Synthetic nanoparticles are typically 1-100 nm in size, allowing them to pass through the blood capillaries, while the larger microspheres trap in the capillaries. Since the particle size is small, the surface area is high compared to the mass and volume of the particles. For comparison, the size of antibodies is about 10×15 nm. Nanoparticles can be made of plastic polymers, metals and metal oxides, lipids, polysaccharides, polypeptides, and so on, offering limitless variations in their physicochemical properties. Nanoparticles could be used to carry drug molecules to the target tissue and have been studied extensively in tumour animal models, and several liposome nanocarriers for drugs are in use (Caracciolo, 2015). Lipid bilayer-gated silica nanocarriers can be tagged with folic acid to further boost the uptake in cancer cells (Desai et al., 2017).
Circulating microparticles (microvesicles, ectosomes) are cell-derived vesicles, 50-1000 nm in size, which can transfer peptides, lipids, and oligonucleotides between tissues (van der Pol et al., 2012). Microparticles form by reverse budding and fission of the plasma membrane. Exosomes, 40-100 nm in size, form through constitutive exocytosis of multivesicular endosomes. Apoptotic bodies are much larger (1000-3000 nm) vesicles that are released at the final steps of apoptosis.
Nano- and microparticles in the blood typically interact with plasma proteins (‘protein corona’) and constituents of red blood cell membranes, which affects their clearance rate. Since albumin itself is protected from endothelial catabolism and renal excretion, conjugation to albumin is one option to affect the clearance of synthetic particles. Lipoproteins (including HDL, LDL, and VLDL) can interact with hydrophobic particles, and protect from degradation and direct the delivery to tissues with lipoprotein receptors. Surface properties of the particles affect the adhesion of complement proteins and opsonization, and PEGylation is one common method to protect particles from activating complement system and avoid phagocytosis. Particles with size >5-6 nm circumvent renal filtration, and can be excreted to urine only after degradation to smaller particles. Mesoporous silicon nanoparticles biodegrade to silicic acid, which is excreted into urine. In kidney disease, much larger nanoparticles can pass through the glomerular filtration barrier. In the liver, the resident macrophages (Kupffer cells) internalize opsonized particles, and even non-opsonized, depending on their size and surface properties. Spleen usually collects the nanoparticles, which can lead to immunogenic reactions via B cells, and increased opsonization and clearance of the second dose of nanoparticles (accelerated blood clearance, ABC effect). PEGylation reduces non-specific opsonization, but leads to increased formation of specific antibodies in the spleen (Bertrand & Leroux, 2012). If not phagocytosed and degraded, nanoparticles may be released from the spleen to circulation within days.
Opsonization and phagocytosis of nanoparticles is not only a bad thing, but it is used to detect active macrophages. Magnetic nanoparticles (MNPs) have an iron oxide or gadolinium core, making MR imaging possible, but, like other nanoparticles, can be additionally labelled with positron emitting isotope. Phagocytosis of nanoparticles has been used to study, for instance, atherosclerosis (Nahrendorf et al., 2008; Majmudar et al., 2013), aortic aneurysm (Nahrendorf et al., 2011), transplant rejection (Ueno et al., 2013), inflammation in pancreas (Gaglia et al., 2011), and cancer (Keliher et al., 2011). Monocytes can be labelled with nanoparticles in vitro and in vivo (Normandin et al., 2015; Yuan et al., 2018).
Reliable large-scale synthesis of nanoparticles with certain properties has been challenging. Additionally, nanoparticles tend to be accumulated non-specifically in the liver and spleen, and blood clearance also usually happens through the hepatobiliary route, instead of faster renal clearance which would be preferred in clinical imaging. Non-degradable particles larger than 6 nm cannot be excreted through kidneys. In vivo PET imaging has been performed using for example 68Ga-, 64Cu-, 18F-, and 89Zr-labelled gold, silica, iron oxide, graphene, and transition metal sulphide -based nanoparticles. Pretargeted PET imaging is possible with TCO-modified mesoporous silicon nanoparticles, using 18F-labelled tetrazine as tracer (Keinänen et al., 2017).
68Ga-labelled carbon nanoparticles (Galligas) can be used for pulmonary ventilation imaging.
Blocker SJ, Shields AF. Imaging of nanoparticle distribution to assess treatments that alter delivery. Mol Imaging Biol. 2018; 20: 340-351. doi: 10.1007/s11307-017-1142-2.
Chowdhury EH: Nanotherapeutics - From Laboratory to Clinic. CRC Press, 2016.
Garg B, Sung CH, Ling YC. Graphene-based nanomaterials as molecular imaging agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015; 7(6): 737-758.
Lahooti A, Sarkar S, Laurent S, Shanehsazzadeh S. Dual nano-sized contrast agents in PET/MRI: a systematic review. Contrast Media Mol Imaging 2016; 11(6): 428-447.
Liu Y, Welch MJ. Nanoparticles labeled with positron emitting nuclides: advantages, methods, and applications. Bioconjug Chem. 2012; 23(4): 671-682.
Llop J, Gómez-Vallejo V, Gibson PN (eds.): Isotopes in Nanoparticles - Fundamentals and Applications. CRC Press, 2016.
Qin S, Seo JW, Zhang H, Qi J, Curry FR, Ferrara KW. An imaging-driven model for liposomal stability and circulation. Mol Pharm. 2010; 7(1): 12-21. doi: 10.1021/mp900122j.
Sun X, Cai W, Chen X. Positron emission tomography imaging using radiolabeled inorganic nanomaterials. Acc Chem Res. 2015; 48(2): 286-294.
Updated at: 2018-07-20
Created at: 2016-05-28
Written by: Vesa Oikonen, Chunlei Han