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Progress in Nanotheranostics Based on Mesoporous Silica Nanomaterial Platforms Rajendra Kumar Singh, Kapil Dev Patel, Kam W. Leong, and Hae-Won Kim ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b16505 • Publication Date (Web): 09 Mar 2017 Downloaded from http://pubs.acs.org on March 10, 2017

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ACS Applied Materials & Interfaces

Progress in Nanotheranostics Based on Mesoporous Silica Nanomaterial Platforms

Rajendra K. Singha,b, #, Kapil D. Patela,b, #, Kam W. Leongb,c, Hae-Won Kima,b,d,* a

Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, South Korea

b

Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative

Medicine, Dankook University, Cheonan 330-714, South Korea c

Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA

d

Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan 330-714, South

Korea

------------#

Both authors contributed equally to this work

*Corresponding author: Hae-Won Kim (E-mail: [email protected]; Tel: +82 41 550 3081; Fax: +82 41 550 3085)

ACS Paragon Plus Environment


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Abstract Theranostics based on nanoparticles (NPs) is a promising paradigm in nanomedicine. Mesoporous silica nanoparticle (MSN)-based systems offer unique characteristics to enable multimodal imaging or simultaneous diagnosis and therapy. They include large surface area and volume, tunable pore size, functionalizable surface, and acceptable biological safety. Hybridization with other NPs and chemical modification can further potentiate the multi-functionality of MSN-based systems toward translation. Here, we update the recent progress on MSN-based systems for theranostic purposes. We discuss various synthetic approaches used to construct the theranostic platforms either via intrinsic chemistry or extrinsic combination. These include defect generation in silica structure, encapsulation of diagnostic NPs within silica, their assembly on the silica surface, and direct conjugation of dye chemicals. Collectively, in vitro and in vivo results demonstrate that multimodal imaging capacities can be integrated with the therapeutic functions of these MSN systems for therapy. With further improvement in bioimaging sensitivity and targeting specificity the multifunctional MSN-based theranostic systems will find many clinical applications in the near future.

Keywords: Mesoporous silica nanoparticles; Intrinsic defect; Extrinsic combination; Multifunctional; Theranostics.

1


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Table of Contents 1. Introduction 2. Imaging modality: A brief summary 3. Why MSN as a theranostic platform 3.1. Significance of mesoporosity 3.2. Manipulation of surface and bulk chemistry 3.3. Biocompatibility aspect 4. How to merge therapeutic and diagnostic functions 4.1. Intrinsic approaches 4.2. Extrinsic approaches 4.2.1. Nanoparticles incorporated within silica 4.2.2. Nanoparticles assembled on silica surface 4.2.3. Conjugation with dye chemicals 4.2.4. Combinatory methods 5. Biological theranostic functions 5.1. Focus on therapeutic functions 5.1.1. Drug and gene delivery 5.1.2. Stimuli-responsive delivery 5.1.3. Photothermal and photodynamic therapy 5.1.4. Ultrasound therapy 5.2. Focus on diagnostic functions 5.2.1. Magnetic Imaging 5.2.2. Optical Imaging 5.2.3. Other imaging modalities 5.2.4. Multi-modality imaging and theranostic applications 6. Concluding remark 7. References

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1. Introduction

Theranostics combines therapeutic and diagnostic capabilities into a single platform to enable more specific and individualized therapies for various diseases and damages

1-2

. Unfortunately, the efficacy of current

treatments of cancers has been limited to certain patents and disease stages. The personalized nanomedicine coined to overcome this can cure the individual disease through the combination of therapeutic and diagnostic functions in one unit. 3

Nanoparticles (NPs) have become one of the key components in theranostics . For example, semiconducting quantum dot (QD) NPs have been a popular fluorescent probe due to their broad absorption spectra, narrow 4

and tunable emission spectra, and high efficiency . Colloidal gold NPs, with their unique optical and electrical properties (e.g. surface plasmon resonance), have been found their use as contrast agents for computed tomography (CT)

5-6

. Gold NPs are also being explored for photoacoustic computed tomography (PAT)

applications. Superparamagnetic iron oxide NPs have been used as contrast agents for magnetic resonance imaging (MRI), drug delivery systems, and biosensors

5-9

. Furthermore, metal-organic frameworks (MOFs)

have recently made significant progress for the theranostic applications, including MRI, CT imaging and 10-12,13-15

optical imaging

.

Among else, mesoporous silica NPs (MSNs) are one of the most widely studied theranostic nano-platforms, primarily thanks to their unique pore structure (i.e. pore size, shape, volume, and alignment), tunable surface and bulk chemistry, and bio-safety and -compatibility, all of which support the potential for imaging and drug delivery in living system

16-17

. Beyond the well-established capacity of MSNs to load and deliver drugs, recent

studies have been spurred to impart imaging properties by the chemical modifications and combinations with novel diagnostic NPs and dye agents. This review updates the current efforts in MSN-based nanomaterials to develop theranostic systems for disease treatment, mainly cancer.

2. Imaging Modality: A Brief Summary Theranostic NPs are required to possess imaging sensitivity, targeting, and controlled delivery of drugs.

3


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Sometimes, development of NPs with high imaging sensitivity sacrifices therapeutic functions. The currently available imaging modalities include MRI, CT, nuclear imaging (positron emission tomography; PET, and single photon emission computed tomography; SPECT), optical imaging, and ultrasound

18-19

, as illustrated in

Figure 1. These modalities allow molecular imaging of the cells and tissues, which can diagnose diseases at early stages. The characteristics and pros/cons of the different imaging modalities are summarized in Table 1 20. To achieve a measurable signal, the required tissue concentration varies among the modalities owing to different chemical nature of reporters. NPs can offer extended opportunity with their functionalized surface, tunable plasma circulation time, and encapsulation of drug and contrast agents

19, 21-22

.

Figure 1. Various molecular imaging modalities. (a) MRI imaging. Reproduced with permission from ref 23. Copyright 2014 American Chemical Society., (b) CT imaging. Reproduced with permission from ref 24. Copyright 2010 Elsevier., (c) PET imaging. Reproduced with permission from ref 25. Copyright 2014 Nature Publishing Group., (d) SPECT Imaging. Reproduced with permission from ref 26. Copyright 2008 Nature Publishing Group., (e) optical imaging. Reproduced with permission from ref 27. Copyright 2009 Nature Publishing Group., (f) ultrasound imaging. Reproduced with permission from ref 28. Copyright 2015 Nature Publishing Group.

Table 1. Summary of the characteristics and pros/cons of various imaging modalities. Reproduced with permission from

4



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ref

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20

. Copyright 2008 Nature Publishing Group.

Imaging modality

Type probe

of

Optical fluorescen ce imaging

Fluorescent dyes, quantum dots

Pros

Cons

In vivo, 2– 5 mm; in vitro, subµm

•High sensitivity •Provide functional information •No radiation exposure

•Low resolution •Limited tissue penetration

50–200 µm

•High spatial resolution. •Ability to differentiate between tissues. •Low radiation exposure

•Require contrast agent for enhanced tissue contrast. •Radiation •Tissue nonspecificity •High cost

25–100 µm

•High resolution •No ionizing radiation •Able to image physiological and anatomical details

•High cost •Cannot be used in patients with metallic devices e.g. pacemakers

1–2 mm

•Ability to biochemical processes

•Radiation •Low resolution •Cost

50–500 µm

•Non-invasive •Ease of procedure •No radiation exposure •Low cost

Sensitivity (M)

Spatial resolution

Bioluminescenc − 15 e — 10 – to 10− 17 Fluorescence — −9 − 12 10 to 10

Computed tomograph y (CT)

Heavy element e.g. iodine

Magnetic resonance imaging (MRI)

Paraor superparamagnet ic metals (e.g. Gd, Mn)

10

Gamma scintigraph y (PET and SPECT)

Radionuclid es (e.g. F18, In-111, Cu-64)

PET — 10− 11 to − 12 10 − 10 SPECT — 10 − 11 to 10

Ultrasound

Gas filled microbubbl es

Not well characterized

−3

−5

to 10

Not well characterized

image

•Low resolution

The MRI signal is based on the precession of water hydrogen nuclei under an applied magnetic field. Upon radiofrequency pulses, the relaxation process of nuclei is converted to an image. To enhance the contrast between tissues, agents are used, which shorten the relaxation parameters (T1 and T2) of water. Paramagnetic molecules (Gd and Mn) are often used with small molecules, polymers, or NPs 29. On the other hand, superparamagnetic iron oxide NPs can also be tagged. Compared to optical imaging, MRI has good spatial resolution, but shows low sensitivity 30.

Optical imaging uses photons. It detects low energy photons thus is relatively inexpensive compared to other imaging methods. Also, the spectrum range (visible to near-infrared (NIR)) shows good spatial resolution. However, this imaging has poor tissue penetration (up to ~2 cm) and is highly susceptible to noise due to the 5


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tissue scattering of photons in the visible region

18, 20

. Optical imaging has also significant background

because of tissue auto-fluorescence and light absorption by proteins and water

31

. However, the NIR (700–

900 nm) window shows reduced auto-fluorescence and tissue scattering, and high penetration depth, allowing for in vivo imaging. The detection of biomarkers with MSNs using responsive gate systems, namely responsive imaging, has also been studied as a part of the optical diagnosis

32-35

.

Gamma-ray (γ-ray) emission is used for SPECT and PET. Unlike MRI, SPECT and PET images have low background signal and require little signal amplification. Both are quantitative methods, thus merited over other modalities such as MRI and optical imaging. Compared to PET, SPECT is less sensitive (~10 times), but it enables concurrent imaging of multiple radionuclides

36

.

The anatomical information can be probed using CT technique by measuring the X-ray absorption of tissues. The ability of CT to distinguish fat, bone, air, and water is owing to the varying X-ray attenuation coefficient and electron density of tissues 37. Among the CT contrast agents, macromolecular and nanoparticulate agents are better compared to low molecular weight CT contrast agents due to their longer presence in the blood. Iodine, bismuth, gold NPs are typical CT contrast agents widely used due to their electron dense elements with high atomic number

38

.

Ultrasound imaging is widely used in clinics owing to its low cost, speed, safety, and simplicity. This modality utilizes transducer which emits high frequency sound waves (>20 kHz). The sound waves, when transmitted through the skin, bounce back from internal organs and produce ultrasound images 39-40.

3. Why MSN as a Theranostic Platform The rationale on the use of MSNs as the platform for theranostic purposes contains three aspects: i) the mesoporous nature, ii) modifiable surface and bulk chemistry, and iii) biocompatibility. The sol-gel processed mesopore generation in the MSN structure, with fine-tuned pore size, shape and arrangement, allows for the incorporation of therapeutic molecules at large quantities; furthermore, the channeled pore is an effective diffusion path for drug molecules to slowly release out. Thus the intrinsic mesoporous nature of MSN provides excellent platform for therapeutics delivery. The internal chemistry (composition) of MSN is also tailorable to allow defect formation that is an intrinsic source for imaging. Not only bulk, but the surface chemistry of MSN 6



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is also easily tunable to multi-functionality, like the conjugation of imaging particles and dye molecules, to adopt diagnostic properties. The excellent cellular and tissue compatibility of the MSNs can attenuate / shield the toxic effects of metallic imaging NPs. All these physico-chemical and biological properties make MSNs fascinating platforms for theranostics, as illustrated in Figure 2.

Figure 2. Illustrating the merits of MSNs as a potential theranostic platform; (a) well-defined pore structure, (b) tunable surface and bulk chemistry, and (c) excellent biocompatibility, enable effective drug loading and controlled release, and allow multi-functional tailoring to improve imaging capacity.

3.1. Significance of Mesoporosity MSNs are characterized to be a ‘mesoporous’ nanomaterial, with the mesopore sizes ranging from a few to tens of nanometers. Through the sol-gel processes of forming silica glass networks the templating chemicals generate highly interconnected mesopores in the structure with unique size, shape and alignment. Due to the presence of pores in the structure, MSNs have high specific surface area and pore volume to incorporate cargo molecules (chemical drugs, proteins and genetic molecules) at large quantities. The properties of the mesopores determine the loading capacity of drug, through the mesopore surface reactions with drug 7


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molecules. Moreover, the subsequent release patterns of drug are controllable by the mesopore properties, such as pore channel geometry. Therefore, how to tailor the mesopore structure of MSNs including pore size, amount, shape, and aligned pattern, as well as the post-chemical treatment such as functionalization of pore walls, is of particular importance to enable controlled and sustained delivery of drugs, and consequently satisfactory therapeutic actions. Table 2 summarizes the differently-tailored mesopore structures of MSNs developed thus far, and the resultant properties and possible effects on the loading and release of drug. The unique structured mesopores are thus considered as a container of drug molecules. The release of drug loaded in the mesopore container is also modulated by the on/off pore-gating with the help of pore-capping materials, which facilitates on-demand and stimuli-responsive therapeutics.

Table 2. Summary of the differently-tailored mesopore structures of MSNs, and the possible effects on the loading and release of drug molecules. Parameter

Tailored properties and refs

Pore size

3-40 nm

Pore shape

cubic, hexagonal, laminar

Pore alignment

oriented, random, wormhole

Surface area

200-1215 m /g

Pore volume

0.45-1.5 cm /g

Possible effects

41,42,43,44,45,46,47,48

drug type, loading amount, release pattern 49,50,51,52

loading amount

41,53

release pattern

2

41,43,45,54,55,44,56, 53

loading amount

3

41,43,45,53,47,48,57,41, 54

loading amount

3.2. Manipulation of Surface and Bulk Chemistry Not only the pore structure, but the composition of MSNs is also easily tunable, potentiating the usefulness in theranostics. Surface chemistry is one of the most important properties of MSN that determines not only the accessibility and stability of biomolecules, but also the dispersibility, cellular internalization, and imaging capacity of the particles. The surface of MSN primarily consists of silanol groups, and a fully hydroxylated MSN has different silanol forms, including free silanol, silanol with physically adsorbed water, siloxane bond, germinal silanol groups (≡Si-OH), and hydrogen-bonded silanol groups. Thus, the concentration and distribution of silanol groups on surface establishes external reactive species 8


58

, determining the type and


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quantity of biomolecules to adsorb. Due to the silanol groups, the surface is highly hydrophilic, favorable for incorporating hydrophilic drug. Often the surface is modified to be hydrophobic with functional groups, like trimethylsilyl

59

to enable the incorporation of hydrophobic drugs. Tailoring the surface with proper chemical

groups is a basis to link imaging agents through chemical bonds or physical adsorptions for the theranostic applications

17, 60-61

. Additionally, the presence of functional groups can introduce targeting ligands for specific

cells or mediating molecules for smart/stimuli-responsive actions. Some representative chemical groups used include carboxyl, amine, phosphate, octadecyl and the combination thereof

62-63

.

Many strategies have been developed for the modification of inner and outer surfaces. While the modification of an inner surface (pore wall) determines mainly the loading of molecules, the functionalization of an outer surface can affect the biological interactions such as protein adsorption and cellular uptake. The site-selective functionalization via co-condensation (in-situ surface functionalization) is one exemplar method for the surface modifications. Through the co-condensation, the functional groups were generally introduced onto the inner wall of pores, while the external surface was exclusively modified depending on the experimental parameters 64-65

. Grafting is a well-known approach for the inner surface modification

66

. A diffusion-based cleavage

approach was used for the grafting of Fmoc (9-fluorenylmethyloxycarbonyl) protected alkylamines in piperidine solution

67

. In calcined MCM-41, the external surface was shown to be more accessible to the

modification than the inner pore surface

68

, implying the limitation of inner surface modification by this grafting

method. However, several findings demonstrated that some grafting reagents including chloro- and trialkoxysilanes could efficiently enter the template-filled pore channels of MSNs and functionalize the inner surface

69-

71

.

The bulk chemistry of MSN is defined by the silica sol-gel process, which is well characterized by the condensation and hydrolysis reactions of inorganic silica networks. In the sol-gel chemistry of inorganic networks, organic parts are often been introduced by several ways. First, the co-condensation of tetraalkoxysilanes (RO)4Si (TEOS of TMOS) with terminal alkoxyorganosilanes (R’O)3SiR in the presence of structure-controlling agents can generate organic residues in the silica networks that are covalently anchored to the pore walls. Second, organic bridges can be incorporated periodically to the networks to form a mesoporous organosilica where the organic phase is an integral component of the silica network

52, 72-74

. The

approaches involve the formation of organized organic arrays, over which the inorganic phase deposits, and the deposition process of inorganic phase on the pre-organized organic surface is based on crystal nucleation 9


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and growth in aqueous solution

75

. These methods also significantly change the pore wall and surface

chemistry. The organically-modified silica NPs that have organic-inorganic arranged networks differ from pure inorganic silica NPs in many physico-chemical properties, such as functional groups, biodegradation, elasticity, mesoporosity, and optical property.

Among the properties, the degradation behavior of MSN depends largely on the bulk chemistry, more specifically the chemical stability of silica networks, and the degradation ultimately determines the biological fate, drug release rate and imaging stability. The dissolution of MSNs is primarily hydrolytic - the ionic attack (corrosion) of biological medium to the amorphous network through the mesopore channels organically-modified, the MSNs show higher resistance against hydrolysis

76

. When

77-78

. Furthermore, MSNs prepared

without thermal treatment can degrade more than those heat-treated at elevated temperatures.

Defects in bulk chemistry (silicon and oxygen vacancies) are an important source for intrinsic optical properties of MSNs 79. The generation of luminescence in silica NPs due to the defect localized at the Si-SiO2 interface suggests the possibility of control over optical properties in nanocrystal structural defects have been observed in heat-treated silica-based nanomaterials

27, 79-81

. Various type

79, 82-83

. These structural

defects account for the variety of luminescence bands extending over the NIR range. The luminescence of MSN demonstrates that defects in non-bridging oxygen yield red band, while hydrogen-related defects, water and impurities generate green and blue band silica NPs was also revealed

84-85

. The origin of luminescence from isolated surface defects in

86-87

. The defect-related luminescent properties can thus be effectively combined

with drug delivery capacity of MSN for the anticancer drug delivery and tumor imaging

88

.

As explained, the simplicity and versatility of silica sol-gel reactions enable diverse control of surface and bulk chemistry of MSNs, which is ultimately helpful to achieve physical, chemical and biological properties required for optimized theranostic functions.

3.3. Biocompatibility Aspect The biocompatibility issue of MSNs, like other NPs, is not simple because the cell and tissue responses largely depend on many parameters of tailored nanomaterials. MSNs can vary in particle properties (dimension, shape, nanotopology, surface chemical group, and degradation) as well as the mesopore 10



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parameters (pore size and porosity). Furthermore, the different physiological conditions lead to various biological outcomes

89-91

. Thus, the biocompatibility of different forms of MSNs needs interpretation taking

these into consideration. In general, the surface functionalized MSNs, compared to native amorphous silica NPs, show significantly enhanced biocompatibility in vitro and in vivo. The unmodified amorphous silica NPs are reported to cause hemolysis with red blood cells (RBC), limiting their use in drug delivery applications such as intravenous administration and transport

92

. Similarly, some reports on the generation of reactive

oxygen species (ROS) and the denaturation of membrane proteins through electrostatic interactions with silica are also encountered. However, the MSNs, with controlled morphology and functionalized surface show excellent cellular entry and viability in vitro

89, 93-96

, as well as tissue compatibility and bio-distribution in vivo

96-

97

.

MSNs are recognized easily to cells due to their hydroxylated silanol groups

98

. However, more often the

surface is functionalized with positive charges to enhance the cellular uptake; negatively-charged cell membrane favors the positive-charged surface of NPs

94, 99

, which is the same for MSNs

100

. The treatment

with polyethylenimine (PEI) and cell penetrating peptide (CPP) is a common strategy to increase the cell penetration efficiency of MSNs

101-102

. Apart from these approaches, PEGylation is a common strategy to

enhance the blood circulating capacity of MSNs. PEGylation can greatly reduce the aggregation of MSNs and improve the in vivo biodistribution

103

, and allows for the escape from capture by liver, spleen, and lung tissues

extending the blood circulation lifetime

104

. Also, the PEGylated MSN showed higher loading of anticancer

drugs and more sustained release compared to bare MSN, supporting the merits of PEGylation in systemic delivery for anticancer therapy

105

. However, the PEGylation of MSNs can reduce the cellular uptake.

Therefore, some recent studies have developed the combined functionalization of PEGylation with PEI or CPP to improve the biocompatibility while exhibiting high cellular uptake

106-108

. The internalized biocompatible

MSNs enable the delivery of therapeutics within cells like genes, and visualize cells and particle-accumulated subcellular components.

While the initial cellular uptake of MSNs is known through a nonspecific adsorptive endocytosis

96

, the

intracellular trafficking pathways are rather complicated and not fully established. The internalized MSNs interact with intracellular machineries to target specific organelles and release therapeutic molecules inside cells, while fractions of them exocytose. One exemplar study demonstrated the cellular internalization pathways of MSNs functionalized with different organic groups, i.e., 3-aminopropyl (AP), N-(2-aminoethyl)-311


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aminopropyl

(AEAP),

(FAP),

N-floate-3-aminopropyl

guanidinopropyl

(GP),

and

3-{N-(2-

guanidinoethyl)guanidino}propyl (GUGP). Based on the results, the FITC-MSN and FAP-MSN are clathrinmediated, the AP-MSN and GP-MSN are caveolae-mediated, whilst the GEGP-MSN remains unclear

109

,

highlighting the importance of surface functional group in intracellular trafficking. The particle size of MSNs also potentially affects the efficacy and pathways of cellular internalization by altering the interaction of particles with cell membrane and vesicles

56, 96, 110-111

. One study using spherical silica NPs with two different

sizes (80 nm and 500 nm) showed 500 nm particles (vs. 80 nm ones) were internalized and accumulated in lysozyme more, and the pathways involved are mainly macropinocytosis (and in part clathrin-mediated) for 500 nm vs. a combination of macropinocytosis, clathrin- and caveolae-mediation for 80 nm

112

. Since

lysozyme is a representative degrading vesicle in cells, the delivered NPs are better to avoid this process; thus caveolae-mediated pathway can be referenced to design MSNs. Apart from the particle size, the particle geometry, nanotopology (due to mesopores), and physical elasticity of MSNs also mediate the cellular endocytosis. Along with endocytosis, exocytosis draws attention as this process is related with the staying period of particles and thus the cellular toxicity 113-114. On the other hand, decrease of exocytosis can increase the delivery efficiency of particles

113

. Although it is often difficult to design MSNs to follow specific intracellular

pathways, due to the multi-factorial (physico-chemical) properties of MSNs, their fine-control can achieve high internalization efficiency with favorable trafficking route that eventually improves the therapeutic efficacy and the imaging quality.

In vivo tissue compatibility studies of MSNs further motivate the tailoring of the properties. Often the delivery route in vivo gives rise to significantly different outcomes; when systemically delivered MSNs raises toxicity issues related with particles properties such as size, concentration, and surface functionalization, compared to when delivered locally. For example, intraperitoneal and intravenous injection of MSNs in mice was found to be lethal whilst no toxicity was noticed in the subcutaneous injection using the same NPs

115

. In the study, the

use of high dosage of particles (1.2 g/kg) evoked thrombosis, a cause of in vivo toxicity. However, the MSNs functionalized well and administered at proper contents showed no toxic effects with good blood compatibility and were suggested to control hemorrhages

116-117

. On the other hand, when subcutaneously injected in rat,

the MSNs with sizes in a broad range (150 nm, 800 nm and 4 µm) were all shown to have good tissue compatibility while the residual materials decreased progressively over 3 months 115.

The bio-distribution of MSNs has also been studied in rodent models, where dye-labelled particles were used 12



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for detection

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118

. Different-sized particles (c.a., 80 nm, 120 nm, 200 nm, and 360 nm) showed no tissue toxicity

with minimal inflammatory signs in all tissues in mice, but distributed differently, with increasing order in kidney/heart, lung, spleen, and liver. The accumulation showed a continuous increase in the initial 5 days and then a significant decrease at 1 month. Also in urine a higher amount of larger particles was found at 30 min, implying that larger particles are more easily captured by the reticuloendothelial system (RES) than smaller one

107

. The shape effect of MSNs (c.a., aspect ratio of 1.5 and 5) was also demonstrated on the in vivo bio-

distribution

119

. The intravenously administered particles were mainly present in the liver, spleen and lung (>

80%). Short particles accumulated in liver whereas long particles in spleen. The excretion of MSN was mainly through urine and feces. More importantly, the clearance rate was particle-shape dependent; short MSN showed rapid clearance than long particles in both excretion routes. Radio-probing of MSNs with chelator-free 89

zirconium-89 ( Zr, t1/2= 78.4 h) labelling supported the bio-stability in mice for 20 days without significant in vivo toxicity, which was concentration- and location-dependent of the deprotonated silanol groups (-Si-O-)

120

.

Taken all, the bio-distribution and in vivo fate of MSNs are highly dependent on the particle parameters, including size, shape, surface functionality, and dose.

Another issue to consider in the biocompatibility of MSNs is the possible degradation nature that has been reported, particularly for the organosilica compositions

63, 78, 121-129

. The physiologically inert nature of −Si–O–

Si– framework of normal MSNs makes it difficult to degrade in biological conditions, which leads to the accumulation of the NPs within the body, and thus raises a biosafety issue. On the other hand, organosilica mesoporous form constitutes a new class of MSNs which can biodegrade. Very recently, the degradability of dendritic structured MSNs has been reported

78, 125-127

. NPs with varying pore sizes (2–13 nm) developed in

oil/water biphasic solutions showed a rapid degradation in simulated body fluid, and the degradation was higher for the NPs with larger pore size. The most rapid degradation was observed to complete within 24 h. Incubating HeLa cells with the dendritic MSNs at concentrations up to 10 µg/mL showed no obvious cellular toxicity

78

. Also mesoporous organosilica nanorods and nanospheres of various sizes were developed as

degradable nanocarriers of drugs for breast cancer cells

128

. Hollow MSNs prepared with five different organic

hybridizations were shown to have good biocompatibility and tunable biodegradation rate

129

. The

incorporation of other ions or degradable materials can also produce biodegradable MSNs. A recent study reported that Mn-doped MSNs accelerated the degradation in either mild acidic or reducing environments through the breaking of Mn–O bonds and a subsequent degradation of Si–O–Si bonds. Importantly, the fast 13


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degradation of Mn-MSNs could enhance the anticancer drug release and T1-weighted MR imaging, as demonstrated in vitro and in vivo

130

. When hydroxyapatite (HAP) was combined, MSN also showed

degradability. The MSNs/HAP hybrid was demonstrated to have good biocompatibility and antitumor effect significantly reducing the side effects of free DOX

131

. As demonstrated in some of the recent reports, the

possible degradability of MSNs, enabled by the organosilica formulation or the ionic/material incorporation, strengthens the potential of MSNs for biomedical uses although more studies need to support the in vivo longterm fate. As discussed, the in vitro and in vivo biocompatibility of MSNs is a complex issue, requiring considerations of the material parameters (particle size and shape, mesopore properties, surface chemistry, and degradability), administered cells, and the delivery route. When tailored properly, particularly with surface functionalized and the size and shape controlled, the bio-responses of MSNs are favorable with sound cell and tissue viability of the accumulated particles and the sufficient in vivo excretion with time. On a positive note, compared to other metallic-based imaging NPs, including QDs and magnetic NPs, MSNs are generally less toxic

132

, and for this

reason, MSNs are preferentially used to cover those NPs, shielding the toxicity while illuminating the diagnostic properties of the NPs. Together with their unique properties, including high mesoporosity and surface functionality, the MSNs are potentially considered as a biocompatible delivery platform for theranostic applications in disease treatment.

4. How to Endow MSNs with Diagnostic Functions The smart packaging of both therapeutic and the diagnostic functions with targeting capability offers an ideal vehicle for personalized medicine. The design and fabrication of silica-based NPs for therapeutic delivery has a long history

133

. Recently, silica-based NPs have gained attention also as diagnostic agents due to their

possibility of exhibiting self-activating fluorescence properties, which enabled by the control of intrinsic defect chemistry. Although there has been significant progress in this area, the intrinsically diagnostic silica NPs still face challenges to overcome, including limited imaging modality and low sensitivity. Other than the intrinsic approach, the combination of diagnostic NPs and dyes extrinsically offers a broad range of imaging modalities. The diagnostic NPs to be combined include quantum dots (c-dot, CdS, ZnS, etc.), magnetic NPs, and gold NPs, and their integration is possible through either within the mesoporous silica shell or on the surface. Some 14



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Page 16 of 63

chemical dyes are conjugated on the silica surface, to allow for optical imaging. Moreover, the diagnostic agents are often integrated together to synergistically provide multi-modal diagnosis. Consequently, the extrinsic imaging modalities, in concert with the drug delivery functions and/or the intrinsic imaging property of MSNs, provide more improved theranostic nano-platforms.

The schematic drawing in Figure 3 illustrates these intrinsic and extrinsic approaches used in silica NPs for the theranostic applications. In the extrinsic approaches, imaging agents (e.g., nanoparticles) or chemicals (e.g., dyes) can be either conjugated on the surfaces or incorporated into the silica networks

134-138

. As an

example, dye-doped MSNs are conjugated with magnetite NPs on their surfaces for the MRI/fluorescence imaging simultaneously while releasing drug

Figure 3.

139

. More exemplar studies are detailed in the followings.

Schematic showing the approaches used to provide imaging modalities to MSNs for theranostic purposes: (a)

intrinsic approach (imaging defects generated in the structure), and (b) extrinsic approach (either imaging NPs incorporated within MSN, imaging NPs assembled on the surface of MSN, imaging chemicals conjugated with MSN, or imaging chemicals incorporated into MSN).

4.1. Intrinsic Approaches In order to track silica-based NPs, it is common to label with fluorophore organic dye molecules, which either physically adsorbed or chemically conjugated; alternatively, NP-fluorophores, like QDs NPs

141

140

or upconversion

are used within the silica shell. However, these methods have some drawbacks; dye leaking, toxicity,

and large particle size. Therefore, the in situ fluorescent-generating methods are developed pioneering work reported luminescent porous silica-based NPs

27

142-144

. A

(Figure 4a,b). The single-crystal silicon

wafers were first etched by HF, and then the porous silicon film was lifted off from the wafer. After 15


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ultrasonication, the particles were filtered through a 0.22 micrometer membrane followed by an activation of luminescence in an aqueous solution. The defects localized at the Si-SiO2 interface and quantum confinement effects generated the luminescence. These luminescent porous NPs deliver doxorubicin (DOX) and also have cytotoxicity on cancer cells. Quick renal clearance is one of the unique features of this NP, as it minimizes risk to the host organs. Motivated by this, oxygen defect-induced self-luminescent silica NPs were also reported

145

(Figure 4c-e).

The use of triethoxysilane as the silicon source, addition of NaCl, use of acidic reaction media, protection under inert atmosphere, moderate sol-gel process and post-calcination at elevated temperature are several key factors for the successful synthesis of the luminescent NPs. Of note, triethoxysilane was selected as a special silicon source to create abundant oxygen vacancies by dehydrogenation between O3Si–H termin al groups during heat-treatment at 600 °C. Similarly, label-free fluorescent MSNs were prepared using three different organosilanes followed by heat treatment at 400 °C. The mesoporous organosilica NPs showed strong fluorescence with photo- and chemical-stability, and showed DOX release and the desired cytotoxicity in tumor cells

146

. Recently carbon defect-related luminescent mesoporous silica nanoparticles (DLMSNs)

were prepared by a templating sol–gel route followed by an annealing treatment for detectable drug carrier (Figure 4f-h)

88

. DLMSNs were mesoporous, dispersed well, and exhibited bright white-blue luminescence.

When heated, residual organic components decomposed and a cleavage occurred in the C–O bonds to create carbon substitutional defects in the networks (−Si–O–C–O–Si−), which was assumed to be the luminescent species. Under an UV excitation, the −Si–O–C–O–Si– cleaved into −Si–O–C• and •O–Si–, which included an electron localized in 2p orbital of the C–O bonds. Although the self-generating optical imaging system has some merits when compared to using other external fluorophore sources, the intrinsically modified selffluorescent signals still need improvement to allow in vivo diagnostic performance, particularly the imaging of deep tissue structures.

16



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Page 18 of 63

Figure 4. Providing imaging properties to silica-based NPs through intrinsic approaches: (a) Schematic diagram of the synthesis of luminescent porous silicon NPs (LPSiNP). (b) Luminescence attributed to the quantum confinement effects and defects localized at the Si-SiO2 interface. Reproduced with permission from ref

27

. Copyright 2009 Nature Publishing

Group. (c) Schematic illustration of the synthesis of self-luminescent MSN after calcination process (MSN; before and MSN-600; after calcined), and (d,e) TEM images of before (d) and after calcination (e). Reproduced with permission from ref

145

. Copyright 2011 Royal Society of Chemistry. C-defect related luminescent MSNs developed for fluorescent drug

delivery (DLMSNs), characterized by TEM image (f), PL excitation/emission spectra and image under UV excitation (365 nm) in dark (g), and confocal images of DLMSNs-DOX in HeLa cells at different times (h); DLMSNs or DOX fluorescence colored in blue or red, respectively. Reproduced with permission from ref

88

. Copyright 2015 American Chemical Society.

4.2. Extrinsic Approaches As illustrated, the extrinsic approaches are the combination of MSNs with ready-made imaging agents those in the form of NPs or chemicals. This is possible by either i) incorporation of imaging NPs within silica structure, ii) assembly of the NPs on the silica surface, or iii) direct conjugation of dye chemicals.

17


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4.2.1. Nanoparticles Incorporated within Silica

While the incorporation of diagnostic NPs within silica matrix imparts imaging modality to MSNs, this concept originates from the need to cover the surface of the imaging NPs such as QDs and magnetic NPs with more biocompatible and mesoporous silica shell

147-148

. Most QDs hold significant toxicity issue and magnetic NPs

largely lack high drug loading capacity; therefore, the modification of those NPs with a thin mesoporous silica layer can moderate such concerns

149-150

. Not just single NP, but a group of NPs can also be incorporated. In

this case, the properties of outer silica layer such as thickness and mesoporosity alter the diagnostic potential of the inner NPs, thus needing balance and optimization of the imaging intensity and the drug delivering capacity. In general, the mesoporous structure imparts better diagnostic and drug delivering capacities than dense structure.

A simple method to encapsulate inorganic NPs within mesoporous silica shell has been established

151

.

Cetyltrimethylammonium bromide (CTAB) was used as a template for the mesopore generation in NPencapsulated silica shell

152

. The oleic acid-stabilized iron oxide NPs, after capping with CTAB, could be

dispersed in aqueous media, and then the silica sol-gel reaction and removal of surfactants could produce silica encapsulating iron oxide NPs (Figure 5a,b). This method is applicable to a range of NPs, including Au, Ag, and QDs, and two different NPs can be simultaneously incorporated in a single silica shell. Since the encapsulated nanoparticles preserve their innate physical properties, the nanocomposite system shows both magnetic and fluorescent properties

153-154

. Similarly, water-soluble CdTe QDs were encapsulated within

40−80 nm silica spheres using a modified Stöber method

155

, although the optical emission intensity was

reduced and the spectrum was broadened, implying that the silica shell possibly attenuates the imaging properties of the core NPs and thus silica encapsulation needs special care in the design.

4.2.2. Nanoparticles Assembled on Silica Surface

While the incorporation of imaging NPs within MSN structure allows theranostic property, the functionalization process of NPs’ surface with silica composition is not always simple, needing NP-dependent conditions. Also, the outer silica layer can attenuate the diagnostic property of the inner NPs. A more straightforward way is the decoration of NPs onto the surface of MSN

156

. Since the type and number of imaging NPs can be chosen, the 18



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Page 20 of 63

surface of MSN can have tunable imaging modalities.

Many methods of linking the NPs to silica surface have been developed. For example, covalent bonding is used to link Au NPs to MSN surface. Au NPs were functionalized with adenosine triphosphate (ATP) aptamer through Au-S bonds (Figure 5c). A derivative of the ATP molecules (adenosine-5-carboxylic acid) was immobilized on the external surface of the amine-functionalized MSN through amidation reaction, and the Au NPs linked on the MSN surface could control the drug delivery (Figure 5d)

157

. Dye-doped MSNs are also

158

used to assemble the iron oxide NPs for optical and MRI diagnostics

. The presence of iron oxide NPs on

the silica surface is advantageous because the T2 MR contrast effect is enhanced by the magnetic NPs 149, 159. As another example, sono-chemical synthesis is used to cover the silica surface with ZnS NPs

160

. An

ultrasound physical irradiation of a slurry (made of amorphous silica, zinc acetate and thioacetamide) creates chemical impacts on the formation, growth and acoustic cavitation of ZnS NPs which are decorated on the silica surface reaction

166

161

. Other decoration methods include layer-by-layer

, in situ formation

167

, sol-gel and refluxing

162

, self-assembly

168

, and redox reaction

169

163-165

, surface chemical

.

Along with the diagnostic function, additional important action, “on-demand” controlled release of encapsulated drugs, is possible by this approach of NP-decoration onto MSN surface. Studies have assembled various inorganic NPs, including Au, QDs, Ag and Fe3O4, on the surface of MSN through tethering with stimuli-responsive molecules

170-172

. These assembled NPs onto the mesopore surface function as a

gatekeeper, controlling the release of drug triggered by intracellular or external stimuli (reduction, pH, enzyme, or light irradiation). However, previous studies focused more on the on/off-gated delivery action of the nanocarrier system, not on the diagnostic properties; therefore, future promising studies will follow more on the theranostic functions of the MSN-based stimuli-responsive smart delivery systems.

4.2.3. Conjugation with Dye Chemicals

In fact, conjugation of dye chemicals with the surface of MSN is the simplest chemical approach to provide imaging modality. The silane chemical group on the surface of MSN is an active reaction site that is versatile to covalently link the dye molecules 173-174. In many cases, the surface was also amine- or thiol-terminated with aminopropylsilane (APS) or mercaptopropylsilane (MPS) on which dye chemicals could link through silane 19


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reactions with the help of coupling agents. Stӧber method was frequently used to prepare dye-doped silica NPs. Amine-containing silane agents (APS and APTS) were used together with TEOS to hydrolyze and cocondense in a mixture of water, ammonia, and ethanol to form silica networks, and the organic fluorescent dye molecules (such as FICT, R6G, and ROX) were covalently attached to the silane agent

173-177

. A physical

encapsulation of dye molecules was also introduced. The dye molecules, such as fluorescein, tetramethylrhodamine (TMR), and alexa fluor 647, were added into the microemulsion (reverse-micelle or water-in-oil), and were physically encapsulated in the silica network during the nucleation and growth process of silica to form highly monodisperse dye-doped silica NPs 134, 169, 178.

The silane coupling reaction was often inhomogeneous and not always applicable to all possible molecules; thus a method of using dense lipid monolayer was developed. For example, paramagnetic gadoliniumdiethylenetriaminepentaacetic acid (Gd-DTPA)-di(stearly amide) was introduced in the lipid, as a contrast agent, to form a QD core / silica-lipid Gd-agent shell, enabling optical and magnetic diagnostic approach of silica NPs. Hydrophobically-modified silica NPs were also used to render paramagnetic agent and PEGylated lipid

179

; in the approach, a cancer targeted action was added through the link with αvβ3-integrin-specific RGD

ligand. PEGylated-phospholipid was used to incorporate dye molecule fluorescein isothiocyanate (FITC) which was coated on the 13-(chlorodimethylsilylmethyl)heptacosane-derived MSNs to provide therapeutic and imaging agent

180

. The folate-enabled targeted delivery was further obtained by the functionalization of surface

of phospholipids.

Another recent approach is the chemical modification of dye molecules. Organic dyes were modified with different functional organosilicon compounds before the incorporation in silica181. For example, a novel 2+

fluorescent “on-off” chemosensor for Cu

ions was developed via labelling MSN with 2-bromomaleimide (BM)

(Figure 5e,f). The non-fluorescent molecules of BM was converted to 2-aminomaleimide (NM) by a nucleophilic addition elimination reaction when grafted on the pores of amino-functionalized MSNs. The fluorescence of MSN labelled with NM was quenched by Cu2+ ions and exhibited sensitive fluorescence “onoff” switching effects for Cu

2+

ions

182

. This method is considered facile to enable dye-doping and silica

networking processes at the same time.

20



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Page 22 of 63

Figure 5. Extrinsic approaches to provide diagnostic functions to MSNs: (a,b) Magnetite nanocrystal core encapsulated in mesoporous silica shell; synthetic procedures and morphologies. Reproduced with permission from ref

152

. Copyright 2008

John Wiley and Sons. (c,d) Assembly of NPs on silica surface; synthetic procedures of Au NPs assembled on MSN for targeted controlled drug delivery. Reproduced with permission from ref

157

. Copyright 2011 American Chemical Society.

(e,f) Dye-conjugated MSNs; synthesis route to prepare NM was grafted on the pore of the surface of MSN. Reproduced with permission from ref

182

. Copyright 2014 Royal Society of Chemistry.

4.2.4. Combinatory Methods

While the aforementioned methods are the basis to provide imaging modality, many cases adopt combinatory approaches; for example, incorporation of magnetic- or QD-NPs together with the conjugation of dye fluorescein for the multi-modal tracking and diagnostics. Multiple modalities that combine fluorescence, X-ray, MRI, and/or ultrasound can achieve higher resolution images with better sensitivity at lower doses of particles 184-185

. Some of the exemplar studies are representatively explained as follows.

21


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Co-encapsulation of QDs and magnetite NPs within organically modified silica NPs generates multifunctional nanoprobes for imaging live cancer cells

186-187

. Co-conjugation of optical dye with magnetic dye GdCl36H2O

onto silica was performed to produce multi-functional nanorods, and the cellular dye imaging capacity was demonstrated 188. Core / multilayer shell formation was effective in synthesizing multi-modal NPs. Gold-coated and/or silica-coated magnetic NPs were prepared with a core-shell structure that was suitable for both MRI and photothermal therapy

189

. Similar method was used to prepare MSN-coated dye NPs with iron oxide NPs

for fluorescence and MRI imaging. DOX was loaded for anticancer theranostics. The multi-functional MSNs were demonstrated to allow cell imaging, and the orange-fluorescence and MRI contrast imaging in mice tumor site with simultaneous DOX-delivered effects

158

. A multilayer core–shell structure was also designed to

consist of upconversion fluorescence particle, silica and Au, namely NaYF4:Yb3+,Er3+@SiO2@Au, as the fluorescence imaging and photothermal therapeutic agent

190

. The method was further developed to a

structure of Fe3O4@nSiO2@mSiO2@NaYF4:Yb3+,Er3+/Tm3+ for MRI and optical imaging upconversion

emission

intensity

of

the

drug

(IBU)

loading

191

. Interestingly, the

particles

(IBU-

Fe3O4@nSiO2@mSiO2@NaYF4:Yb3+,Er3+) increased in tandem with the cumulative release of IBU, representing a possibility of optical imaging-aided drug-release documentation.

5. Biological Theranostic Functions Combining the methodologies to provide imaging modalities as described above, with the smart, controllable and targeted drug delivery actions, has been a research focus on theranostic MSNs. How to introduce the imaging agents (e.g., organic dyes, QDs, upconversion particles, MRI contrast agents, CT contrast agents, etc.) and therapeutic agents (anticancer drugs, DNA, siRNA, proteins, hyperthermia-inducing particles, ROSgenerating agents, etc.) upon and within the MSN structure determines the theranostic functions in vitro and in vivo. In general, two main streams in this research field are found: i) focusing on the improvement of smart and targeted therapeutic functions with endowed imaging ability, and ii) focusing on obtaining better diagnostic sensitivity and modalities with drug delivery action.

5.1. Focus on Therapeutic Functions 22



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Page 24 of 63

The capacities to load and deliver various types of biomolecules motivate further development of MSNs as multi-functional theranostic nanocarriers, when the imaging modality is secured through aforementioned strategies. Therefore, substantial effort has been exerted to provide specialized delivery tasks to MSNs. For the gene and drug delivery, the surface functionalization and size control is highly demanding for more targeted actions (i.e., specific cell type, intracellular organelles, and nucleus). Responsiveness to external stimuli, along with sustained and controlled release, makes MSNs become smart and useful for on-demand delivery. This smart action, together with photothermal and photodynamic therapies, is also considered fascinating delivery systems particularly for cancer treatment. We discuss here the recently developed MSNbased theranostic delivery systems focusing on in vitro and in vivo therapeutic demonstrations.

5.1.1. Drug and Gene Delivery

MSNs have a long history as delivery nanocarriers of drugs and genes

55, 133, 192-194

. Unique characteristics

(high porosity and surface area) of MSNs allow high loading of those molecules. The porous space protects them inside the channeled pores until to reach target and release. Furthermore, the surface capping enables sustained and controlled release of the molecules, and functionalized surface chemistry allows subsequent link with targeting moieties. The MSNs with optimal drug and gene delivery potential possess high loading of those molecules, sustained and controlled release, and targeted delivery actions.

There are generally two approaches to load drugs onto MSNs; encapsulation and conjugation. The former focuses control of pore structure to incorporate molecules within the pore channels; while the non-hollow MSNs with various mesopore structures comprise a major drug loading carrier, a hollowed structure is also developed to encapsulate drugs at the central part

142, 195

. This method adopts a non-covalent binding process,

similar to physical adsorption, thus the molecular activity can be preserved well

196-197

. Recently developed

MSN-based hollow NPs exhibited extraordinary drug loading capacity compared to traditional ones

92, 142

presence of a hollow structure at the center of NPs endows large space for drug encapsulation92,

. The

142

; in

addition, the combination of well-defined 3D mesopores with a hollow provides a diffusion path for drug molecules. To create hollow structure, a core template made of soft or hard inorganic NPs (polystyrene, hydroxyapatite, etc.) is generally used to form a central void through the sol-gel reaction and elimination step 92, 154, 198-199

. Recently prepared hollow MSNs showed high loading capacities of various molecules, including 23


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DOX

92

, siRNA

200

, IBU

201

, CPT

202

, and docetaxel (Dtxl)

203

. In particular, the Dtxl-loading reached as high as

32% thanks to the hollow cavity. Further, the Dtxl was released sustainably to kill the cancer cells effectively. A rattle-type hollow NPs (Fe3O4 within MSN) modified with PEG and folic acid was effective for targeting anticancer drug delivery and bio-imaging links of drugs to MSN

204-205

138

. On the other hand, the conjugation method involves covalent

. While the covalent links more stabilize the drug on the particle’s surface, and thus

can sustain the release, the biological activity of molecules can often be altered and degraded.

Along with the effort in loading high drug quantities, substantial works have been made to prolong and control the drug release. The reason to prolong the release profile is to sustain the drug therapeutic activity over the delivery period, where the system needs often continual administration otherwise unwantedly overdosed. Possible ways include tuning mesopore size, hollow structuring, and optimizing surface charge to hold drug molecules for longer periods. The controlled release of drug is mostly made by a capping approach, i.e., use of nanoparticle caps to on/off control the drug release from the mesopores upon the internal or external stimulus, including pH, temperature, enzyme, light, and magnetism. The capped materials liberate upon the stimulus and on-demand release the therapeutic molecules from the mesopores. A detailed discussion on this is in the following section. One thing to note here is the different consideration of the on-demand delivery between drug and genetic molecule. The on/off action for gene is needed at the intracellular space whereas it is not significant for drug either extracellularly or intracellularly though the intracellular action may be more effective; thus the stimulus mode should be properly designed and may sometimes be limited.

Targeted actions are the prime asset for MSNs as delivery systems. For this, specific strategies to target cell membrane, intracellular organelles, or nucleus are needed. Folic acid is commonly used to link to the MSN surface to target cancer cells and internalization through folate-receptor mediated endocytosis (Figure 6a)

206

.

Fluorescent MSNs conjugated with folic acid were internalized better than those without, into the cancer cells that were up-regulated to express folate-receptors. Anticancer drug camptothecin (CPT) loaded on the target NPs induced cytotoxicity, and inhibited tumor growth in vivo (Figure 6b) 207.

Targeting subcellular components like mitochondria or nucleus pore proteins is an emerging area in drug delivery systems. One exemplar study modified MSN with mitochondria-targeted therapeutic agent (Tpep) triphenylphosphonium (TPP) and antibiotic peptide (KLAKLAK)2 via disulfide linkage, and then with polyanion PEG-blocked-2,3-dimethylmaleic

anhydride-modified

poly(L-lysine)

(PEG-PLL(DMA))

24


via

electrostatic


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Page 26 of 63

interaction. The acidic microenvironment at tumor site helps the degradation of DMA blocks in the shell and the cellular uptake was significantly improved by the cationic NPs. When endocytosed, the presence of intracellular glutathione cleaved disulfide bonds, leading to a release of pharmacological agents (Tpep and antineoplastic drug topotecan) from the carriers, which subsequently induced the specific damage of mitochondria and anti-tumor effects (Figure 6c-d)

208

.

Aiming to potentiate the therapeutic functions of delivered molecules and particularly to overcome the drug resistance of cancer cells, a recent focus has been given to co-delivery of different types of drugs, genes or their combinations. The difference in properties of the molecules to deliver, including size and charge, often limits the co-delivery, requiring modifications of MSNs and incorporating methods. For instance, DOX drug and Bcl-2-targeted siRNA were loaded within mesopores and on the surface of MSNs, respectively, to tackle the multiple drug resistance of A2780/AD human ovarian cancer cells (Figure 6e-f)

209

. The siRNA delivery

effectively silenced the Bcl-2 gene, resulting in suppression of non-pump DOX resistance and subsequent enhancement of DOX cytotoxicity. The co-delivery strategy could silence the expression of drug efflux transporters such as p-glycoprotein, which is known as one of the major reasons for drug resistance in tumor cells. Similarly, a co-delivery of DOX and Pgp siRNA through PEI-functionalized MSNs was effective for drugresistant cancer cell line (KB-V1 cells), as the siRNA could downregulate the gene expression of the drug exporter leading to increased drug cytotoxicity

101

.

25


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Figure 6 (a) Schematic showing the folic acid conjugated MSNs targeting cancer cell receptors. Reproduced with 206 permission from ref . Copyright 2013 Royal Society of Chemistry. (b) The effect on tumor growth of camptothecin (CPT)loaded MSNs and F-MSNs on human pancreatic cancer PANC-1 xenograft on nude mice and intraperitoneal injections at day 14. Control received saline solution, group 2 was treated with pure MSNs (no drug), Group 3 was CPT dissolved in DMS and diluted in saline (as CPT). Group 4 MSN loaded with CPT (final concentration of CPT is same as group 3) (MSN-CPT). Group 5 was treated with floate-modified loaded with CPT (F-MSN-CPT). Injection was performed twice per week until the end of experiment (52 day). (i) Image of subcutaneous tumors collected at day 52. (ii) A human pancreatic cancer cell line, MiaPaca-2, was used for xenograft establishment on nude mice. Representative image of nude mice with 207 . Copyright 2012 Elsevier. (c) SC tumors at last day of experiment are shown. Reproduced with permission from ref Schematic showing the design and intracellular process of mitochondrial targeting MSNs; (I) modified MSNs under physiological condition, (II) charge-conversional detachment of PEGylated corona in acidic tumor micro environment, (III) adsorption-interaction between positively charged nanoparticles and cell membrane, (IV) intracellular GSH-triggered TPep and TPT release, and (V) specific binding and disrupting of mitochondria. (d) TEM images of (i) untreated (control) KB cells, and treated with (ii-iv) MSN-TPep/PEG-PLL (DMA) for 36 h at pH 6.8. (Mitochondria; M). Reproduced with permission from ref 208. Copyright 2014 Nature Publishing Group. (e) Schematic showing the MSN-based co-delivery system to deliver DOX and Bcl-2-targeted siRNA simultaneously, and (f) fluorescence image of A2780/AD human ovarian cancer cells, (i) light image (ii) siRNA green fluorescence (iii) DOX red fluorescence, treated with MSNs for 6 h, vs. (iv) red free DOX for 5 h. Reproduced with permission from ref 209. Copyright 2009 John Wiley and Sons.

5.1.2. Stimuli-responsive delivery

26



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Page 28 of 63

Through on-demand controlled delivery, the stimuli-responsive carriers reduce the systemic toxicity and increase the therapeutic function of cargos

17, 210-211

. The intelligent actions are triggered by inner (internal)

and/or outer (external) environmental changes such as temperature, pH, light, enzymes, ultrasound, and magnetism

17, 210-212

. In cancer therapy, anticancer drugs are often administrated systematically at high doses

to ensure therapeutic efficacy. However, highly-dosed systemic administration causes side-effects of toxicity in healthy tissues in liver, kidney, heart, and bone

76

. Therefore, the on-demand controlled delivery is of great

merit.

MSN-based stimuli-responsive systems use ‘gatekeeper’ over the pore entrance, and upon its on/off action the loaded drugs are released out

16

. Various types of gatekeepers are summarized in Figure 7a. In Type I,

solid NPs (Au, ZnO, Fe3O4,and CdS ) are covalently-linked to the pore opening and are removed by external stimuli. The Type II (liner molecule) and Type IV (multilayer) gatekeepers are chemically bound to the surface of MSN. The Type III (macrocyclic molecule) gatekeepers (e.g., cyclodextrins, crown ethers, and cucurbit 6 uril) can be linked to the pore opening via covalent/non-covalent interactions

213

. In general, the stimuli

depending on the types of gatekeepers are classified into, i) physical exogenous (temperature, light, magnetic, electric, and ultrasound), and ii) biological endogenous (temperature, pH, redox, and enzyme) mode

214

.

Among else, pH-responsive controlled delivery have been the most widely studied because of the pH gradient in certain tissues and subcellular compartments

215

. Tumor and inflammatory tissues are more acidic than

normal tissues. As an example, macrocyclic β-cyclodextrin (β-CD) (Type III) was used as a gatekeeper

216

.

The binding between β-CD and the stalk becomes weaken under mildly lysosomal acidic conditions, resulting in sliding of β-CD and drug release. Similarly, a pH-responsive gatekeeper was synthesized based on MSNs covering α-cyclodextrin (α-CD) rings and p-anisidino linkers

217

. The pH-responsive nanoparticles exhibited

high stability with no drug leakage at neutral pH ~7.4, and released drug in both H2O and medium at pH ~5.5 when p-anisidino nitrogen atom was protonated. The delivery capability of α-CD gatekeeper based on MSNs was tested in various types of cancer cells at lysosomal acidic pH levels. Temperature is another common internal trigger. A well-known temperature-sensitive polymer, poly(Nisopropylacrylamide) (PNIPAM), has been used as a gatekeeper (Type II) through the hydrophilic-hydrophobic transition at the ‘lower critical solution temperature’ (LCST) of ~32 °C

218

. Depending on the pore size of MSNs,

PNIPAM is integrated onto the interior surface (for large pore sizes) or the exterior surface of MSNs (for small pore sizes). MSNs capped with polymerized PNIPAM inside pores were developed to show thermo27


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responsive ibuprofen delivery at around LCST

219

. Because the LCST of pure PNIPAM is below the body

temperature, efforts have also been exerted to increase LCST to near body temperature

218, 220-222

. Thiol-

functionalized MSNs with pyridyl disulfide terminated PNIPAM demonstrated well the temperature-responsive release of fluorescein at around 38ºC. The LCST of polymers can also be varied by ultrasound- or NIR223-225

irradiation, salt-induction

, and polymer concentration

226-228

. Other polymers like poly{γ-2-[2-(2-

methoxyethoxy)ethoxy]ethoxy-ε-caprolactone}-b-poly(γ-octyloxy-ε-caprolactone

(PMEEECL-b-POCTCL)

,

pluronic F-127, polyacrylic acid (PAA) have also been developed as thermo-responsive capping materials

229-

231

.

Redox potential is considered an effective biological trigger owing to the difference in glutathione (GSH) concentration between intracellular (10 mM) and extracellular (2 µM) conditions. Also, the intracellular GSH levels in tumor cells are higher (over 4 times) than those in normal cells capped with CdS NPs (Type I) were developed

232

. A redox-responsive MSNs

233

. The disulfide links between MSNs and CdS NPs were

cleaved by GSH, leading to a rapid release of drugs. A cross-linked polymeric network onto the pore opening 234

also served as a redox-responsive capper

. Similarly, enzymes in living organisms were also effective

endogenous stimuli to trigger drug release. Different saccharides were used to modify the surface of MSNs as gatekeepers (Type II)

235

. The loaded dye molecules showed limited release until β-D-galactosidase was

added; β-D-galactosidase hydrolyzed the glycosidic bond between β-D-galactose and β-D-glucose and opened the pore gates.

Unlike the internal triggers, external stimuli can perform on/off actions at specific location and time. Light is a facile external trigger. For example, thymine derivatives were grafted on the pore outlet of MSNs (Type II)

236

.

When the NPs were exposed to 240 nm UV irradiation, cyclobutane dimer was cleaved, which allowed for drug release. An NIR-responsive drug release system was reported based on upconversion nanoparticle (UCNP) coated MSNs structure (Type II)

237

. By coating UCNP with azobenzene group-tethered MSNs, the

release of drug was controlled by the NIR intensity and duration time.

Magnetic stimulus is another possible external trigger. Externally applied alternating magnetic field generates thermal energy in magnetic NPs which in turn controls the release of drugs incorporated within the pores of MSNs. Monodispersed Fe3O4 NPs were capped onto MSNs through a chemical bonding

222, 238-239

. Under a

magnetic stimulus, the chemical bonds break down and Fe3O4 NPs remove from the surfaces, releasing drugs rapidly. DNA-based magnetic stimulus-responsive system was also designed. DNA-magnetic NP conjugates 28



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Page 30 of 63

were capped onto the complementary strand-functionalized MSNs through DNA hybridization

240

. Under an

alternating magnetic field, the magnetic NPs reach hyperthermic temperatures (42–47°C), which disassembles the DNA strand and releases drug, suggesting the possibility of a remote magnetic controlled drug delivery system.

Often the stimuli are combined for more effective controlled actions. Multi-responsive release systems use two or more stimuli applied either independently or cooperatively. A pH- and photo-responsive gold NP-capped MSN-based delivery system is an example

241

. The interaction between boronic acid functionalized gold NP

and saccharide-modified MSN surface is reversibly regulated by pH owing to the formation of boroester bonds. The laser-induced plasmonic heating properties of gold NP account for the photo-responsiveness of this system. Similarly, pH-responsive nanovalves and light-responsive nanoimpellers were reported for dualstimuli drug delivery system

242

. Multi-responsive supramolecular capped MSN was reported by grafting β-CD-

bearing polymer on the MSN and crosslinking with disulfide groups to block the pores

243

. The release of

preloaded calcein dye was demonstrated not only upon UV irradiation, but also upon the addition of α-CD and disulfide reducing agent DTT, and the latter led to isomeric transformation of azobenzene groups (α-CD to βCD), and cleavage of disulfide bond between β-CD and polymer main chains, respectively.

Zhao et al.

244

reported triple-responsive nanocarries (pH, reduction and light) based on hollow MSN modified

with poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) (Figure 7b). In neutral or alkaline (e.g., pH 7.4) conditions, PDEAEMA polymer chains become a collapsed state, holding drug to release from the mesopores channels. However, in acidic environments (pH 5), the protonated polymer chains become an extended conformation, opening pores for drug release. Also, the pH-responsive PDEAEMA was introduced on the surface of hollow MSNs via reduction-cleavable disulfide and photolabile o-nitrobenzyl ester (ONB). While the disulfide bond is stable in physiological environment, it is easily cleaved in reducing condition. The photolabile ONB group became rapid isomerization upon UV irradiation at 365 nm, and cleaved the chromophore for drug release 244.

Another release platform recently developed is free of block units and is manipulated by light. The freeblockage gatekeeper is based on hydrophobic effects. Light-responsive spiropyrans were often used to gate on MSNs

245-246

. Fluorencein disodium and camptothecin drug molecules could be loaded onto the MSN pores

derived from hydrophobic interactions

246

. Under UV light irradiation, the wetting of the surface due to the 29


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hydrophilic change of spiropyran resulted in the release of drug molecules in vitro enhancing cytotoxicity of cells

246

. Similarly, hydrophobic N-carboxyethyl-nitrospiropyran photoisomerizable units were also used as a

gatekeeper

247

. The visible light irradiation enabled the positively charged nitrospiropyran group to open the

channels and release the loaded dye, and the uncapping mechanism was shown to be reversible upon visible light irradiation, which regenerated the neutral nitrospiropyran state. The phenylamine (Ph) group, which has a convertible hydrophobic/hydrophilic property between deprotonation and protonation, was also used onto the internal surface of the nanopores of MSN

248

. The Ph-functionalized nanopores were hydrophobic to trap drug

at pH 7.0, which became hydrophilic at reduced pH due to the protonation of Ph groups, consequently releasing drugs.

While the gatekeepers are mainly designed for on/off action in drug delivery, those with imaging properties (e.g., QDs, gold NPs, and magnetic NPs) can also perform diagnostic function. Compared to other stimuliresponsive NPs such as liposomes, and dendrimers, MSN-based system has some unique advantages; i) tunable pores and openings and the surface chemistry provide great diversity in gatekeepers, and ii) the grafting moieties only break away upon stimuli without disintegrating the carrier. The multi-functional silicabased NPs with on-demand controlled drug delivery and bio-imaging capacities, which though not been realized, can be a promising theranostic nanocarrier platform in the future.

30



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Figure 7. (a) Schematic representation of types of gatekeepers capped on the surface of MSNs to enable stimuliresponsive drug delivery. (b) Representative example of triple-responsive drug release system of HMSNs-PDEAEMA; schematic illustration of the release mechanism, and the in vitro DOX release at 37 °C monitored at different pH values 244 with or without DTT, as well as under the UV light. Reproduced with permission from ref . Copyright 2015 American Chemical Society.

5.1.3. Photothermal and Photodynamic Therapy

Without using therapeutic molecules, disease therapy is also possible. Both photothermal therapy (PTT) and photodynamic therapy (PDT) use light as a trigger. In PTT, NIR absorbing agents are generally involved for anticancer treatment. Under light irradiation the light energy is converted into heat, which raises the local temperature of tumor and kills cancer cells

249-250

. In PDT, photosensitizers are used which can transfer the

absorbed light energy to surrounding oxygen molecules, and can create cytotoxic singlet oxygen (1O2) or reactive oxygen species (ROS) to damage and kill cancer cells

251

.

31


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PTT utilizes light sources. Among else, laser enables accurate lesion positioning and controlled power input/duration

252-253

. It is suitable for the treatment of superficial tissues rather than deep tissues. As the

material platform, gold NPs are widely used, and in particular, gold nanorods have excellent NIR plasmonic properties

254-255

. However, gold nanomaterials exhibit low drug loading capacity, thus coating with MSNs is

effective for chemotherapy simultaneously with PTT

255-256

. The heat generated by gold nanorods is not

sacrificed when a thin mesoporous silica layer is covered; while anticancer drugs can be effectively loaded with additional controlled delivery actions. The combinatory effects of the chemo- and photothermal-therapy were reported in vitro cancer cells and in vivo tumor models delivery is well illustrated in Figure 8a,b

257-258

. The MSN/gold nanorod system with DOX

257

. The NIR laser irradiation at a low intensity was used to enhance

drug release for chemotherapy, whereas the irradiation at high intensity gave rise to hyperthermia. Importantly, two-photon optical imaging modality was used to visualize the co-localization of carriers with DOX in cells. A recent study has also reported the CT scannability of the gold nanorods, suggesting additional theranostic functions of the MSN/gold nanorods

259

. Based on the silica/gold nanocarrier system, iron oxide (Fe3O4) NPs

were further combined to allow additional MRI 260.

A PTT-induced nanotheranostic system was recently reported based on mesoporous silica-coated gold nanorods (GNR@SiO2)

258

, which were to deliver indocyanine green (ICG), and 5-fluorouracil (5-FU) for in

vivo multimodal imaging guided synergistic therapy (Figure 8c). The in vivo PTT effect in mice was noticed at 24 h of post-injection of GNR@SiO2-NH2 and GNR@mSiO2-5-FU-ICG under NIR light (808 nm, 1.0 W/cm2, 5 min). The temperature of tumor tissues could be controlled below 47°C by regulating laser power density and irradiation time, thus guaranteeing the therapeutic effect as well as avoiding damage of surrounding healthy tissues. Similarly, multi-functional silica-gold based nanoshells, injected intratumorally into transmissible venereal tumors in mice, were effective in increasing temperature under NIR laser (820 nm) irradiation for 46 min, thus damaging tumor tissues

258, 261

.

PDT is another light-triggered therapeutic modality and it is non-invasive and selectively destructs tumors

258,

262-264

. The the irradiation of photosensitizers by external light (e.g., laser) generates highly reactive oxygen

species (ROS), such as peroxides, singlet oxygen, hydroxyl radicals, to destruct tumor cells. However, the photosensitizers have drawbacks; low targeting efficiency, instability and easy excretion from bodies, thus NPs were used to encapsulate photosensitizers. The unique properties of MSNs are considered to be promising for the delivery of photosensitizers

258, 262, 264-265

. An exemplar study covalently coupled porphyrin photosensitizers 32



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

to MSNs, and showed the functions in MDA-MB-231 breast cancer cells

Page 34 of 63

266

. When treated with particles and

light irradiation cancer cells died ~45%, and when mannose was used to target cells, the cell death reached ~99%. This nanocarrier system was improved for in vivo studies by substituting the porphyrin with a twophoton excitable photosensitizer; this enables deep tissue penetration 262. When the nanocarriers were treated at doses of 16 mg/kg to HCT-116 tumor bearing mice, and irradiated at 760 nm (3 min, 80 mW), around 70% tumor mass was reduced, as contrasted to other groups. The results suggest in vivo PDT efficacy of the photosensitizer-bearing MSNs.

A recent report also combined the PTT and PDT using highly integrated nanomaterials based on mesoporous silica-coated gold nanorods (MSGNR) for tri-synergistic (PTT, PDT, and chemotherapy) tumor therapy (Figure 8d)

264

. A photosensitizer (PS) molecule (e.g., AlPcS4) was used on the silica layer and β-CD was used as a

gatekeeper. For a rapid AlPcS4 release, glutathione (GSH) was selected as a reducing agent; ~58% of AlPcS4 released after 24 h, thus to exert PTT effect (Figure 8e). Moreover, the PDT was possible by the ROS generation under irradiation with NIR (660 nm). The MMSGNR-AlPcS4, compared with free AlPcS4, could generate 1O2 more effectively in the targeted tumor cells (Figure 8f,g). Upon 808 or 660 nm laser irradiation, the amount of dead tumor cells increased significantly while the nanotherapeutic system little damaged the normal cells.

33


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Fig. 8. Photothermal and photodynamic therapies based on MSN/gold nanohybrids: (a) Mesoporous silica-coated gold nanorods (Au@SiO2) as a cancer theranostic platform, and (b) DOX release profiles with and without NIR laser irradiation 257 at different pH values. Reproduced with permission from ref . Copyright 2012 John Wiley and Sons. (c) Infrared thermal images of tumor-bearing mice at different time points under laser irradiation 24 h post-injection. Reproduced with 258 permission from ref . Copyright 2016 John Wiley and Sons. (d-g) MMSGNR-AlPcS4 based tri-modal tumor therapy; schematic illustration of the multiple therapeutic actions (d), AlPcS4 release profile under different conditions (e), single oxygen generation (from MMSGNR, MMSGNR-AlPcS4, and free AlPcS4) under 660 nm laser irradiation by using RNO as a sensor (f), and in vitro PDT/ PTT antitumor performance of MMSGNR-AlPcS4, with confocal image of calcein and PI 264 containing HepG2 cancer cells and COS7 cells (g). Reproduced with permission from ref . Copyright 2016 John Wiley and Sons.

5.1.4. Ultrasound Therapy

High intensity focused ultrasound (HIFU) is another noninvasive and nonradioactive therapeutic mode, that is clinically used for cancer surgery. Ultrasound penetrates tissues and confers thermal, mechanical and cavitation effects to destroy tumor vasculature and necrosis of cancer cells 34


39-40, 267-269

. Conventional


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Page 36 of 63

ultrasound cancer surgery has some drawbacks due to the relatively high ultrasound power input adopted in clinics, i.e., therapeutic efficiency in deep tissues is low and normal tissues can be damaged. Nanotechnology has offered a solution to this.

Silica-based NPs have been explored as a means to enhance the current HIFU therapeutic efficacy. The encapsulation of perfluorohexane (PFH) within silica NPs can function as an effective HIFU sensitizer. The PFH-loaded NPs are echogenic, increasing ultrasound scattering and intensifying local thermal deposition 39-40, 270

. An exemplar study developed a hollow form of silica nanocapsules to impregnate PFH that has a phase

transition temperature of ~56°C (Figure 9). When the HIFU was applied at proper conditions, the PFH loaded was effective in increasing the volume tissue ablation ex vivo

39

. Similarly, gold-silica nanoshells loading PFH

were developed to decrease the exposure time of HIFU necessary to achieve a thermal lesion

270

. HIFU

applied twice at 400 W for 2 s per application was shown to be effective in suppressing VX2 tumor in rabbits when administered with the PFH-loaded hybrid nanoshells. The HIFU-enabled theranostic system was further combined with MRI imaging agent and loaded cell viable growth factors

267, 271-272

. This system demonstrated

multi-functionality in terms of: i) offering ultrasound and MRI signal to guide implantation into the peri-infarct zone, ii) serving as a slow release reservoir of insulin-like growth factor to increase cell survival, and iii) enabling PFH-delivered chemotherapy and HIFU-based therapy.

35


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Figure 9. High intensity focused ultrasound therapy using mesoporous silica nanocapsules loading perfluorohexane: (a) Preparation procedure of MSNC-PFH, (b) TEM of MSNC, (c) Ex vivo results of HIFU exposure at different ultrasound exposures, and (d) In vivo ultrasonic images on rabbit liver tumors, before (left) and after (right). Reproduced with 39 permission from ref . Copyright 2012 John Wiley and Sons.

5.2. Focus on Diagnostic Functions Due to the unique features of well-defined mesoporosity and surface chemistry, MSNs provide promising diagnostic platforms with drug delivering capacity. Various imaging agents are integrated with MSNs to enable clinically relevant imaging modalities, including MRI, PET, optical imaging, ultrasonography, and the combinations thereof, to provide multi-imaging for more precise and effective diagnosis. Simultaneously with the imaging, therapeutic treatment with the delivered drug molecules is enabled within the MSN-based nanoplatforms. This part focuses on the recent efforts exerted to improve diagnostic functions of MSN-based systems for theranostic purposes.

5.2.1. Magnetic Imaging

MRI is one of the most representative imaging modalities in clinic due to high spatial resolution and superior 3D soft tissue contrast

273-274

. MRI is based on the production of excitation pulse by relaxation of protons

triggered by an external magnetic field. There are two relaxations; spin-lattice (relaxation time T1, longitudinal relaxivity) and spin-spin relaxation (relaxation time T2, transverse relaxivity). Magnetite (Fe3O4) provides large T2 relaxation effects, and thus is used as T2-weighted MRI contrast agents. The most popular T1 contrast agent used in MRI is manganese (Mn2+), and gadolinium (Gd3+)-containing nanoprobes, because of their large magnetic moment. These ions can be either in the form of oxide (e.g., iron oxide), incorporated as a dopant within a nonmagnetic matrix, or chelated to the surface of nanoparticles (as illustrated in Figure 10a). For multi-functionality, fluorescence dyes, genes, or drugs are also additionally conjugated to the surface 273-278.

Magnetic NPs are widely used contrast agent for T2-weighted MRI. Nanoparticles were synthesized by different methods, including thermal decomposition process

279

. A thin mesoporous silica coating improves

dispersibility, hydrophilicity, and the surface functionality. Anchoring of different polymeric materials (e.g., PEG, PEI-PEG) is required for prolonged blood circulation and/or for targeted diagnosis and therapy 36


183, 280

. In a


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typical study on the silica-shelled magnetite NPs, the r1 and r2 relaxivity values were attained 3.40 and 245 mM−1 s−1, respectively

183

, and after PEGylation, the T2-weighted MRI signals visualized the accumulation of

NPs in tumors after intravenous administration into nude mice (Figure 10b).

The imaging efficacy of the manganese- or gadolinium-based T1-weighted MRI contrast agents can be improved. The mesopore structure of MSNs helps the access of water molecules, enabling the paramagnetic centers to be dispersed at large quantity

281

. The MSNs grafted with gadolinium-containing silane derivative

(Gd-MSNs) produce highly efficient T1-weighted MRI

282

. The in vitro r1 values reached as high as 28.8 mM

−1

s−1 (3.0 T) and 10.2 mM−1 s−1 (9.4 T). The in vivo results showed that Gd-MSNs could act as highly efficient intravascular T1-weighted MRI contrast agents as well as T2-weighted MRI contrast agents for soft tissues when applied at higher doses (Figure 10c). This excellent performance is attributed mainly to the high dispersity of Gd-based paramagnetic centers, which allows ease of interaction with water molecules. The chelation of Gd3+ ions within the channels of silica-shelled magnetite could increase the transverse relaxivity −1

(r2) from 97 to 681 mM

−1

s , thus demonstrating an effective MRI for lymph nodes

283

. Similarly, MSNs

incorporating Gd2O3 clusters in the mesopores showed enhanced in vitro r1 relaxivity (13.48 mM−1s−1) with −1 −1

respect to commercial Magnevist (r1 = 4.75 mM s ), suggesting effective T1 contrast agents for tumor MRI 284

. Manganese ions were also employed as MRI-T1 contrast agents

95, 285-287

. Recently, mesoporous silica-

coated hollow manganese oxide NPs were developed as T1-weigted MRI contrast agents for the labeling and MRI tracking of adipose-derived MSCs

285

. However, the MRI performance was not optimal based on the low

−1 −1

r1 value (0.99 mM s , 11.7 T), probably owing to the protection of active Mn

2+

ions by the silica coating; this

fact suggests improved mesopore design is needed to enhance the interaction of ions with water molecules.

37


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Figure 10. Magnetic MSNs for MRI: (a) Schematic showing two modes of MRI using MSN-based magnetic NP. (b) Tumor nude mouse- in vivo T2-weighted MRI of tumor-bearing nude mouse before and after of silica shelled magnetite NPs. 183 Reproduced with permission ref . Copyright 2008 John Wiley and Sons. (c) Aorta signal enhancement of T1-weighted MRI of mouse using Gd-MSNs(i, ii), and T2-weighted MRI showing liver signal loss (iii, iv). Reproduced with permission ref 282 . Copyright 2008 American Chemical Society.

5.2.2. Optical Imaging

Optical imaging has large room for probe selection, high sensitivity, and non-ionization safety when compared with MRI. To label and image cancer cells both in vitro and in vivo, various fluorescent molecules or nanomaterials are explored such as rare-earth doped upconversion, organic fluorescein, and QDs

250

.

Furthermore, the silica matrix is optically transparent, thus not significantly influencing the excitation and emission of light during a pass through the matrix.

A common method to produce fluorescent MSNs is to combine organic dyes available in the NIR range of biological window (700–900 nm)

288

. Cyanine dyes such as trimethine cyanines (Cy3), pentamethine cyanines

(Cy5), heptamethine cyanines (Cy7) and indocyanine green (ICG) are commonly used. For example, ICG NIR contrast agent was absorbed onto the pores of trimethylammonium-modified MSN by an electrostatic 38



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attraction

Page 40 of 63

289

; the bio-distribution of optical MSN in rat liver after intravenous injection was well demonstrated

by the high fluorescent intensity. Recently, IR-783, a negatively charged and water-soluble cyanine NIR dye agent, was electrostatically adsorbed onto the silica shell

290

. The fluorescence (Figure 11a) and X-ray CT

imaging taken at 4 h post injection of the probe into a nude mice revealed the in vivo performance

290

.

Similarly, NIR dye ZW800 was conjugated onto MSN to optically image tumor tissue without any quenching effects in vivo

291

. Although traditional organic dyes are relatively biocompatible, easy to prepare, and cost-

effective, they easily bio-erode and degrade.

Therefore, NP-based phosphors, owing to the characteristics of high quantum yields, wavelength tunability, photostability and resistivity to photo-bleaching, are used widely for optical bio-imaging. Silica-shelled fluorescent NP is a typical form. PEGylated liposome-coated QDs with mesoporous silica shell was synthesized for molecular imaging

292

, demonstrating excellent optical imaging efficiency in labeling cancer

cells while enhancing the biocompatibility and stability of QDs. In fact, the cytotoxicity of traditional Cd-based QDs has been a serious concern for their in vivo uses

293

. More recently, rare-earth based upconversion NPs

showed fluorescence upon the 980 nm laser excitation. The NIR-Vis upconversion fluorescence has good tissue penetration and is free of tissue auto-fluorescence, the rare-earth based upconversion NPs are considered to replace traditional semiconductor QDs for live-imaging of cells and organs in small animal models

294-295

. Monodispersed upconversion NP, NaYF4:Tm/Yb/Gd

296

, layered with a thin mesoporous silica,

showed excellent fluorescent imaging performance after the intratumor administration

296

. A rattle-structured

nanotheranostics (UCMSN) was also recently designed with NaYF4:Yb/Er/Tm@NaGdF4 (UCNP) as the core and mesoporous silica as the shell. The core-shell NPs showed a strong NIR UCL signal in the tumor tissue by an intravenous injection (Figure 11b)

297

.

An intrinsic approach of using oxygen defects in the MSN structure is also explored for optical imaging

27

(Figure 11c). Porous silicon NPs prepared by an electrochemical etching generated a luminescence property, being attributed to quantum confinement effects and defects localized at the Si–SiO2 interface. The luminescent porous NPs loaded with DOX were shown to accumulate mainly in liver and spleen when injected intravenously into mice. Interestingly, the NPs accumulated in the organs were completely cleared in 4 weeks. Considering other inorganic NPs with diameters > 5.5 nm have slow clearance in vivo, this unique feature of rapid body clearance improves the biological safety.

39


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As discussed, compared to the organic fluorescence dye, the semiconductor QDs have still merits in terms of better optical performance in vivo. Yet, the innate toxicity and quenching of QDs limited widespread uses in clinic. Comparatively, upconversion fluorescent NPs are currently gaining more interest as new optical imaging agents. Thus, the combination of those fluorescent NPs with MSNs, such cas NP/silica core/shell, is considered optimal to illuminate the imaging capacity while satisfying biocompatibility. Furthermore, the drug loading and controlled delivery of therapeutic molecules can be realized through shelled mesopores. However, the in vivo theranostic performance of the silica-shelled NPs is not piled up enough, requiring substantial animal studies using target disease models in the future.

Figure 11. MSN-based nano-platforms for optical imaging: (a) Organic dye-conjugated MSNs. In vivo of MSN-IR-783 images of nude mice 4h after injection, from the (A) back side and (B) abdominal side using (1) bright field and (2) NIR 290 fluorescence. Reproduced with permission from ref . Copyright 2015 American Chemical Society. (b) MSN combined with UCNP, NaYF4:Yb/Er/Tm@NaGdF4 with rattle structure; TEM image (i), and in vivo biodistribution NIR upconversion luminescent imaging (UCL) of dissected organs of a tumor-bearing mouse after intravenous injection at the tumor site (ii) 297 bright field and (iii) NIR-UCL imaging. Reproduced with permission from ref . Copyright 2014 Elsevier. (c) Oxygendefect generated fluorescence in MSNs. In vivo images after intravenous injection (i), and the clearance of the injected 27 NPs in the liver and bladder (ii). Reproduced with permission from ref . Copyright 2009 Nature Publishing Group.

5.2.3. Other Imaging Modalities

Apart from the MRI and fluorescent agents, radionuclide is introduced to MSNs for PET imaging. PET has 40



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Page 42 of 63

high sensitivity and is clinically available for diagnosis of tumors at an early stage. Its merit includes also high depth penetration and a broad range of probes. The commonly used PET agents include heavy metal 68

Ga,

99

mTc and

111

In labeling with drug targeted, as well as radioisotopes

11

C,

18

F and

64

Cu,

15

O labeling with

targeted molecules. Recently, radionuclide 64Cu chelated MSNs were developed for long-term PET imaging 291. Moreover,

64

Cu-CuS@MSN-TRC105 theranostic nanoparticles were developed for in vivo tumor targeted PET

imaging (Figure 12a)

298

. PET revealed a time-dependent breast tumor uptake of

64

Cu-CuS@MSN-TRC105;

4.9% ID/g at 4 h and 6.0% at 24 h post-injection. In contrast, without the conjugation of TRC105, the 4T1 tumor uptake of 64Cu-CuS@MSN was found to be around 1% ID/g at all time points for non-targeted group, indicating

that

TRC105

conjugation

is

likely

the

controlling

factor

for

enhanced

tumor

64

accumulation. Administration of 1 mg/mouse of free TRC105 1 h before Cu-CuS@MSN-TRC105 (∼1 mg/kg) injection reduced the tumor uptake to 3.0 ± 0.1 and 2.3 ± 0.3% ID/g at 4 and 24 h, respectively. The serial PET scans reflected higher uptake of CuS@MSN-TRC105 than CuS@MSN at all time points. Ultrasound imaging is noninvasive, nonionizing, real-time and cost-effective method; however, the sensitivity and resolution of ultrasonography is relatively low (vs. MRI, CT or PET). Thus, one key solution is to develop the contrast agents with high performance. Although organic microbubbles were conventionally used to enhance the contrast, they have large (micrometers) particle sizes and are instable thus the diagnosis of diseases at early stages was not easy. On the other hand, the recently developed silica NPs offered a solution to this

269-270, 299-301

. Compared to nonporous hollow form, the mesoporous hollow structure showed better

ultrasonographic resolutions, implying that the mesopore hollow space functions for amplifying ultrasound imaging as well as for therapeutics delivery in tumor theranostics. In vivo results in rabbits bearing VX2 liver tumor showed clear contrast at the tumor site under ultrasound guidance (Fig. 12b)

302

. The perfluoropentane

filled within the hollow silica NPs with sizes of sub- to a few-micrometers was released to amplify the ultrasound imaging contrast 269-270, 303.

When silica NP is combined with unique nanomaterials, such as gold, other imaging applications are possible. Gold NPs or nanorods encapsulated within silica were shown to produce photoacoustic signals to a significantly higher level (3 times in intensity) than uncoated ones

304

. In addition, one recent study reported

Raman molecular imaging of the gold-silica NPs as multimodal contrast agents

305

. As discussed, the MSN-

based imaging probes are tunable and versatile through the combination with imaging agents and NPs, and more effort is currently exerted toward multi-modal imaging strategy. 41


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Figure 12. (a) MSN-based PET imaging: In vivo serial coronal PET images of 64Cu-CuS@MSN-TRC105 nanoconjugates (targeted group), 64Cu-CuS@MSN (non-targeted group) and 64Cu-CuS@MSN-TRC105 with a large dose of free TRC105 (blocking group) in 4T1 murine breast tumor-bearing mice at different time points post-injection. Reproduced with permission from ref 298. Copyright 2015 American Chemical Society. (b) MSN-based ultrasound imaging; in vivo liver tumor ultrasonograms of pre- (i-iii) and post- (ii-iv) puncture administrations of PEGylated MnOx-hollow MSNs under the guidance of ultrasound imaging (10 mg/mL, 1 mL) using rabbits bearing VX2 tumor as animal model in harmonic (i: before and iii: after administration) and conventional B-mode (ii: before and iv: after administration), and the in vivo acoustic 302 intensities (gray value) of the tumor shown below. Reproduced with permission from ref . Copyright 2012 Elsevier.

5.2.4. Multi-modality Imaging and Theranostic Applications

The multimodal imaging significantly enhances the diagnosis accuracy and sensitivity, thus many recent studies on MSN-based theranostics focus on this approach. For example, the integration of fluorescent and magnetic domains into MSNs produces bi-modality imaging probes with combined merits, i.e., noninvasiveness of optical mode with high spatial resolution of MRI

306

. The combination of MRI and

ultrasound imaging enhances clinical availability because MRI is used for the pre-surgical evaluations while ultrasound is applied in the surgical process for real-time monitoring and guidance of tissues

307

. Below are

details of the multi-modal imaging studies based on MSNs, where therapeutics delivery is also pursued for multi-functional theranostics

308-309

.

42



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Dye-doped MSNs with covalently linked multiple small magnetic NPs onto the surface were designed for simultaneous MRI and optical imaging while delivering anticancer drug DOX (Figure 13a) 158. The introduction of numerous iron oxide NPs onto the silica surface is helpful because the T2 MR contrast effect is improved by the clustered NPs

310

. The hybrid NPs significantly improved the MR contrast, and the relaxivity value r2

increased by 2.8 times compared to the pure magnetic NPs. PEGylation further improved the colloidal stability in aqueous solution and enabled accumulation of NPs at the tumor site after intravenous injection into a nude mouse. A clear signal drop in T2-weighted MR image at 3 h after injection demonstrated the in vivo MRI of target tumor tissue. The red fluorescence of DOX also enabled visualization of the drug accumulation at tumor sites directly.

The combination of upconversion NPs offers effective synergism for multi-modal imaging. The selection of lanthanide ions in the host lattice enables a wide range of choices in imaging modality. Core-shell structured hybrids such as BaGdF5:Yb3+/Tm3+ fmSiO4@SPIN

314

311

, BaYbF5:Tm@BaGdF5:Yb

312

, Ho3+-doped NaYbF4

313

, and i-

were developed as imaging probes for tri-modality, i.e., CT/MRI/photoluminescence imaging.

Recently, multifunctional yolk-like GdOF:Ln@SiO2 nanocapsules decorated with ZnPc photosensitizers and photothermal carbons were designed and loaded with DOX for NIR light-triggered multi-model therapy (PDT, PTT, and chemotherapy) and imaging (CT, MRI, UCL) (Figure 13b)

306

. ZnPc photosensitizers were modified

1

to endow GdOF:Ln@SiO2 with ability to produce singlet oxygen ( O2) when excited by red emission due to the co-doped Yb/Er/Mn derived from NIR irradiation, and the attached carbon dots (CDs) are to create thermal effect upon NIR laser irradiation. Simultaneously, the thermal increase enhances DOX release for synergistic effects. Also, the MRI, X-ray CT together with the UCL imaging were employed for simultaneous diagnostics 306

3+

3+

3+

. TaOx-decorated NaYF4:Yb /Er /Tm @NaGdF4 core/shell upconversion also showed excellent in vivo

CT/MR/optical tri-modal imaging

315

. More recently, NaLuF4:Yb,Tm@NaGdF4(153Sm) core/shell upconversion

NPs were reported for quad-modal imaging (SPECT/CT/MR/photoluminescence)

316

. These multi-modal

therapeutic and imaging approaches of nanoparticles based on MSNs are currently in rapid progress, which enabled by reaping up the simultaneous and synergistic actions of different chemicals and nanomaterials.

43


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Figure 13. Multi-modal imaging strategies based on MSNs: (a) Magnetic NP and dye-doped MSN enabling MRI and fluorescence bi-modal imaging; (i) scheme of hybrid NPs, (ii) TEM image, (iii) in vivo T2-weighted MR images of the tumor site, and (vi) fluorescence image of tumor section showing red colored DOX delivered from the NPs; reproduced with 158 permission from ref . Copyright 2010 American Chemical Society. (b) Multifunctional yolk-like GdOF:Ln@SiO2 nanocapsules decorated with ZnPc photosensitizers for CT/MR/PT/UCL multi-modal imaging and anti-tumor therapy. 306 Reproduced with permission from ref . Copyright 2015 American Chemical Society.

6. Concluding Remarks We can witness the potential of MSNs for theranostic purposes through the efforts and findings collected in this Review. The excellent mesoporous properties, tunable surface and bulk chemistry, and acceptable biocompatibility enable MSNs to be a fascinating nano-platform for combining therapeutics delivery and diagnostic function.

Fine-tuning the mesopore structure (pore size, shape and porosity) and chemistry of MSNs (inner and outer surface) is essential to gain high loading capacity and sustained and controlled release of drugs as well as to achieve sensitive and high resolution imaging contrast. Defect-based intrinsic approach to generate imaging 44



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property is one simple way of utilizing MSNs for theranostics, which mainly adopts optical imaging modality. More potential and diverse is based on the extrinsic strategies, where imaging agents and NPs are combined with MSNs either within the internal structure or on the external surface. In such ways, MSNs can be armored with potential diagnostic functions with synergized therapeutic actions for the treatment of cancer diseases.

The intrinsic approach is simple and generates defects within a silica network that can contribute to luminescent signals, and the imaging color spectrum can vary depending on the defect type and size. However, the intrinsic method is largely limited to an optical imaging modality. The extrinsic approach, on the other hand, facilitates a wide range of imaging modalities depending on the NPs and dye chemicals introduced. When the imaging agents were incorporated within MSN the outermost surface is shelled with mesoporous silica which not only prevents the possible toxicity of the inner particles but also possibly attenuates the imaging intensity; however, the thin and mesoporous nature is known to save the diagnostic properties of the incorporated particles. When the dyes and NPs are tethered onto the outer surface of MSN the diagnostic benefit is straightforward; but in this case, the possible leaching of dyes and ions from NPs can exert unwanted toxicity issue. Therefore, the combination of imaging materials and agents with MSN needs special care to preserve the biocompatibility as well as the diagnostic properties.

Using the MSN-based theranostic carriers, substantial efforts have been taken to control the loading and delivery of drugs and genes. For the efficient loading of drugs, the pore structure and surface chemistry of MSNs have been significantly tailored. Moreover, multi-modal pores have recently demonstrated to be effective in loading of different sized drugs, which may be beneficial for the delivery of multiple drugs as the co-delivery of therapeutic molecules is considered a promising approach for drug-resistant cancer treatments. Targeting is one of the key elements for smart therapeutics. Not only cell membrane but the intracellular organelles (e.g., mitochondria) and nucleus have also been a research focus to accumulate MSN-based carriers in specific cellular compartments which can ultimately eliminate or boost targeted functions. In this application, the imaging property of MSN-based systems can contribute to visualize the intracellular localization of the nanocarriers and consequently elucidate the cellular mechanism of therapeutic actions.

Providing a stimuli-responsiveness to MSN theranostic systems is a representative strategy for on-demand delivery of therapeutic molecules. Theranostic functions are possible by the use of imaging agents, such as QDs, carbon dots, gold NPs, and magnetic NPs, as gatekeepers (capping nanomaterials). In this way, the 45


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release of drugs can be ‘on/off’ controlled upon the different stimuli provided either internally (temperature, pH, and enzyme) or externally (light, sound, and magnetic field). Along with the molecular chemotherapy, the photothermal and photodynamic treatments are also possible promising therapies affordable by the MSNbased hybrid systems. To enhance the anti-tumor effects, the chemotherapy and photothermal/photodynamic-therapy are often used in combination; Au NPs are hybridized with MSNs to deliver anti-cancer drug and photosensitizer together, as well as to action stimuli-responsively to light sources. Ultrasound is another noninvasive therapeutic mode, and has been clinically used for cancer surgery. Although the therapy has several limitations in terms of low therapeutic efficiency in deep tissues and possible damages of normal tissues, recent NP-based systems have shown some promise. The perfluorohexane-encapsulated MSNs could increase ultrasound scattering and intensify local thermal deposition without damaging normal tissues.

The excellent therapeutic functions of MSN-based carriers have been harmonized with a wide spectrum of imaging modalities (MR, PET, CT, optical, and ultrasound imaging) to represent multifunctional nanotherapeutic platforms. Most of all, multi-modality is currently an important agenda to improve the diagnostic functions satisfactory for clinical settings, which is also intensely explored in MSNs. Because each modality has its own pros and cons in terms of resolution, sensitivity, tissue specificity, penetration ability, tissue damage, cost, and procedure, the multi-modal imaging exploited in a single NP domain can play complementary or synergistic roles. Therefore, the materials and dyes to combine with MSN should be chosen properly, to optimize the coupled diagnostic ability as well as to maximize the therapeutic functions. Upconversion NPs are, in this sense, one of the emerging conjugate materials to illuminate multi-modal imaging capabilities (e.g., CT/MRI with optical imaging) in the MSN-based nanotheranostic systems.

Indeed, MSN-enabled nanotheranostics is a speedily growing promising field. The recent research progress has shed light on the in vitro and in vivo capability of MSN systems, e.g., MRI/optical-imaging of lymph node and tumor suppression in mice, highlighting the possibility of clinical uses. Even so, more studies are necessary, particularly as to those on large animal models with a long-term efficacy, those with more targeted actions to cells, intracellular components and nucleus, and those relevant for clinically uses. Meanwhile, MSNs should always keep eyes on the ongoing development of imaging technologies, new nanomaterials, and drug and genetic engineering, to form optimized nano-theranostic platforms in disease treatments. The joint efforts of the researchers in multidisciplinary fields (chemistry, materials science, biology, and medicine) will strengthen the future of MSN-based nanotheranostics for targeted and personalized treatment of tumors 46



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and intractable diseases.

Acknowledgments This research was supported by the Priority Research Centers Program (2009-0093829) and Global Research Laboratory Program (GRL; 2015032163) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology.

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TOC graphic 19x13mm (600 x 600 DPI)


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