies, the encapsulated drug, and control over how/when the
`diseased site interacts with this drug) in a “plug-and-play” format to
`treat additional or other diseases.
`
`3 | CLINICALLY APPROVED
`NANOPARTICLES/MICROPARTICLES
`
`Currently, there are a number of nanoparticle therapeutics,
`
`imaging
`
`agents, and technologies that have been approved for clinical use, either
`
`by the FDA in the United States, or the European Medicines Agency
`
`(EMA) in the European Union (Table 1). In this section, we will highlight
`
`the currently approved nanoparticles and their clinical indications.
`
`3.1 | Cancer nanoparticle medicines
`
`Many clinically approved nanoparticle formulations are used in treat-
`
`ing various cancers at a variety of stages. Interestingly, all but one of
`
`these systems (Abraxane) is liposomal systems encapsulating an anti-
`
`cancer drug. Doxil, polyethylene glycol (PEG) functionalized liposomal
`
`doxorubicin, was the first approved (FDA 1995) cancer nanomedi-
`cine.8 Soon after, other liposomal formulations such as liposomal dau-
`norubicin (DaunoXome),28 liposomal vincristine (Marqibo),29 and most
`recently liposomal irinotecan (Onivyde)30 were approved by the FDA,
`whereas non-PEGylated liposomal doxorubicin (Myocet)31 and liposo-
`mal mifamurtide (MEPACT)32 were approved by the EMA. The lone
`nonliposomal nanoparticle system currently approved for cancer treat-
`
`ments is Abraxane, which is an albumin-bound paclitaxel nanopar-
`ticle.33 The majority of these formulations are not PEGylated, with the
`exception of Doxil and Onivyde,34 which is perhaps surprising given
`the widely known advantages even small amounts of PEG have shown
`to confer to nanoparticle delivery systems.35–37 Additionally, all of
`these formulations are passively targeted, with no active or chemical-
`
`based targeting moieties; again, this is despite the proven advantages
`of active-targeting in preclinical settings.25,26,38 It is likely that the
`other advantages, notably their reduced toxicity stemming from their
`
`ability to preferentially accumulate at tumor sites and limit off-target
`side effects via the enhanced permeation and retention (EPR) effect,39
`
`ANSELMO AND MITRAGOTRI
`
`are responsible for the success and increased efficacy that these
`approved particles have over their free drug counterparts.
`
`3.2 | Iron-replacement nanoparticle therapies
`
`Another clinical area where nanoparticles have made a significant
`impact is in iron-replacement therapies for treatment of anemia (Table
`1).40–42 In these applications, the nanoparticle (iron-oxide colloids) is
`the therapeutic with the goal being to increase iron concentration in
`the body.43 These nanoparticle approaches originated from the need
`to address toxicity issues associated with the injection of
`free
`iron.40,42 Using colloidal iron coated with sugars, many of these toxic-
`ity issues were resolved.40,42 It should be noted that nanoparticles
`indicated for iron-replacement undergo vastly different approval pro-
`cedures, by both the FDA and EMA, as they are nonbiological complex
`drugs; it is a widely held belief that additional factors, stemming from
`their colloidal and nanoparticle nature, need to be considered during
`their approval (e.g., manufacturing conditions).41,44
`
`3.3 | Nanoparticle/microparticle imaging agents
`
`Alongside colloid-based iron-replacement therapies, similar iron-oxide
`nanoparticles are clinically approved as contrast agents for MRI (Table
`1).45,46 For imaging applications, the innate magnetic responsiveness
`of iron-oxide nanoparticles is used with MRI to generate contrast for
`imaging a variety of cancers and pathologies.47,48 The combination of
`an iron-oxide nanoparticle’s MRI responsiveness and small size, which
`facilitates preferential uptake in tumors, provides accurate and precise
`imaging of cancerous tissues. Interestingly, the majority of colloidal
`iron-oxide imaging agents have been discontinued in the United States
`and most of Europe.13 In addition to MRI contrast enhancers, particles
`can be used as intravenous ultrasound enhancing agents. In these
`cases, particles typically take the form of micron-sized microbub-
`bles.49,50 These microbubbles provide a means to enhance contrast by
`stabilizing and encapsulating air bubbles, which are near-perfect
`reflectors of ultrasound and would otherwise rapidly dissolve in blood
`if not encapsulated/formulated.49 Few of these products are approved
`and currently used in the clinic, for example, Definity (FDA approved)
`and SonoVue (EMA approved) are fluorocarbons or sulfur hexafluoride
`encased in lipid shells, respectively. Optison (FDA and EMA approved)
`is another ultrasound contrast agent formulated as human serum albu-
`min encased perflutren.
`
`3.4 | Nanoparticles for vaccines, anesthetics, fungal
`treatments, and macular degeneration
`
`Nanoparticles, or in these cases liposomes, are also used in a number
`of other clinical applications (Table 1). The first of these is Diprivan,51
`which was FDA approved in 1989 as a general anesthetic.52 Two vac-
`cines, Epaxal for vaccination against hepatitis A53 and Inflexal V for
`vaccination against influenza,54 are liposomal systems that have been
`approved in many European countries. Interestingly, these two vac-
`cines use their viral glycoprotein-liposomal template as the primary
`adjuvant,55 with Epaxal doing so in lieu of traditional adjuvants such as
`
`

`

`ANSELMO AND MITRAGOTRI
`
`TABLE 1 Clinically approved intravenous nanoparticle therapies and diagnostics, grouped by their broad indication
`
`Name
`
`Particle type/drug
`
`Approved application/indication
`
`Approval (year)
`
`Investigated application/indication
`
`ClinicalTrials.gov identifier
`
`Cancer Nanoparticle Medicines
`
`Doxil/Caelyx
`(Janssen)
`
`Liposomal doxorubicin
`(PEGylated)
`
`DaunoXome (Galen)
`
`Liposomal daunorubicin
`(non-PEGylated)
`
`Ovarian cancer (secondary to platinum
`based therapies)
`HIV-associated Kaposi’s sarcoma
`(secondary to chemotherapy)
`Multiple myeloma (secondary)
`HIV-associated Kaposi’s sarcoma
`(primary)
`
`FDA (1995)
`EMA (1996)
`
`Various cancers including: solid
`malignancies, ovarian, breast, leukemia,
`lymphomas, prostate, metastatic, or liver
`
`166 studies mention Doxil
`90 studies mention CAELYX
`
`FDA (1996)
`
`Various leukemias
`
`32 studies mention
`DaunoXome
`
`32 studies mention Myocet
`
`295 studies mention Abraxane
`
`Myocet (Teva UK)
`
`Abraxane (Celgene)
`
`Liposomal doxorubicin
`(non-PEGylated)
`
`Treatment of metastatic breast cancer
`(primary)
`
`Albumin-particle bound
`paclitaxel
`
`Advanced nonsmall cell lung cancer
`(surgery or radiation is not an option)
`Metastatic breast cancer (secondary)
`Metastatic pancreatic cancer (primary)
`
`EMA (2000)
`
`FDA (2005)
`EMA (2008)
`
`Various cancers including: breast,
`lymphoma, or ovarian
`
`Various cancers including: solid
`malignancies, breast, lymphomas, bladder,
`lung, pancreatic, head and neck, prostate,
`melanoma, or liver
`
`Marqibo (Spectrum)
`
`Liposomal vincristine
`(non-PEGylated)
`
`Philadelphia chromosome-negative
`acute lymphoblastic leukemia (tertiary)
`
`FDA (2012)
`
`Various cancers including: lymphoma,
`brain, leukemia, or melanoma
`
`23 studies mention Marqibo
`
`MEPACT (Millennium)
`
`Liposomal mifamurtide
`(non-PEGylated)
`
`Treatment for osteosarcoma (primary
`following surgery)
`
`EMA (2009)
`
`Osteosarcomas
`
`Onivyde MM-398
`(Merrimack)
`
`Liposomal irinotecan
`(PEGylated)
`
`Metastatic pancreatic cancer
`(secondary)
`
`FDA (2015)
`
`Various cancers including: solid
`malignancies, breast, pancreatic, sarcomas,
`or brain
`
`4 studies mention MEPACT: 3
`active/recruiting
`
`7 studies mention MM-398/
`Onivyde: 6 active/recruiting
`
`Iron-replacement nanoparticle therapies
`
`CosmoFer/INFeD/
`Ferrisat
`(Pharmacosmos)
`
`DexFerrum/DexIron
`(American Regent)
`
`Iron dextran colloid
`
`Iron deficient anemia
`
`FDA (1992)
`Some of Europe
`
`Iron deficient anemia
`
`6 studies mention INFeD:
`1 recruiting
`
`Iron dextran colloid
`
`Iron deficient anemia
`
`FDA (1996)
`
`Iron deficient anemia
`
`6 studies mention DexFerrum
`
`Ferrlecit (Sanofi)
`
`Iron gluconate colloid
`
`Iron replacement for anemia treatment
`in patients with chronic kidney disease
`
`FDA (1999)
`
`Iron deficient anemia
`
`Iron sucrose colloid
`
`Iron replacement for anemia treatment
`in patients with chronic kidney disease
`
`FDA (2000)
`
`Iron deficient anemia
`Following autologous stem cell
`transplantation
`
`13 studies mention Ferrlecit: 2
`recruiting
`
`44 studies mention Venofer
`
`Iron polyglucose
`sorbitol
`carboxymethylether
`colloid
`
`Iron deficiency in patients with chronic
`kidney disease
`
`FDA (2009)
`
`Iron deficient anemia
`Imaging: brain metastases, lymph node
`metastases, neuroinflammation in
`epilepsy, head and neck cancer,
`myocardial infarction, or multiple sclerosis
`
`57 studies mention Ferumoxytol:
`6 recruiting/active for anemia
`treatment
`22 recruiting/active for imaging
`applications
`
`Iron deficient anemia
`
`FDA (2013)
`
`Iron deficient anemia
`
`Treating iron deficiency and anemia
`when oral methods do not work or
`when iron delivery is required
`immediately
`
`Some of Europe
`
`Iron deficient anemia
`
`50 studies mention Ferinject
`8 studies mention Injectafer
`
`22 studies: 3 active/recruiting
`
`| 13
`
`Iron deficient anemia
`
`Some of Europe
`
`Iron deficient anemia
`
`1 recruiting study
`
`Injectafter/Ferinject
`(Vifor)
`
`Iron carboxymaltose
`colloid
`
`Monofer
`(Pharmacosmos)
`
`10% Iron isomaltoside
`1000 colloid
`
`Diafer
`(Pharmacosmos)
`
`5% Iron isomaltoside
`1000 colloid
`
`Venofer (American
`Regent)
`
`Feraheme (AMAG)/
`Rienso (Takeda)/
`Ferumoxytol
`
`

`

`14 |
`
`ANSELMO AND MITRAGOTRI
`
`TABLE 1 (Continued)
`
`Name
`
`Particle type/drug
`
`Approved application/indication
`
`Approval (year)
`
`Investigated application/indication
`
`ClinicalTrials.gov identifier
`
`Nanoparticle/microparticle imaging agents
`
`Definity (Lantheus
`Medical Imaging)
`
`Perflutren lipid
`microspheres
`
`Ultrasound contrast agent
`
`FDA (2001)
`
`Feridex I.V. (AMAG)/
`Endorem
`
`Iron dextran colloid
`
`Imaging of liver lesions
`
`Optison (GE
`Healthcare)
`
`Human serum albumin
`stabilized perflutren
`microspheres
`
`Ultrasound contrast agent
`
`FDA (1996)
`Discontinued
`(2008)
`
`FDA (1997)
`EMA (1998)
`
`SonoVue (Bracco
`Imaging)
`
`Phospholipid stabilized
`microbubble
`
`Ultrasound contrast agent
`
`EMA (2001)
`
`Resovist (Bayer
`Schering Pharma)/
`Cliavist
`
`Ferumoxtran-10/
`Combidex/Sinerem
`(AMAG)
`
`Nanoparticle vaccines
`
`Epaxal (Crucell)
`
`Inflexal V (Crucell)
`
`Particle anesthetics
`
`Iron carboxydextran
`colloid
`
`Imaging of liver lesions
`
`Iron dextran colloid
`
`Imaging lymph node metastases
`
`Liposome with hepatitis
`A virus
`
`Liposome with
`trivalent-influenza
`
`Hepatitis A vaccine
`
`Influenza vaccine
`
`Diprivan
`
`Liposomal propofol
`
`Induction and maintenance of
`sedation or anesthesia
`
`Some of Europe
`Discontinued
`(2009)
`
`Only available in
`Holland
`
`Some of Europe
`(Discontinued)
`
`Some of Europe
`(Discontinued)
`
`FDA (1989)
`
`Ultrasound enhancement for: liver or
`breast or intraocular or pancreatic tumors,
`pulmonary diseases, heart function,
`transcranial injuries, strokes, or liver
`cirrhosis
`
`N/A: No current studies
`
`Ultrasound enhancement for: lymph node,
`renal cell carcinoma, myocardial
`infarction, pulmonary transit times, or
`heart transplant rejections
`
`Ultrasound enhancement for: liver
`neoplasms, prostate or breast or
`pancreatic cancer, or coronary/pulmonary
`disease
`
`N/A
`No current studies
`
`Imaging lymph node metastases
`
`58 studies mention Definity
`
`4 studies mention Endorem
`2 studies mention Feridex
`No current active or recruiting
`studies
`
`11 currently active or
`recruiting studies
`
`43 studies mention SonoVue
`
`2 studies mention Resovist: No
`current active or recruiting
`studies
`
`11 studies mention
`ferumoxtran-10: 1 active
`
`Safety and immunogenicity of hepatitis A
`vaccine
`
`6 studies mention Epaxal: 1
`recruiting
`
`Safety and immunogenicity of influenza
`vaccine
`
`14 studies mention Inflexal V:
`All completed
`
`General anesthesia in specific situations:
`morbidly obese patients, open heart
`surgery, or spinal surgery
`
`110 studies mention Diprivan
`
`Nanoparticles for fungal treatments
`
`AmBisome (Gilead
`Sciences)
`
`Liposomal
`amphotericin B
`
`Cryptococcal Meningitis in HIV-
`infected patients
`Aspergillus, Candida, and/or
`Cryptococcus species infections
`(secondary)
`Visceral leishmaniasis parasite in
`immunocompromised patients
`
`FDA (1997) Most
`of Europe
`
`Preventing or treating invasive fungal
`infections
`
`50 studies mention AmBisome
`
`Nanoparticles for macular degeneration
`
`Visudyne (Bausch and
`Lomb)
`
`Liposomal verteporfin
`
`Treatment of subfoveal choroidal
`neovascularization from age-related
`macular degeneration, pathologic, or
`ocular histoplasmosis
`
`FDA (2000)
`EMA (2000)
`
`Macular degeneration
`
`52 studies mention Visudyne
`
`

`

`ANSELMO AND MITRAGOTRI
`
`aluminum hydroxide.53 However, these vaccines have since been
`phased out of the clinic. In other applications, liposomes or lipid-based
`
`nanoformulations have been clinically approved for fungal and para-
`
`sitic infections. For example, the highly toxic antifungal drug ampho-
`
`infections, has been
`tericin B, used for treating systemic fungal
`formulated in liposomes (AmBisome).56 In doing so, toxicity is dramati-
`cally reduced as the pharmacokinetics and tissue distribution is
`
`improved via liposomal encapsulation. Furthermore, the liposomal for-
`
`mulation addresses a significant issue of the free drug form of ampho-
`
`tericin B, which is its insolubility in pH 7 saline. While not true
`
`liposomes, other FDA approved lipid-complexed formulations of
`amphotericin B exist, such as Abelcet and Amphotec.57 Visudyne® is
`a light-activated liposomal
`formulation of verteporfin. Liposomal
`
`encapsulation offers enhanced uptake in proliferating cells which par-
`
`ticularly enhances targeting and subsequent uptake by targets neovas-
`
`cular
`
`areas, which,
`
`following
`
`light
`
`stimulation damages
`
`the
`
`endothelium and blocks local blood vessels to prevent and treat
`neovascularization.58
`
`4 | CURRENT N ANOPARTICLE/
`MICROPARTICLE CLINICAL TRIAL S
`
`Given the successes of many of these formulations in the clinic and
`
`commercial realm, significant efforts continue to explore currently
`
`approved nanomedicines as well as developing new ones. Here, we
`
`will: (a) briefly review the current clinical trial landscape for currently
`
`approved nanoparticles (Table 1), (b) review the current clinical trial
`
`landscape regarding cutting-edge nanoparticle formulations which are
`
`seeking approval (Table 2), and (c) highlight key technologies attempt-
`
`ing to integrate targeting and stimuli-responsive functions into nano-
`
`particle delivery systems.
`
`4.1 | Previously approved nanoparticles
`
`By seeking approval for additional
`
`indications, currently approved
`
`nanoparticle systems experience a more direct path to clinical approval
`
`as compared to a newer, developing, technology. This is because
`
`already approved nanoparticles have proven their safety and efficacy
`
`in humans and,
`
`if commercialized,
`
`likely meet good manufacturing
`
`practice (GMP) standards.
`
`4.1.1 | Cancer nanoparticle medicine
`
`| 15
`
`4.1.2 | Iron-replacement nanoparticle therapies
`
`Of all the FDA approved iron-replacement nanoparticle therapies, only
`
`few remain active in clinical trials. For example, CosmoFer/INFeD/Fer-
`
`risat, DexFerrum/DexIron, Ferrlecit, Monofer, and Diafer show limited
`
`activity in current clinical trials, whereas Ferinject/Injectafer, Fera-
`
`heme/Rienso/Ferumoxytol, and Venofer show dramatically more
`
`activity, mostly for iron-replacement in various clinical settings. Special
`
`attention should be placed on ferumoxytol/Feraheme/Rienso, as addi-
`
`tional approval is being sought for a number of imaging applications
`
`which is beyond its approved indication of iron-replacement (dis-
`
`cussed in detail in the next section).
`
`4.1.3 | Nanoparticle/microparticle imaging agents
`
`FDA or EMA approved iron-oxide contrast agents all show extremely
`
`low activity in current clinical trials. As stated earlier, Feridex I.V./
`
`Endorem, Resovist/Cliavist, and Combidex/Sinerem were all discontin-
`
`ued which is reflected by their lack of presence in current clinical trials.
`
`It is unlikely that these approved products will resurface in the clinic
`
`given that the manufacturer no longer produces them, either for clini-
`
`cal or research purposes. However, ferumoxytol (Feraheme or Rienso),
`
`which is approved for iron-replacement therapies is broadly investi-
`
`gated for imaging applications in the clinic. Indeed, ferumoxytol is the
`
`most widely investigated iron-oxide particle with the majority of clini-
`
`cal trials focused on imaging of various cancers or other pathologies
`
`(22 for imaging vs. 6 for anemia treatment). This is likely because there
`
`is a severe unmet need of iron-oxide imaging agents in the clinical,
`
`stemming from the discontinuation of all other iron-oxide imaging
`
`products. Approval of an iron-oxide formulation that is already used in
`
`the clinic and also mass-produced, is likely a more straight-forward
`
`path to approval as opposed to a nonapproved technology. The ultra-
`
`sound contrast enhancers SonoVue, Optison, and Definity are all being
`
`investigated in a number of clinical trials: 43, 11 active/recruiting, and
`
`58, respectively. While not a currently approved indication, except for
`
`SonoVue, few of these current clinical trials are investigating micro-
`
`bubble use for tumor imaging applications.
`
`4.1.4 | Nanoparticles for vaccines, anesthetics, fungal
`treatments, and macular degeneration
`
`Epaxal and Inflexal V, approved in some European countries as
`
`liposomal-based vaccines, are not investigated in current clinical studies,
`
`likely because they have been phased out of clinical use. In addition, the
`
`As cancer nanomedicines were approved by the FDA over 20 years
`
`platform of intravenous virosomes developed by Crucell does not
`
`ago, it is not surprising that these currently approved nanoparticles are
`
`appear to be in any current clinical trials, for any vaccine. FDA-approved
`
`investigated in the largest number of current clinical trials. For exam-
`
`Visudyne, approved for treating neovascularization is currently being
`
`ple, Doxil and Abraxane are mentioned in over 160 and 290 clinical
`
`investigated in clinical trials focused on combining it with other neovas-
`
`studies, respectively. More recently approved products such as Mar-
`
`cularization therapies. Diprivan, FDA approved in 1989, still persists in
`
`qibo, MEPACT, and Onivyde, also have a strong presence in clinical tri-
`als. These trials build on each individual nanoparticle’s current
`indications by seeking approval for: (a) additional cancer types, (b) a
`
`clinical trials, mostly for approval as an anesthetic for special cases (e.g.,
`
`morbidly obese patients, spinal or open-heart surgeries). AmBisome,
`
`approved nearly two decades ago in 1997 by the FDA, is still studied in
`
`combination therapy with other therapeutic agents, or (c) upgrading
`
`the clinic for additional bacterial/fungal infections and in tolerability and
`
`their use from a secondary therapy to a primary first-line therapy.
`
`efficacy in patients with other diseases or complications.
`
`

`

`16 |
`
`ANSELMO AND MITRAGOTRI
`
`Intravenous nanoparticle therapies and diagnostics which have not been clinically approved and are currently undergoing clinical tri-
`TABLE 2
`als (not yet recruiting, recruiting, or active), grouped by particle type as well as well as application
`
`Name (company)
`
`Particle type/drug
`
`Investigated application/indication
`
`ClinicalTrials.gov
`identifier (phase)
`
`Pegylated liposomal mitomycin-C
`
`Solid tumors
`
`NCT01705002 (Ph I)
`
`Liposomes (cancer)
`
`PROMITIL (Lipomedix
`Pharmaceuticals)
`
`ThermoDox® (Celsion)
`
`Lyso-thermosensitive liposomal
`doxorubicin
`
`Temperature-triggered doxorubicin
`release:
`Breast cancer recurrence at chest wall
`(microwave hypothermia)
`Hepatocellular carcinoma
`(radiofrequency ablation)
`Liver tumors (mild hypothermia)
`Refractory solid tumors (magnetic
`resonance high intensity focused
`ultrasound)
`
`VYEXOS CPX-351 (Celator
`Pharmaceuticals)
`
`Liposomal formulation of cytarabine:
`daunorubicin (5:1 molar ratio)
`
`Leukemias
`
`Oncoprex (Genprex)
`
`FUS1 (TUSC2) encapsulated liposome
`
`Lung cancer
`
`Halaven E7389-LF (Eisai)
`188Re-BMEDA-liposome
`
`Mitoxantrone Hydrochloride
`Liposome (CSPC ZhongQi
`Pharmaceutical Technology)
`
`Liposomal eribulin mesylate
`188Re-N,N-bis (2-mercaptoethyl)-N0,N0-
`diethylethylenediamine pegylated
`liposome
`
`Solid tumors
`
`Advanced solid tumors
`
`Mitoxantrone liposome
`
`Lymphoma and breast cancer
`
`JVRS-100
`
`Cationic liposome incorporating
`plasmid DNA complex for immune
`system stimulation
`
`Leukemia
`
`NCT00826085 (Ph I/II)
`NCT02112656 (Ph III)
`NCT02181075 (Ph I)
`NCT02536183 (Ph I)
`
`NCT01804101 (Not
`Provided)
`NCT02286726 (Ph II)
`NCT02019069 (Ph II)
`NCT01943682 (Ph I)
`NCT02269579 (Ph II)
`NCT02533115 (Ph IV)
`NCT01696084 (Ph III)
`
`NCT01455389 (Ph I/II)
`
`NCT01945710 (Ph I)
`
`NCT02271516 (Ph I)
`
`NCT02131688 (Ph I)
`NCT02596373 (Ph II)
`NCT02595242 (Ph I)
`NCT02597387 (Ph II)
`NCT02597153 (Ph II)
`
`NCT00860522 (Ph I)
`
`Lipocurc (SignPath Pharma)
`
`Liposomal curcumin
`
`Solid tumors
`
`NCT02138955 (Ph I/II)
`
`LiPlaCis (LiPlasome Pharma)
`
`MM-302 (Merrimack
`Pharmaceuticals)
`
`LIPUSU® (Nanjing Luye
`Sike Pharmaceutical Co.,
`Ltd.)
`
`Liposomal formulated cisplatin with
`specific degradation-controlled drug
`release via phospholipase A2 (PLA2)
`
`HER2-targeted liposomal doxorubicin
`(PEGylated)
`
`Paclitaxel Liposome
`
`Liposomes (gene therapy: cancer)
`
`TKM-080301 (Arbutus
`Biopharma)
`
`Lipid particle targeting polo-like kinase
`1 (PLK1) for delivery of siRNA
`
`Advanced or refractory tumors
`
`NCT01861496 (Ph I)
`
`Breast cancer
`
`Advanced solid tumors, or gastric,
`breast cancer
`
`NCT01304797 (Ph I)
`NCT02213744 (Ph II/III)
`
`NCT01994031 (Ph IV)
`NCT02142790 (Ph IV)
`NCT02163291 (Ph II)
`NCT02142010 (Not
`Provided)
`
`Hepatocellular carcinoma
`
`NCT02191878 (Ph I/II)
`
`siRNA-EphA2-DOPC
`
`siRNA liposome for EphA2 knockdown
`
`Solid tumors
`
`PNT2258 (ProNAi
`Therapeutics)
`
`BP1001 (Bio-Path Holdings)
`
`Proprietary single-stranded DNAi
`(PNT100) encapsulated in lipid
`nanoparticles
`
`Growth factor receptor bound protein-
`2 (Grb-2) antisense oligonucleotide
`encapsulated in neutral liposomes
`
`Lymphomas
`
`Leukemias
`
`DCR-MYC (Dicerna
`Pharmaceuticals)
`
`Atu027 (Silence
`Therapeutics GmbH)
`
`DsiRNA lipid nanoparticle for NYC
`oncogene silencing
`
`Solid tumors, multiple myeloma,
`lymphoma, or hepatocellular carcinoma
`
`AtuRNAi liposomal formulation for
`PKN3 knockdown in vascular
`endothelium
`
`Pancreatic cancer
`
`NCT01591356 (Ph I)
`
`NCT02378038 (Ph II)
`NCT02226965 (Ph II)
`NCT01733238 (Ph II)
`
`NCT01159028 (Ph I)
`
`NCT02110563 (Ph I)
`NCT02314052 (Ph I/II)
`
`NCT01808638 (Ph I/II)
`
`

`

`ANSELMO AND MITRAGOTRI
`
`TABLE 2 (Continued)
`
`Name (company)
`
`Particle type/drug
`
`Investigated application/indication
`
`SGT-53 (SynerGene
`Therapeutics)
`
`Cationic liposome with anti-transferrin
`receptor antibody, encapsulating
`Wildtype p53 sequence
`
`Glioblastoma, solid tumors, or
`pancreatic cancer
`
`| 17
`
`ClinicalTrials.gov
`identifier (phase)
`
`NCT02354547 (Ph I)
`NCT00470613 (Ph I)
`NCT02354547 (Ph I)
`NCT02340156 (Ph II)
`
`NCT01517464 (Ph I)
`
`NCT01829971 (Ph I)
`
`NCT02369198 (Ph I)
`
`Solid tumors
`
`Liver cancer
`
`Mesothelioma and nonsmall cell lung
`cancer
`
`SGT-94 (SynerGene
`Therapeutics)
`
`MRX34 (Mirna
`Therapeutics)
`
`TargomiRs (EnGeneIC)
`
`Liposomes (gene therapy: other)
`
`ND-L02-s0201 (Nitto
`Denko)
`
`ARB-001467 TKM-HBV
`(Arbutus Biopharma)
`
`Patisiran ALN-TTR02
`(Alnylam Pharmaceuticals)
`
`Liposomes (other)
`
`CAL02 (Combioxin SA)
`
`Nanocort (Enceladus in
`collaboration with Sun
`Pharma Global)
`
`RGI-2001 (Regimmune)
`
`RB94 plasmid DNA in a liposome with
`anti-transferrin receptor antibody
`
`Double-stranded RNA mimic of miR-
`34 encapsulated in liposomes
`
`Anti-EGFR bispecific antibody minicells
`(bacteria derived nanoparticles) with a
`miR-16 based microRNA payload
`
`siRNA lipid nanoparticle conjugated to
`Vitamin A
`
`Lipid particle containing three RNAi
`therapeutics that target three sites on
`the HBV genome
`
`Lipid nanoparticle RNAi for the
`knockdown of disease-causing TTR
`protein
`
`Sphingomyelin and cholesterol
`liposomes for toxin neutralization
`
`Liposomal Prednisolone (PEGylated)
`
`Liposomal formulaton of a-GalCer
`
`Sonazoid
`
`F-butane encapsulated in a lipid shell
`
`Polymeric and micelles (cancer)
`
`AZD2811 (AstraZeneca
`with BIND Therapeutics)
`
`BIND-014 (BIND
`Therapeutics)
`
`Aurora B kinase inhibitor in BIND
`therapeutics polymer particle accurin
`platform
`
`PSMA targeted (via ACUPA) docetaxel
`PEG-PLGA or PLA-PEG particle
`
`Hepatic fibrosis