Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases Dong Hyun Jo MD, Jin Hyoung Kim PhD, Tae Geol Lee PhD, Jeong Hun Kim MD, PhD PII: DOI: Reference:

S1549-9634(15)00109-4 doi: 10.1016/j.nano.2015.04.015 NANO 1125

To appear in:

Nanomedicine: Nanotechnology, Biology, and Medicine

Received date: Revised date: Accepted date:

18 October 2014 26 March 2015 29 April 2015

Please cite this article as: Jo Dong Hyun, Kim Jin Hyoung, Lee Tae Geol, Kim Jeong Hun, Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases, Nanomedicine: Nanotechnology, Biology, and Medicine (2015), doi: 10.1016/j.nano.2015.04.015

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Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases

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Dong Hyun Jo, MDa,b, Jin Hyoung Kim, PhDa, Tae Geol Lee, PhDc, Jeong Hun Kim, MD,

Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research

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a

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PhDa,b,d*

Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul

110-799, Republic of Korea c

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b

Center for Nano-Bio Measurement, Korea Research Institute of Standards and Science,

Daejeon 305-340, Republic of Korea d

Department of Ophthalmology, College of Medicine, Seoul National University, Seoul 110-

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744, Republic of Korea

*Correspondending author: Jeong Hun Kim, MD, PhD, Fight against Angiogenesis-

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Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, and Department of Ophthalmology, College of Medicine, Seoul National University,

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Seoul 110-744, Republic of Korea. Tel: +82-2-740-8387. Fax: +82-2-741-3187. E-mail:

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[email protected]

Competing interests: There are no competing interests to report.

This study was supported by the Seoul National University Research Grant (800-20140542), the Pioneer Research Program of NRF/MEST (2012-0009544), the Bio-Signal Analysis Technology Innovation Program of NRF/MEST (2009-0090895), and the research grant from NRF/MEST, Republic of Korea (2014M3A7B6034509).

Word count for abstract: 134 Complete manuscript word count (body text and figure legends): 4,056 Number of references: 100 Number of figures: 2 Number of tables: 2

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Abstract Nanoparticles can be valuable therapeutic options to overcome physical barriers to reach

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central nervous system. Systemically administered nanoparticles can pass through blood-

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neural barriers; whereas, locally injected nanoparticles directly reach neuronal and perineuronal cells. In this review, we highlight the importance of size, surface charge, and

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shape of nanoparticles in determining therapeutic effects on brain and retinal diseases. These

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features affect overall processes of delivery of nanoparticles: in vivo stability in blood and other body fluids, clearance via mononuclear phagocyte system, attachment with target cells, and penetration into target cells. Furthermore, they are also determinants of nano-bio interfaces: they determine corona formation with proteins in body fluids. Taken together, we

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emphasizes the importance of considerations on characteristics of nanoparticles more suitable for the treatment of brain and retinal diseases in the development of nanoparticle-based

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therapeutics.

Keywords: nanoparticles, CNS disease, drug delivery systems, nanoparticle design, blood-

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neural barriers

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Nanoparticles as novel therapeutics for human diseases

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Nanoparticles have several advantages as therapeutic materials for various human

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diseases including brain and retinal diseases. 1) They can pass through biological barriers, especially blood-neural barriers including blood-brain barrier (BBB) and blood-retinal barrier

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(BRB).1 It is critical to develop modalities to enhance bioavailability in target organs, the

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brain and the retina, in the development of therapeutic agents for brain and retinal diseases.2 2) At the same time, as a novel drug delivery system, nanoparticles help therapeutic agents to stay longer in target organs. Generally, physicochemical properties of nanoparticles enhance bioavailability of therapeutic agents after both systemic and local administration.3,4 3)

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Furthermore, nanoparticles by themselves exert therapeutic actions. Cerium oxide nanoparticles (nanoceria) are known to induce anti-inflammatory effects.5 Interestingly,

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inorganic nanoparticles such as gold, silver, and silica nanospheres also exhibit ‘self-

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therapeutic’ effects without surface modification.6-9 Then, which characteristics of nanoparticles make them attractive for therapeutic uses?

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First of all, nanoparticles are smaller than previously developed drug delivery systems such as microparticles and liposomes. Nanoparticles are defined as small particles of which three dimensions are nanoscale, one to few hundred nanometers.10 The size of nanoparticles (less than 1 μm) enables penetration over biological barriers and extended bioavailability in tumor tissues.1,11 ‘Small’ nanoparticles can pass through barriers even when they are intact. Therefore, they penetrate leaky tumor vessels more easily. The more attractive characteristics of nanoparticles is that we can control the properties of nanoparticles including size, shape, and surface characteristics. Addition of ligands or receptors onto the surface of nanoparticles enhances target-specificity.12 Furthermore, various conditions and additives result in a diverse spectrum of nonspherical and spherical nanoparticles such as nanospheres, nanocubes,

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nanorods, nanocages, and platonic solids during colloid-chemical synthesis.13,14 In addition, ‘top-down’ engineering techniques produce mono-disperse shape-specific nanoparticles with

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microfluidic systems or imprint lithography approaches.15

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With these characteristics, well-designed nanoparticles enhance or suppress biological activity regarding pathological conditions. In particular, it is remarkable that most of

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biological interactions occur among nano-sized molecules such as growth factors, cell surface

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receptors, intracellular organelles, and signaling molecules. Nanoparticles also interact with proteins in biological media,16 inhibit biological activity of growth factors by binding with them as antibody does,17 and utilize cell machinery including cell surface molecules and intracellular organelles.18 Interestingly, physicochemical characteristics of nanoparticles can

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affect cellular uptake, biological distribution, penetration into biological barriers, and resultant therapeutic effects.11,19 These features may be related with therapeutic effects on

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brain and retinal diseases in which blood-neural barriers act as an obstacle to therapeutic

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agents.

In this review, we focused on the therapeutic potential of nanoparticle-based therapeutics

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for brain and retinal diseases. Particularly, we discussed differential effects of size, surface characteristics, and shape of nanoparticles on biological activity. Shape, inter alia, has to receive more attention because relatively less studies were performed about it than the other factors (size and surface charge). In addition, we mentioned the complexity of nano-bio interface, the formation of ‘corona’ around nanoparticles, which is implicated in the biological activity of nanoparticles and affected by differential characteristics of nanoparticles as well. A schematic understanding of the roles of physicochemical properties of nanoparticles on therapeutic effects might help to design rationale-based nanoparticles for the treatment of brain and retinal diseases.

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Nanoparticles and diseases of central nervous system (CNS)

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Nanoparticles and brain diseases

As in other organs, malignant tumors are one of the most frequently studied target

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diseases of nanotherapeutics among brain diseases. In particular, various pathological

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mechanisms including reactive oxygen species (ROS), biological actions of growth factors, and signaling pathways of proliferative potentials could be addressed with nanoparticle-based therapeutics.20,21 In addition, dual functions of nanoparticles in both imaging and therapy, socalled theranostics, are still attractive concepts.22 A notable characteristics of nanoparticles is

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that it is possible to enhance bioavailability of therapeutic agents in brain tumors by conjugation of specific ligands onto the surface of nanoparticles which are loaded with

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therapeutic materials. BBB could be an obstacle to therapeutic agents as well as toxic

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materials.23 Bioavailability can be enhanced by ligand modification with peptides targeting cell surface receptors which are abundant in endothelial cells lining brain vasculatures, such

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as transferrin receptor and low-density lipoprotein receptor.24,25 Therapeutic materials including conventional chemotherapeutic agents and small interfering RNA can be loaded in nanoparticles. In addition, ligand modified nanoparticles enhances cellular uptake of therapeutic materials into malignant tumor cells by conjugation with ligands which bind to surface molecules specific to glioma cells.26 Packing with two or more therapeutic materials into nanoparticles is also a plausible strategy in the treatment of brain tumor.27

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Neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases, are also the targets of nanoparticle-based therapeutic approaches. Similarly to

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malignant tumors, overcoming BBB is one of the causes for the use of nanoparticles in the

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treatment of neurodegenerative diseases. Biomolecules including nerve growth factor (NGF), brain-derived neurotrophic factor, and thyrotropin-releasing hormone (TRH) exert

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neuroprotective effects, but are limited in the biological activity because they are rapidly

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metabolized in systemic circulation and cannot overcome BBB. Nanoparticle-based approaches open the opportunity for these molecules in the treatment of neurodegenerative diseases.28-30 Intravenous administration of NGF-containing poly(butyl cyanoacrylate) nanoparticles coated with polysorbate 80 demonstrates the efficient transport of NGF across

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the BBB.28 In this study, polysorbate 80 coating is a tool for targeting of therapeutic nanoparticles to brain.31 In a study using biodegradable nanoparticles, anticonvulsant effects

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of TRH are observed with intranasal delivery of TRH-loaded polyactide nanoparticles even

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without surface modification with specific ligands.30 Likewise, poly(lactic-co-glycolic) acid (PLGA) nanoparticles enhances brain delivery of nicotine, which provides neuroprotection

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against ROS-induced parkinsonism.32 In addition, ligand modification with lactoferrin, of which receptor is highly expressed in neurons, can be a strategy to increase the concentrations of therapeutic agents in the brain.33 Ischemic injury in the brain might receive benefits from the development of adequate nanotherapeutics. Overcoming pathological events associated with reperfusion is the focus of the development of therapeutic agents for ischemic stroke. In this context, researches have been performed to improve the bioavailability of antioxidant molecules and to investigate the antioxidant effects of nanoparticles by themselves.34-37 Dendrigraft poly-L-lysine nanoparticles conjugated with dermorphin, a μ-opiate receptor-specific heptapeptide, enhances the delivery of short hairpin RNA targeting apoptosis signal-regulating kinase 1,

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which is involved in oxidative stress, to the brain with intravenous administration.34 Similarly, PLGA nanoparticles containing superoxide dismutase, one of antioxidants, also showed

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localization in the brain, reduced infarction volume, and improved behavior in mice with

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cerebral ischemia-reperfusion injury.35 Another interesting part regarding therapeutic potential of nanoparticles is that they exert therapeutic actions by themselves without surface

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modification. 3 nm-sized platinum nanoparticles and nanoceria demonstrate protective effects

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on ischemic cell death in mice.36,37 These approaches illustrate the therapeutic potential of nanoparticle-based therapeutics in the treatment of various brain diseases. Therapeutic potential and requirements of nanoparticles for brain diseases are summarized in Table 1.

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Nanoparticles and retinal diseases

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Due to BRB, consisting of retinal endothelial cells and pigment epithelial cells, it is hard

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for systemically injected therapeutic agents to reach the retina at effective concentrations. In this context, the potential of nanoparticles has been studied in a series of papers. We

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previously reviewed therapeutic attempts using nanoparticles in the treatment of retinal diseases.10,38 As in brain diseases, the delivery of therapeutic genetic material is one of strategies in the treatment of retinal degeneration in various degenerative diseases including retinitis pigmentosa and Stargardt disease. For example, subretinal injection of DNAcompacted nanoparticles efficiently induces gene expression in retinal neuronal cells and slows degenerative changes in mice with a haploinsufficiency mutation in the retinal degeneration slow gene.39 A different approach is the use of nanoceria in the treatment of retinal degeneration.40,41 By scavenging ROS, nanoceria down-regulate the level of oxidative stress in the retina and prevent pathological changes induced by degeneration of photoreceptor cells. Furthermore, they exert anti-angiogenic effect on pathological retinal

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angiogenesis with similar mechanisms.42,43 The more prominent anti-angiogenic effects of nanoparticles by themselves come from

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inorganic nanoparticles such as gold, silver, silica, and titanium dioxide nanoparticles.

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Interestingly, similar anti-angiogenic effects of inorganic nanospheres have been repeatedly reported from several research groups.7-9,17,44-47 In particular, we have observed anti-

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angiogenic effects of inorganic nanospheres on choroidal and retinal neovascularization,

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which is implicated in the development of vision-threatening disorders including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity with intravitreous injection, local administration of nanoparticles into the vitreous cavity of the eye.7,8,44,45 There are also provisional approaches using nanoparticles as drug carriers containing therapeutic

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peptides, genetic materials, and currently utilized anti-VEGF monoclonal antibody.48-51 These approaches enhances the delivery of therapeutic materials to the retina and further the focuses

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of pathological events, choroidal and retinal neovascularization.

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The other target disease of nanotherapeutics in the eye is uveitis, an inflammatory disease in uveal tissues including iris, ciliary body, and choroid.38 Uveitis is characterized by

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chronic clinical courses. Therefore, prolonged admistration of therapeutic agents is one of goals in the treatment of uveitis for the suppression of chronic inflammation. Both poly(lactic acid) nanoparticles containing betamethasone phosphate and polyethylene glycol (PEG) nanoparticles loaded with tamoxifen effectively suppress the inflammatory changes in mice with experimental autoimmune uveitis and maintain the concentrations of therapeutic materials for prolonged periods.52,53 Therapeutic potential and requirements of nanoparticles for retinal diseases are summarized in Table 2.

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Physicochemical properties of nanoparticles suitable for biomedical application: 3S

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These therapeutic effects of nanoparticles are governed by physicochemical properties

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of them. Size, surface characteristics, and shape are major determinants of actions of nanoparticles in biological systems. Furthermore, tissue-specific microenvironments should

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be considered in the design of nanoparticle-based therapeutics. In this section, we reviewed

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various studies about the effects of size, surface charge, and shape on cellular uptake and biodistribution of nanoparticles. Based on these works, researchers might find the appropriate designs of nanoparticles which meet their purposes of application (Figure 1). The physicochemical properties of nanoparticles affect in vivo stability in blood, cerebrospinal

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fluid, and vitreous, clearance via mononuclear phagocyte system, attachment with target cells,

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and penetration into target cells and blood-neural barriers.

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Size

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The size of nanoparticles suitable for systemic administration for therapeutic purposes might be in the range between 2 and 200 nm.19,54 Systemically administered nanoparticles (through intravenous injection) travel along blood circulation and get into organs with abundant vasculatures other than target organs. It is reasonable to design nanoparticles which can escape the removal process of lung, liver, spleen, and kidney and effectively reach target tissues. Nevertheless, too small nanoparticles are vulnerable to renal excretion and clearance from target tissues. A study using in vivo fluorescence imaging after intravenous injection of fluorescent quantum dots demonstrates that hydrodynamic diameter is a main determining factor of renal excretion.55 Nanoparticles of which final hydrodynamic diameter is less than 5.5 nm are rapidly excreted by the kidney in this study. Furthermore, too small nanoparticles

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(< 5 nm) can be easily secreted from target tissues even after they escape renal excretion.56 In particular, tumor vessels tend to be more permeable than normal vessels, which lets passive

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accumulation of nanoparticles in tumor tissues (this characteristic is the basis of enhanced

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permeability and retention (EPR) effect). It is a plausible scenario for too small nanoparticles that they easily enter the tumor parenchyme through tumor vasculatures, but also rapidly

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secreted from the tumor. In the development of therapeutics against CNS diseases, 20 nm,

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large enough to escape renal glomerular filtration, is thought to be sufficiently small size. Nanoparticles of which size is around 20 nm can pass through BRB compared to 100 nmsized nanoparticles which cannot.1 On the other hand, the upper limit of the length of any dimension of nanoparticles is thought to be around 200 nm, although it depends on the

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shape.19,54 Larger particles above 2 μm are captured by pulmonary capillary vessels. 57 In addition, reticuloendothelial systems, principally Kupffer cells in the liver and macrophages

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in the spleen, scavenge nanoparticles of which diameter is larger than 200 nm.19,58

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The size of nanoparticles also affects cellular uptake of them. This should be considered in the design of nanoparticles for biomedical application because cellular uptake of

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nanoparticles is implicated in elimination by phagocytes and biological action in target cells. In a study using gold nanospheres of which diameters are 14, 30, 50, 74, and 100 nm, cellular uptake of nanoparticles by HeLa cells, from a representative cervical carcinoma cell line, is the most prominent with 50 nm-sized nanospheres.59 The preference of 50 nm-sized nanoparticles by HeLa cells is also observed with 30, 50, 110, 170, 280 nm-sized mesoporous silica nanoparticles.60 Cellular uptake and nuclear localization in HepG2 cells from human hepatoma cell line are the most evident when they are treated with 45 nm-sized hydroxyapatite nanoparticles.61 These results indicate that cellular uptake is affected by the size of nanoparticles.

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Surface charge

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Surface charge also determines cellular uptake, biodistribution, and interaction with

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other biological environments.62,63 Generally, positively charged nanoparticles are known to be more easily internalized than neutral and negatively charged nanoparticles.64 Positively

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charged PEG-oligocholic acid based micellar nanoparticles are also taken up more efficiently

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by macrophages and ovarian cancer cells.65 However, this discrepancy is not consistent from studies to studies. In a study using quantum dots of which zeta potentials are in the range from -2 to -32 mV, internalization of quantum dot is positively correlated with the absolute value of surface charge.66 Furthermore, protein adsorption onto nanoparticle surface can lead

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to a shift in zeta potential to slightly negative surface charge regardless of original surface charge (positive/neutral/negative).67,68 In this regard, cellular uptake of nanoparticles by

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phagocytes or target cells should be tested before further investigation on biological

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application.

Surface charge definitely affects the fate of nanoparticles administered in biological

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systems. Unintended liver uptake is the most definite in the most positively charged nanoparticles among nanoparticles of which zeta potential is in the range of -26.9 ~ +37.0 mV.65 This observation is similar with more rapid plasma clearance of cationic macromolecules.69 An in vitro three dimensional model study using fluorescein-carrying gold nanoparticles demonstrates that positively charged nanoparticles are more significantly taken up by proliferating cells; whereas, negatively charged nanoparticles more rapidly diffuse in tumor cylindroids demonstrating fast diffusion in tissues.70 These differential effects of surface charge on biodistribution should be born in mind in the design of nanoparticle-based therapeutic agents.

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Shape

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As we previously mentioned, various shapes of nanoparticles can be manufactured from both

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‘top-down’ and ‘bottom-up’ approaches.13-15 Interestingly, particle shape also have an important impact on the performance of nanoparticles as a carrier of therapeutic agents and

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therapeutics by themselves through changes in ligand targeting, cellular uptake, transport, and

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degradation.71 For example, HeLa cells readily internalize rod-like particles of which diameter is larger than 100 nm when the aspect ratio is larger than 3.72 These phenomenon might come from cellular machineries which have a role in internalization of invasive pathogens such as bacteria.72,73 In contrast, PEGylated gold nanorods are less readily taken up

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by macrophages than nanospheres.74 Similarly, in nanoparticles of which the largest dimension is less than 100 nm, cellular uptake by HeLa cells is negatively correlated with the

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aspect ratio.59,75

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Shape also affects biodistribution of nanoparticles. In addition to ‘cell-evading’ property of non-spherical nanoparticles, effects of the shape on in vivo circulation might influence

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therapeutic efficacy of nanoparticle-based therapeutics. Interestingly, non-spherical particles tend to show deviating hydrodynamic behavior in blood vessels with shear flow.76,77 Furthermore, shape determines the adhesion pattern of nanoparticles, resulting in improved efficacy of drug carriers with non-spherical shape.78 Various shapes of nanoparticles which can be utilized for therapeutic application are schematically demonstrated in Figure 2. We speculated that nanocrystals (e.g., octahedrons, icosahedrons) and other shapes of nanoparticles other than widely-utilized nanospheres and Nanorods could be included in future application for therapeutic purposes.

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A caveat is that these differential effects of size, surface charge, and shape of nanoparticles on biological actions might be different case by case. Surface modification,

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protein adsorption, and manufacturing processes also affect the action of nanoparticles.

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Accordingly, nanoparticle-specific biological characterization should be performed before further investigation for biomedical application of nanoparticles. In addition, it is more

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important to prepare well-controlled and mono-disperse nanoparticles for biomedical

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application.

Obstacles to nanoparticles in the treatment of CNS diseases

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Rationale-based modulation of physicochemical properties of nanoparticles will lead to prolonged exposure of therapeutic materials, enhanced targeting to target tissues, or improved

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cellular uptake for intracellular delivery of therapeutic materials. Especially, BRB and BBB

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act as a protective obstacle against toxic materials as well as one of hurdles to nanoparticles to reach the brain and the retina.23 Moreover, it is possible to administer nanoparticles by

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other routes than intravenous injection: intranasal and intravitreous administration. Likewise in intravenous injection, size, surface charge, and shape might affect the delivery and further therapeutic actions of nanoparticles in these administration methods.

Delivery via systemic approach: overcoming BBB and BRB

In intravenous injection, nanoparticles should escape the elimination through reticuloendothelial system to maintain prolonged effective concentrations. 79 In addition, it is necessary to overcome BBB and BRB to reach neuronal tissues in the brain and the retina. BBB and inner BRB are composed of endothelial cells lining brain and retinal vasculatures.23

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In principle, there are three approaches to pass through blood-neural barriers. First, surface ligands which bind to surface receptors abundant in brain and retinal endothelial cells help to

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target to them.24,25,49 Specific peptides targeting to transferrin receptor or low-density

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lipoprotein receptor might help to overcome blood-neural barriers through receptor-mediated endocytosis. Second, certain physicochemical characteristics of nanoparticles are suitable for

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penetration into BBB and BRB. We previously reported that 20 nm-sized gold nanoparticles

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were observed in the retina after intravenous injection.1 Furthermore, some pathological conditions in the brain and the retina are related with increased permeability as in tumor vasculatures in cancers which demonstrate EPR effect.80 These combinations of characteristics of nanoparticles and pathological vasculatures would make blood-neural

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barriers more vulnerable to nanoparticle penetration. Third, surface modification improves targeting to neuronal tissues. Partial coating of nanoparticles with polysorbate 80 enhanced

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brain targeting of therapeutic materials contained in nanoparticles.28,31 In addition, specific

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peptides composed of peptides identify corresponding receptors in neuronal cells or cancer cells in the brain or the retina.26,34 Dual targeting of target cells and endothelial cells might

cancers.81

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boost targeting of nanoparticles to parenchymal tissues in the brain and the retina as in

Delivery via intranasal approach for brain diseases

The potential of local injection is a more interesting part in the use of nanoparticles in the treatment of brain and retinal diseases. Nanoparticles travel through olfactory nerve axons, accumulate in the olfactory bulb in the forward part of the brain, and diffuse into the rest of the brain after taken up from nasal mucosa.82,83 In this system, nanoparticles experience different environment from intravenous injection. They should utilize transport system in

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neuronal cells, pass through synaptic cleft, or diffuse into adjacent neuronal cells instead of penetration into BBB. Nevertheless, physicochemical properties of nanoparticles still affect

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the fate of intranasally administered nanoparticles.84 Modification of surface properties with

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Delivery via intravitreous approach for retinal diseases

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chitosan and PEG improves the delivery of nanoparticles deep into the brain.84

Vitreous cavity indicates the space between the lens and the retina and is composed of water, glycosaminoglycan, and matrix proteins including collagen, fibronectin, and laminin.85,86 The mesh-like structure of vitreous body can be a barrier to nanoparticles

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according to the physicochemical properties of nanoparticles.86,87 Interestingly, particles larger than 1 μm are immobilized in the vitreous gel; whereas, polystyrene nanoparticles of

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which diameter is 510 nm rapidly penetrates the vitreous gel.87 Similarly, ~100 nm-sized

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human serum albumin nanoparticles are diffused through vitreous network of matrix protein fibers.88 In addition, surface charge affects the fate of nanoparticles when they are

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administered into the vitreous cavity. Repeated reports demonstrate that anionic nanoparticles are better than cationic ones in the penetration into the vitreous cavity.87-89 We also investigated the biological action of intravitreally administered inorganic nanospheres of which size is 20 to 50 nm and surface charge is around -30 mV, resulting in significant antiangiogenic effects on choroidal and retinal neovascularization as in in vitro angiogenesis assays.7,8,44,45 In the development of nanoparticles for intraocular delivery, researchers should pay attention to these effects of nanoparticle characteristics on the movements of nanoparticles in the vitreous cavity.

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Nano-bio interface according to the physicochemical properties of nanoparticles

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Background

Due to relatively large surface area compared to the size and positive/negative surface

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charge, nanoparticles without surface modification are easy targets of proteins in biological

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systems. Between nanoparticles and proteins occur various interactions which are observed between other molecules: Van der Waals interaction, hydrogen bond, electrostatic force, hydrostatic interaction, π-π stacking interaction, and salt bridge.90 These interactions initiate and reinforce the binding between nanoparticles and proteins. Interestingly, it seems that

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there is a relative specificity of protein binding onto nanoparticles.16,67,91 Among ~100 total proteins bound to various types of nanoparticles, relative abundance of common top 20

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proteins is above 70%.91 Furthermore, there is a study demonstrating no definite change in

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the composition of proteins, but only increase in the quantity (during 24 hours) after rapid formation of plasma protein corona (in 30 seconds).67 On the other hand, the concept of hard

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and soft corona is widely accepted among researchers.91 Nanoparticles form stronger bonds with certain proteins (hard corona) and then nanoparticle-protein complexes further interact with other proteins by weaker interaction (soft corona). Similarly, the composition of nanoparticle corona is not totally changed by transition between different biological fluids. 92 To understand biological actions of nanoparticles, it is essential to figure out proteinnanoparticle interactions properly.93

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Biological effects

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Likewise other physiocochemical properties of nanoparticles, proteins attached to

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nanoparticles affect biological actions of them.91,94 Opsonization with immunoglobulin and complements is an example.79,95,96 Binding of certain proteins to nanoparticles results in

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clearance by reticuloendothelial system and further clearance from the body.95,96 Furthermore,

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corona formation determines the pattern of hemolysis, thrombocytocyte activation, and cellular uptake of nanoparticles.67 Extra attention is required for nanoparticles with ligand modification because protein binding interrupts binding moiety of surface ligands. 94 In addition, protein binding affects surface properties of nanoparticles, providing additional

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layer of complexity in the interpretation of the effects of nanoparticle characteristics on

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biological actions.67,68,97

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Effects of physicochemical properties on corona formation

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Conversely, physicochemical properties of nanoparticles also affect the formation of corona around them. Size is one of the main factor determining protein binding to the nanoparticles.16,98 A study with different sizes of amorphous silica nanoparticles (20, 30, and 100 nm) demonstrates that even 10 nm change significantly affects the composition of the nanoparticle corona.16 Similarly, shape also makes a difference in the amount and composition of adsorbed proteins.99,100 Interestingly, gold nanorods adsorb more proteins than nanospheres, implying that differences in biological activity of these nanoparticles are partly due to differential corona formation.100

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Conclusions

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Nanoparticles are an attractive platform which can be utilized as novel drug delivery

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systems and therapeutic approaches by themselves. A more interesting part of nanoparticles is that we can modify the physicochemical properties of nanoparticles during the synthesis

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process. Furthermore, these nanoparticle characteristics directly affect in vivo therapeutic

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effects of nanoparticles. In this context, it is essential to understand the effects of nanoparticle properties on biological actions of nanoparticles. In addition, the actions of nanoparticles in different biological environments also should be thoroughly investigated. According to the administration routes, nanoparticles experience different environments: systemic circulation

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in intravenous injection, a chain of neurons in intranasal administration, and a mesh of matrix proteins and glycosaminoglycan after intravitreous injection. Therefore, these variables

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should be taken into consideration in the design of nanoparticles for biomedical application.

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In our opinion, the adequate size of nanoparticles for therapeutic purposes is thought to be in the range between 20 and 100 nm. Surface charge depends on the strategy of nanoparticle

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administration. For example, negative surface charge is proper for intravitreous injection. Instead, a wide variety of possible shapes of nanoparticles can add up diversity and flexibility in the use of nanoparticles for therapeutic application. We expect that current high-technology in synthetic chemistry on nanoparticles enhance therapeutic potential of nanoparticles in the treatment of CNS diseases.

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Figure Legends Figure 1. Biological activities related with physicochemical properties of nanoparticles.

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Size, surface charge, and shape determine therapeutic potential of nanoparticles in the

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treatment of CNS diseases by differential effects on biological activities including penetration into blood-neural barriers, escape from reticuloendothelial organs, protein binding, and

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cellular uptake.

Figure 2. Schematic drawings of various shapes of nanoparticles for biomedical application. Nanoparticles of these shapes can be prepared through ‘top-down’ or ‘bottomup’ approaches. (A) sphere (B) cube (C) rod (D) pyramid (E) rectangular nanoplate (F)

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triangular nanoplate (G) octahedron (H) icosahedron

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Table 1. Therapeutic potential and requirements of nanoparticle-based therapeutics for brain

Requirements of nanoparticles

Brain tumor

Intravenous injection

Neurodegenerative disease

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Target diseases

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diseases

- Evasion from reticuloendothelial system - Adequate systemic pharmacokinetic profiles (not too fast

- Huntington’s disease

clearance, not too prolonged retention in systemic circulation)

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- Alzheimer’s disease

- Parkinson’s disease

- Penetration into blood-brain barrier - Targeting to brain neuronal cells

Brain infarction

Intranasal injection

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- Rapid cellular uptake at nasal mucosa - Utilization of intracellular transport and endocytosis

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machineries during movement through axons

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- Targeting to brain neuronal cells

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Table 2. Therapeutic potential and requirements of nanoparticle-based therapeutics for retinal

Requirements of nanoparticles

Retinal degeneration

Intravenous injection

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Target diseases

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diseases

- Evasion from reticuloendothelial system

- Retinitis pigmentosa

- Adequate systemic pharmacokinetic profiles (not too fast

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- Stargardt’s disease

- Penetration into blood-retinal barrier

blindness Age-related

macular

degeneration

and neuronal cells

- Diabetic retinopathy -

- Targeting to retinal constituent cells including endothelial

Retinopathy

of

- Diffusibleness throughout vitreous cavity - Penetration into retinal layers

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prematurity

Intravitreous injection

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clearance, not too prolonged retention in systemic circulation)

Angiogenesis-related

- Targeting to retinal constituent cells including endothelial

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Uveitis

and neuronal cells

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Fig. 1

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Fig. 2

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Graphical Abstract

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Size, surface charge, and shape determine various actions of nanoparticles including cellular

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uptake by reticuloendothelial systems, targeting to target cells, in vivo distribution, and corona formation with proteins in body fluids and matrix structures. In addition, we expect

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that there are differential effects of nanoparticle characteristics on therapeutic potential according to the administration routes for the treatment of central nervous system diseases. In

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this context, a wide variety of shapes of nanoparticles can add up diversity and flexibility in

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the use of nanoparticles for therapeutic application.

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Graphical Abstract