Engineered Nanomaterials: The Challenges and Opportunities for Nanomedicines

Figures & data

Table 1 Essential Applications of ENMs^172–176

Categories	Applications	Ref.
Medical diagnosis	Bioimaging	[^Citation1,^Citation178,^Citation179]
	In-vitro diagnosis	[^Citation180,^Citation181]
	Biosensing	[^Citation182,^Citation183]
Therapeutic techniques	Drug delivery	[^Citation184^–^Citation186]
	Gene therapy	[^Citation179,^Citation186,^Citation187]
Disease control or applications	Tissue engineering	[^Citation184,^Citation188]
	Vaccination	[^Citation185,^Citation188]

Table 2 List of FDA-Approved Nanomedicine

Name	Particle type/drug	Approved application/indication	year of approval (FDA)
VYXEOS CPX-351 (Jazz Pharmaceuticals)	Liposomal formulation of cytarabine:daunorubicin (5:1M ratio)	Acute myeloid leukemia	2017
ONPATTRO Patisiran ALN-TTR02 (Alnylam Pharmaceuticals	Lipid nanoparticle RNAi for theknockdown of disease-causingTTR protein	Transthyretin (TTR)-mediated amyloidosis	2018
Doxil Caelyx (Janssen)	Liposomal doxorubicin (PEGylated)	Ovarian cancer (secondary to platinum based therapies) HIV-associated Kaposi’s sarcoma (secondary to chemotherapy) Multiple myeloma (secondary)	1995
DaunoXome (Galen)	Liposomal daunorubicin (nonPEGylated)	HIV-associated Kaposi’s sarcoma (primary)	1996
Abraxane (Celgene)	Albumin-particle bound paclitaxe	Advanced non-small cell lung cancer (surgery or radiation is not an option) Metastatic breast cancer (secondary) Metastatic pancreatic cancer (primary	2005
Marqibo (Spectrum)	Liposomal vincristine (non-PEGylated)	Philadelphia chromosomenegative acute lymphoblastic leukemia (tertiary)	2012
Onivyde MM-398 (Merrimack)	Liposomal irinotecan (PEGylated)	Metastatic pancreatic cancer (secondary)	2015
CosmoFer INFeD Ferrisat (Pharmacosmos	Iron dextran colloid	Iron deficient anemia	1992
DexFerrum DexIron (American Regent)	Iron dextran colloid	Iron deficient anemia	1996
Ferrlecit (Sanofi)	Iron gluconate colloid	Iron replacement for anemia treatment in patients with chronic kidney disease	1999
Venofer (American Regent)	Iron sucrose colloid	Iron replacement for anemia treatment in patients with chronic kidney disease	2000
Feraheme (AMAG) Rienso (Takeda) Ferumoxytol	Iron polyglucose sorbitol carboxymethylether colloid	Iron deficiency in patients with chronic kidney disease	2009
Injectafer Ferinject (Vifor)	Iron carboxymaltose colloid	Iron deficient anemia	2013
Definity (Lantheus Medical Imaging)	Perflutren lipid microspheres	Ultrasound contrast agent	2001
Feridex I.V. (AMAG) Endorem	Iron dextran colloid	Imaging of liver lesions	1996
Optison(GE Healthcare)	Human serum albumin stabilized perflutren microspheres	Ultrasound contrast agent	1997
Diprivan	Liposomal propofol	Induction and maintenance of sedation or anesthesia	1989
AmBisome (Gilead Sciences)	Liposomal amphotericin B	Cryptococcal meningitis in HIVinfected patients Aspergillus, Candida and/or Cryptococcus species infections (secondary) Visceral leishmaniasis parasite in immunocompromised patients	1997
Visudyne (Bausch and Lomb)	Liposomal verteporfin	Treatment of subfoveal choroidal neovascularization from age-related macular degeneration, pathologic, or ocular histoplasmosis	2000

Notes: Reproduced from Anselmo AC, Mitragotri S.  Nanoparticles in the clinic: An update. Bioeng Transl Med. 2019;4(3):e10143⁴⁷.

Figure 1 Trends in the development of nanomedicines. (A) FDA-approved nanomedicines stratified by category; (B) FDA-approved nanomedicines stratified by category overall.

Notes: Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature; Nature Nanotechnology; Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33:2373–2387; Copyright 2016.⁴⁵

Figure 2 Four directions in utilizing ENMs in nanomedicine in refining their cancer-treating performance.

Notes: Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature; Nature Nanotechnology; van der Meel R, Sulheim E, Shi Y, et al. Smart cancer nanomedicine. Nat Nanotechnol. 2019;14:1007–1017; Copyright 2019.⁵³

Figure 3 Nanomaterials used as therapeutic agents in nanomedicines, particularly ocular.

Notes: Mehra NK, Cai D, Kuo L, Hein T, Palakurthi S. Safety and toxicity of nanomaterials for ocular drug delivery applications. Nanotoxicology. 2016;10:836–860, reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).⁶⁰

Figure 4 The fate of ENMs, their effects and cycle in human body.

Table 3 The Common Effects of ENMs and Their Mechanisms

Type of Effect	Description	Mechanism	Ref.
Biodistribution-related toxicity	The behavior of an ENM in the physiological surrounding will be determined by its dispersion in various organs; heart, lungs, kidney, spleen, liver, brain, testis and thymus, and by physicochemical properties such as hydrophobicity, dissolution, and aggregation state. Also, cell uptake and route of administration.	Dissolution can result in a redox reaction, altering the chemical reactivity of the ENM. Adsorption of matrix components, the agglomeration or sedimentation of the ENM can significantly impact the delivery of the material and its bioavailability	[^Citation71,^Citation78,^Citation79]
Reactive oxygen species	During the mitochondrial electron transport of aerobic respiration or oxidoreductase enzymes and metal-catalyzed oxidation, reactive molecules and free radicals are emitted as by-products. These by-products can be susceptible to causing a series of catastrophic occurrences in the body.	Superoxide anion, hydrogen peroxide and nitric oxide	[^Citation31,^Citation78,^Citation85]
Inflammation	A major process where the body repairs damaged tissue and protect its organs from outside invaders. Acute inflammation is a typical response to an incoming threat to eradicates foreign bodies, damaged tissue, and stopping additional injury	Macrophages present in the tissue acts as the tissue’s primary immune response, releasing numerous cytokines and immune factors. Upon interaction of macrophage with ENM, macrophages differentiated to pro-inflammatory or anti-inflammatory phenotypes depending on the ENM nature	[^Citation75,^Citation76,^Citation83^–^Citation85,^Citation190]
Cell membrane damage	The cell membrane separates and protects the inner organelle of cells from the outside environment. ENMs can pass cell membrane by endocytosis or thru penetration. This may provoke permanent cell damage and toxicity depends on ENMs concentration and properties.	Cell membrane disruptions and cell death typically depending on various ENMs physiochemical properties, such as size, surface charge, or hydrophilicity. Adsorption of ENMs on cell membranes may lead to blocking cellular ducts, causing changes to membrane structures, or inhibiting metabolism or ion intake causing cell death	[^Citation93,^Citation122]
Genotoxicity	Describes the damage of the genetic information within a cell as a result of oxidation of critical cell biomolecules lead to chromosomal aberrations, gene mutations, apoptosis and carcinogenesis	Alterations of redox equilibrium in the cell among produced reactive oxygen species and antioxidant leading to DNA damage.	[^Citation71,^Citation84,^Citation85,^Citation191,^Citation192]

Figure 5 Pyramid model on the determination of ENMs design, production and toxicity assessment.

Notes: Adapted with permission from Mirshafiee V, Jiang W, Sun B, Wang X, Xia T. Facilitating translational nanomedicine via predictive safety assessment. Mol Ther. 2017;25:1522–1530. .¹²¹

Figure 6 Knowledge-sharing platform in assessing the toxicity of ENMs in nanomedicine.

Notes: Reprinted by permission from Springer Nature CustomerService Centre GmbH: Springer Nature; Nature Nanotechnology; Fadeel B, Farcal L, Hardy B, et al. Advanced tools for the safety assessment of nanomaterials. Nat Nanotechnol. 2018;13:537–543; Copyright 2018.¹¹⁸

Figure 7 The extrinsic-intrinsic properties balance for the selection of ENM to be used in nanomedicine.

Table 4 Physiochemical Properties of ENMs and Their Associated Effects and Characterization Methods

Physicochemical Properties	Effects	Characterization Method	Ref.
Size and size distribution	Effect the body absorption of the ENMs, their biodistribution and excretion. Determines the cytotoxic response Affects the cell uptake and endocytosis process Altering the ENMs intracellular fate a common consensus on literature that as the size of the ENMs become smaller, the degree of cytotoxicity is greater.	Dynamic light scattering (DLS) Brunauer–Emmett–Teller (BET) Nanoparticle tracking analysis (NTA) Field flow fractionation (FFF) coupled sizing detectors (DLS-multi angle light scattering [MALS]) Transmission electron microscopy (TEM)	[^Citation75,^Citation116,^Citation117,^Citation120,^Citation135,^Citation136,^Citation156,^Citation193]
Surface and morphology	Affects the cell uptake mechanism cytotoxicity of ENMs depend on the particle’s morphology	FFF-MALS-DLS FE-SEM Transmission electron microscopy (TEM) Brunauer–Emmett–Teller (BET)	[^Citation31,^Citation71,^Citation103,^Citation137,^Citation138,^Citation156]
Surface coating and charge on ENMs	ENMs surface coating act as interfaces between nanostructure-cell Affects the intrinsic interactions, cell uptake, cytotoxicity Determines the ENMs charges cell uptake positively charged ENMs more effectively lead to more toxicity effects compared to neutral or negatively charged ENMs	Zeta Potential analysis Fourier transform infrared spectrometer (FTIR) Transmission electron microscopy (TEM) Energy-dispersive X-ray coupled SEM (SEM–EDX) X-ray diffraction (XRD) Raman Spectra	[^Citation31,^Citation71,^Citation103,^Citation137,^Citation138,^Citation156]

Figure 8 Illustration of the advantage of separation hyphenation with multi-detectors vs DLS technique.

Mørk M, Pedersen S, Botha J, Lund SM, Kristensen SR. Preanalytical, analytical, and biological variation of blood plasma submicron particle levels measured with nanoparticle tracking analysis and tunable resistive pulse sensing. Scand. J. Clin. Lab. Invest. 2016;76(5):349–360. doi:10.1080/00365513.2016.1178801

 PubMed Web of Science ®Google Scholar

Nelemans LC, Gurevich L. Drug delivery with polymeric nanocarriers-cellular uptake mechanisms. Materials (Basel). 2020;13:1–21. doi:10.3390/ma13020366

 Google Scholar

Valavanidis A, Vlachogianni T. Engineered nanomaterials for pharmaceutical and biomedical products new trends, benefits and opportunities. Pharm Bioprocess. 2016;4:13.

 Google Scholar

El-Hamadi M, Schätzlein AG. Nanoparticles in medical imaging. Fundam Pharm Nanosci. 2013;6:543–566.

 Google Scholar

Herranz F, Almarza E, Rodríguez I, et al. The application of nanoparticles in gene therapy and magnetic resonance imaging. Microsc. Res. Tech. 2011;74:577–591. doi:10.1002/jemt.20992

 PubMedGoogle Scholar

Sohal IS, O’Fallon KS, Gaines P, Demokritou P, Bello D. Ingested engineered nanomaterials: state of science in nanotoxicity testing and future research needs. Part Fibre Toxicol. 2018;15. doi:10.1186/s12989-018-0265-1

 PubMedGoogle Scholar

Kermanizadeh A, Pojana G, Gaiser BK, et al. In vitro assessment of engineered nanomaterials using a hepatocyte cell line: cytotoxicity, pro-inflammatory cytokines and functional markers. Nanotoxicology. 2013;7:301–313. doi:10.3109/17435390.2011.653416

 PubMed Web of Science ®Google Scholar

Applications B, Pirzada M, Altintas Z. Nanomaterials for Healthcare. Sensors. 2019;19:5311–5367. doi:10.3390/s19235311

 PubMedGoogle Scholar

Holzinger M, Goff Le A, Cosnier S. Nanomaterials for biosensing applications: a review. Front Chem. 2014;2:1–10. doi:10.3389/fchem.2014.00063

 Google Scholar

Shi J, Votruba AR, Farokhzad OC, et al. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 2010;10:3223–3230. doi:10.1021/nl102184c

 PubMed Web of Science ®Google Scholar

Lim M, Badruddoza AZM, Firdous J, et al. Engineered nanodelivery systems to improve dna vaccine technologies. Pharmaceutics. 2020;12:1–29. doi:10.3390/pharmaceutics12010030

 Google Scholar

Chen J, Guo Z, Tian H, Chen X. Production and clinical development of nanoparticles for gene delivery. Mol Ther - Methods Clin Dev. 2016;3:16023. doi:10.1038/mtm.2016.23

 PubMed Web of Science ®Google Scholar

Hasan A, Morshed M, Memic A, et al. Nanoparticles in tissue engineering: applications, challenges and prospects. Int J Nanomedicine. 2018;13:5637–5655. doi:10.2147/IJN.S153758

 PubMed Web of Science ®Google Scholar

Mohammadi MR, Nojoomi A, Mozafari M, et al. Nanomaterials engineering for drug delivery: a hybridization approach. J Mater Chem B. 2017;5:3995–4018. doi:10.1039/C6TB03247H

 PubMed Web of Science ®Google Scholar

Anselmo AC, Mitragotri S. Nanoparticles in the clinic: An update. Bioeng Transl Med. 2019;4(3):e10143

 PubMed Web of Science ®Google Scholar

Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33:2373–2387. doi:10.1007/s11095-016-1958-5

 PubMed Web of Science ®Google Scholar

van der Meel R, Sulheim E, Shi Y, et al. Smart cancer nanomedicine. Nat Nanotechnol. 2019;14:1007–1017. doi:10.1038/s41565-019-0567-y

 PubMed Web of Science ®Google Scholar

Mehra NK, Cai D, Kuo L, Hein T, Palakurthi S. Safety and toxicity of nanomaterials for ocular drug delivery applications. Nanotoxicology. 2016;10:836–860. doi:10.3109/17435390.2016.1153165

 PubMed Web of Science ®Google Scholar

Anuje M, Sivan A, Khot VM, Pawaskar PN. Cellular interaction and toxicity of nanostructures. In: Nanomedicines for Breast Cancer Theranostics. Elsevier; 2020:193–243. doi:10.1016/b978-0-12-820016-2.00010-0

 Google Scholar

Shah JN, Shah AP, Shah HJ, Sutariya VB. Biointeractions of Nanomaterials. Biointeractions of Nanomaterials. CRC Press; 2014. doi:10.1201/b17191

 Google Scholar

Qiao R, Jia Q, Hüwel S, et al. Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier. ACS Nano. 2012;6:3304–3310. doi:10.1021/nn300240p

 PubMed Web of Science ®Google Scholar

Podila R, Brown JM. Toxicity of engineered nanomaterials: a physicochemical perspective. J Biochem Mol Toxicol. 2013;27:50–55. doi:10.1002/jbt.21442

 PubMed Web of Science ®Google Scholar

Fernández-Bertólez N, Costa C, Bessa MJ, et al. Assessment of oxidative damage induced by iron oxide nanoparticles on different nervous system cells. Mutat Res Genet Toxicol Environ Mutagen. 2019;845:402989. doi:10.1016/j.mrgentox.2018.11.013

 PubMed Web of Science ®Google Scholar

Kumar A, Kumar P, Anandan A, et al. Engineered nanomaterials: knowledge gaps in fate, exposure, toxicity, and future directions. J Nanomater. 2014;2014:1–16. doi:10.1155/2014/130198

 Google Scholar

De Matteis V. Exposure to inorganic nanoparticles: routes of entry, immune response, biodistribution and in vitro/in vivo toxicity evaluation. Toxics. 2017;5:29. doi:10.3390/toxics5040029

 PubMedGoogle Scholar

Zhou X, Liu Y, Wang X, Li X, Xiao B. Effect of particle size on the cellular uptake and anti-inflammatory activity of oral nanotherapeutics. Colloids Surfaces B Biointerfaces. 2020;187:110880. doi:10.1016/j.colsurfb.2020.110880

 PubMed Web of Science ®Google Scholar

Semaeva E, Tenstad O, Skavland J, et al. Access to the spleen microenvironment through lymph shows local cytokine production, increased cell flux, and altered signaling of immune cells during lipopolysaccharide-induced acute inflammation. J. Immunol. 2010;184:4547–4556. doi:10.4049/jimmunol.0902049

 PubMed Web of Science ®Google Scholar

Sukhanova A, Bozrova S, Sokolov P, et al. Dependence of nanoparticle toxicity on their physical and chemical properties. Nanoscale Res Lett. 2018;13:1–21. doi:10.1186/s11671-018-2457-x

 PubMed Web of Science ®Google Scholar

Quarta A, Piccirillo C, Mandriota G, Di Corato R. Nanoheterostructures (NHS) and their applications in nanomedicine: focusing on in vivo studies. Materials (Basel). 2019;12:1–37. doi:10.3390/ma12010139

 Google Scholar

Sahu SC, Casciano DA. Nanotoxicity: From in vivo and in vitro Models to Health Risks. 2009. doi:10.1002/9780470747803

 Google Scholar

Doak SH, Liu Y, Chen C. Genotoxicity and Cancer. In: Adverse Effects of Engineered Nanomaterials: Exposure, Toxicology, and Impact on Human Health. 2nd ed. Elsevier Inc; 2017:423–445. doi:10.1016/B978-0-12-809199-9.00018-5

 Google Scholar

Kristensen BW, Noer H, Gramsbergen JB, Zimmer J, Noraberg J. Colchicine induces apoptosis in organotypic hippocampal slice cultures. Brain Res. 2003;964:264–278. doi:10.1016/S0006-8993(02)04080-5

 PubMedGoogle Scholar

Mirshafiee V, Jiang W, Sun B, Wang X, Xia T. Facilitating translational nanomedicine via predictive safety assessment. Mol Ther. 2017;25:1522–1530. doi:10.1016/j.ymthe.2017.03.011

 PubMedGoogle Scholar

Fadeel B, Farcal L, Hardy B, et al. Advanced tools for the safety assessment of nanomaterials. Nat Nanotechnol. 2018;13:537–543. doi:10.1038/s41565-018-0185-0

 PubMed Web of Science ®Google Scholar

Li SD, Huang L. Pharmacokinetics and biodistribution of nanoparticles. In: Molecular Pharmaceutics. Vol. 5. Mol Pharm; 2008:496–504.

 Google Scholar

Nel AE. Implementation of alternative test strategies for the safety assessment of engineered nanomaterials. J Intern Med. 2013;274:561–577. doi:10.1111/joim.12109

 PubMed Web of Science ®Google Scholar

Gioria S, Caputo F, Urbán P, et al. Are existing standard methods suitable for the evaluation of nanomedicines: some case studies. Nanomedicine. 2018;13:539–554. doi:10.2217/nnm-2017-0338

 PubMed Web of Science ®Google Scholar

Zhang T, Gaffrey MJ, Qian WJ, Thrall BD. Oxidative stress and redox modifications in nanomaterial–cellular interactions. In: Molecular and Integrative Toxicology. Springer Science+Business Media B.V; 2020:127–148. doi:10.1007/978-3-030-33962-3_8

 Google Scholar

Zhu M, Nie G, Meng H, et al. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate. Acc. Chem. Res. 2013;46:622–631. doi:10.1021/ar300031y

 PubMed Web of Science ®Google Scholar

Clogston JD, Hackley VA, Prina-Mello A, et al. Sizing up the next generation of nanomedicines. Pharm Res. 2020;37. doi: 10.1007/s11095-019-2736-y

 Google Scholar

Bhatia S, Bhatia S. Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications. In: Natural Polymer Drug Delivery Systems. Springer International Publishing; 2016:33–93. doi:10.1007/978-3-319-41129-3_2

 Google Scholar

Palacios‐Hernandez T, Diaz‐Diestra DM, Nguyen AK, et al. Cytotoxicity, cellular uptake and apoptotic responses in human coronary artery endothelial cells exposed to ultrasmall superparamagnetic iron oxide nanoparticles. J. Appl. Toxicol. 2020;40:918–930. doi:10.1002/jat.3953

 PubMedGoogle Scholar

Hou WC, Westerhoff P, Posner JD. Biological accumulation of engineered nanomaterials: a review of current knowledge. Environmental Sciences: Processes and Impacts. 2013;15:103–122.

 PubMed Web of Science ®Google Scholar

Zhu M, Perrett S, Nie G. Understanding the particokinetics of engineered nanomaterials for safe and effective therapeutic applications. Small. 2013;9:1619–1634. doi:10.1002/smll.201201630

 PubMedGoogle Scholar