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In this review, we first summarize the recent progress on the synthesis of the small gold nanorods with three different methods. Then, the SPR absorption properties and the surface modification of small gold nanorods were mainly discussed. Finally, we highlight the recent advances of small gold nanorods for a NIR light-mediated multifunctional theranostic platforms, including bio-imaging and cancer therapy.

The synthesis of monodispersed small gold nanorods has attracted much attention for their optical properties and biomedical applications. Many methods have been developed for the synthesis of monodispersed small gold nanorods with different aspect ratios, including the seed-mediated method, the seedless method, and the high-temperature seedless method. The seed mediated method is the typical and more commonly used method for preparing gold nanorods due to the high quality and yield of nanorods, and their tunable size. Generally, two steps are included for the seed-mediated method: the first step is to prepare a small-sized gold seed; the second step is the growth of gold nanorods, which is initiated by the gold seed in the growth solution.

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The size, aspect ratios, and yield can be tuned by controlling the size of the seed, seed amount, and reaction parameters in the growth solution, including surfactant amount, gold precursor concentration, pH value, and so on. The seed-mediated growth method was originated in by Jana et al. First, the citrate-capped gold seed and growth solution which contained cetyltrimethyl ammonium bromide CTAB , acetone, hexane, and water, were prepared separately.

Then, the growth of the gold nanorods was started by adding the freshly-prepared ascorbic acid to the mixture of gold seed and growth solution in the presence of AgNO 3. In , El-Sayed et al. One uses the stronger CTAB stabilizer to cap the gold seed; the other introduced silver nitrate to the gold solution before seed addition to facilitate the rod formation and also tune the aspect ratio.

The seed-mediated method is a typical synthesized method for large size gold nanorods, but it is not very good for Au nanorods smaller than 6 nm. Until now, only several reports use the seed-mediated method to synthesize the small gold nanorods. They are named GmSn, G, and S, referring to the growth solution and the seed solution, respectively; m is the volume of the surfactant solution used in preparing the growth solution, and n is the volume of the seed solution.

They demonstrate that the molar ratio of the seed-to-Au III plays an important effect on the size. When the seed concentration increased in a given growth solution, the size of the obtained gold nanorods will decrease. However, it is difficult to obtain diameters less than 6 nm by this method. For the seedless growth method, no seed preparation step is required for growth of the small-sized gold nanorods, due to nucleation and growth occurring in the same solution. The small gold nanoparticles formed by adding NaBH 4 can play the role of seeds to prepare the gold nanorods [ 43 , 44 ].

The seedless method was discovered by Jana et al. In the CTAB micellar solution of the HAuCl 4 , the strong NaBH 4 and weak ascorbic acid reducing agents were introduced, in which the CTAB micelle was the template for nanorod growth, strong reducing agent was used to generate the seed in the growth solution directly and the weak reducing agent helped the nanoparticles to grow.

They found that if the nucleation kinetics of nanoparticle formation are properly adjusted, the elongated rod-like micelle surface can be a useful template, and the resulting nanoparticles would be highly anisotropic and near-monodisperse.

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However, the nucleation kinetics of nanoparticle formation is difficult to control and the preparation process is accompanied by a large number of spherical gold nanoparticles, resulting in a low yield of gold nanorods. El-Sayed et al. They found that the pH plays a crucial role in the monodispersity of the nanorods when the NaBH 4 concentration of the growth solution was adjusted to control the reduction rate of the gold ions.

The reducing power of ascorbic acid and NaBH 4 decreases with decreasing pH, and the homogeneity of the small gold nanorods increased. The higher concentration of CTAB in the growth solution stabilized initial single crystalline nuclei and decreased the growth of rods more than usual, so the gold nanorods were smaller compared to those prepared at a lower CTAB concentration. In addition, the concentration of silver ions in the growth solution was found to be pivotal in controlling the aspect ratio of the nanorods.

The aspect ratio decreases as the silver ions concentration decreases. By this new method, it is easier to prepare higher yield, high quality, and ultra-small gold nanorods. Typical TEM images of the small gold nanorods obtained by Jana et al. Many groups have reported methods for synthesizing gold nanorods at room temperature. Perez-Juste et al. However, Zijlstra et al. High-temperature gold nanorod synthesis opens the door to resolving two important issues which have not been addressed in the literature so far.

First, ultrafast high-temperature synthesis presents a better system for rapid production of gold nanorods for potential commercial applications. Second, the fact that gold nanorods form at high temperatures suggests that using a thermally-activated reducing agent is possible. Most reports on gold nanorod synthesis utilize NaBH 4 to initiate the formation of gold nanorods [ 39 ].

NaBH 4 reacts with water and has to be used immediately after preparation, which compromises reproducibility. Using a thermally-activated reducing agent would avoid the use of the unstable NaBH 4 , resulting in stock growth solutions that are stable at room temperature. The scale bars indicate 50 nm.

B Particle dimension as obtained from TEM analysis. The error bars represent the error in the mean value of the distribution of the respective dimension. C Evolution of the integrated absorbance vs. The solid lines are sigmoidal fits to the experimental data points [ 44 ]. Even though CTAB is an almost necessary surfactant for the synthesis of the gold nanorods, the high cytotoxity of CTAB limited its application in biochemistry and biomedicine [ 46 ].

Thus, the CTAB must be removed from the surface of the gold nanorods before it is used for bio-applications. Until now, several strategies have been investigated for solving these problems [ 18 , 47 , 48 , 49 , 50 , 51 , 52 ]. Among of them, coating organic or inorganic materials on Au nanorods and replacing the CTAB by thiol-terminated molecules have been proven to be the most effective approaches for improving their biocompatibility.

For the surface coating method, SiO 2 or polymers e. Due to the effective and high hardness of SiO 2 coating, the gold nanorods coated with SiO 2 can not only reduce the toxic effect, but also prevent them from aggregating. In addition, the pores are generated in the SiO 2 coating, and the SiO 2 -coated gold nanorods can also be used for drug delivery [ 47 ]. Bovine serum albumin BSA is one kind of low cost biomacromolecules and is widely used for biomedicine. In order to improve the biocompatibility of the gold nanorods, BSA has also been used to coat the surface of the gold nanorods.

Due to strong thiol binding sites on the BSA, the gold nanorods are easily been coated by the BSA when they mix together. It was easily demonstrated if the BSA was coated on the gold nanorods by the extinction spectra, the absorption maxima of the gold nanorods showed a distinct redshift after being covered by BSA. It have been demonstrated that BSA-coated small gold nanorods exhibit better biocompatibility [ 48 ].

The ligand exchange method is another commonly used method to remove the CTAB on the surface of the gold nanorods. Several studies [ 49 , 50 ] have demonstrated that mercaptoundecanoic acid can replace the CTAB on the Au nanorods effectively. The thiol of the mercaptoundecanoic acid can bind on the Au nanorods firmly via the Au-S bond, while the carboxyl of the mercaptoundecanoic acid can be used to conjugate with other biomolecules, which is beneficial to the application of gold nanorods in biomedicine fields.

However, the low water content of the mercaptoundecanoic acid capped gold nanorods limits its wide usage in bio-applications. Due to the ability of PEG to prevent undesired protein adhesion while at the same time being nontoxic and having good water solubility [ 51 ], the thiol-terminated polyethylene glycol SH-PEG with functional group —NH 2 or —COOH has been widely used in the surface modification of gold nanorods.

Several reports have demonstrated that the PEG-capped gold nanorods can improve biocompatibility effectively and they have been used as imaging and photothermal therapy agents [ 18 , 52 ].

Schematic illustration of the surface modification of small gold nanorods by surface coating and ligand exchange methods. In the field of non-invasive diagnostic and therapeutic fields for cancer, real-time imaging of cancer is a goal that people have been pursuing [ 53 , 54 , 55 ]. Fluorescence imaging as a pure optical imaging technology has been widely used for cancer detection [ 56 , 57 , 58 ].

Even though the sensitivity of fluorescence imaging is very high, most of the fluorescence sensor is based on ultra-violet-visible UV-VIS light [ 59 ] and the low penetration depth limits their applications in vivo. Therefore, it is necessary to find a high-contrast and high-resolution non-destructive medical imaging method. Photoacoustic tomography PAT , which is based on the NIR laser, developed quickly recently as a non-destructive medical imaging method [ 60 , 61 , 62 ], which combines the high contrast characteristics of optical imaging and the high penetration depth characteristics of ultrasound imaging [ 63 , 64 , 65 ].

Photoacoustic PA imaging agents that show strong NIR absorption can effectively improve the contrast and also be investigated widely by the researchers [ 62 ]. Among all of the photoacoustic agents including organic dyes [ 66 ], semiconductors [ 67 , 68 ], and noble metal materials [ 69 , 70 ], gold nanorods are the most widely used as the NIR absorption can be precisely regulated by adjusting the aspect ratio. Pini et al. They tested photostability of different sized Au nanorods by acquiring the PA response at the level of single laser shots Figure 5.

PA signals with good signal-to-noise ratios were recorded from all samples at fluences below the maximal permissible exposure limits. Within this test, Au nanorods suffered from partial reshaping and sublimation or fragmentation, which changed their plasmon bands and limited their value as a PA contrast agent.

However, there is an interesting phenomenon in that smaller nanoparticles provides better stable signals and have tolerate higher fluencies Figure 5 B. These results provide new inspiration and indications for small Au nanorods for specific PA applications in biomedical imaging. Subsequently, Song et al. A Sketch of the setup used for the photoacoustic experiments O, objective; L, focusing lens; BS, beam splitter; EM, energy meter ; B trend of F th as a function of effective nanoparticle radius r eff.

Several types of nanoparticles including gold nanoparticles, carbon nanotubes, and quantum dots [ 75 , 76 ] have been studied for ultrasensitive photothermal imaging applications. However, these nanoparticles have to be excited at their plasmon resonance at around nm which is similar with background signal from endogenous cellular components. The use of gold nanorods as small probes absorbing in the near infrared is a promising strategy for single-particle level detection, as they would combine good subcellular accessibility, low contribution from intrinsic cellular signals, and perfect photostability [ 77 ].

Concerning this, Lounis et al. Photothermal imaging microscopy Figure 6 A is constructed with a two-color excitation beam and a near infrared probe beam that can resonate the nanorods in its transverse or longitudinal plasma resonance. Due to the strong optical absorption tunable from the red to the near infrared, the use of small gold nanorods based on this imaging technology can minimize background signals from the cell organelles. As shown in the Figure 6 B, the cellular mitochondrial structures are clearly visible under nm excitation Figure 6 B b , which complicates the identification of nanorods around the mitochondria at this excitation wavelength.

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By contrast, background signals originating from mitochondria are notably reduced under nm excitation Figure 6 B. In addition, individual nanorods display notably higher PhI signals under nm excitation compared with nm excitation, facilitating their detection in cellular environments. This small gold nanorod-based photothermal imaging microscopy technology will constitute next generation photothermal probes for studying complex molecular dynamics in biological systems owing to their small size, tunable NIR-absorption, absolute photostability, and chemical suitability for surface functionalization and bioconjugation.

A Schematics of the two-color photothermal imaging microscopy with a near infrared probe beam at nm and excitations beam at or nm; B White light a and PhI images of COS 7 cells incubated with nanorods under b and c nm excitation. Photothermal imaging microscopy recorded under red excitation shows very weak mitochondrial background signals compared to those acquired under green excitation [ 78 ].

NIR light — nm for NIR optical imaging [ 79 ] can penetrate several centimeters into tissue, because hemoglobin and water, the primary absorbers of visible and infrared light, experience their lowest absorptions in the NIR region. Thus, NIR-absorbing imaging could offer a potentially non-invasive and real-time characterization method for disease using NIR imaging probes [ 80 ].

Among the reported NIR imaging probes, including quantum dots, fluorescent dye-doped nanoparticles, etc. Haam et al. Consequently, specific targeting of cRGD-PGNRs to the tumor region was observed via a significant increase in the absorption signal high absorbance, blue color that was maintained for 12 h. However, when control cRAD-PGNRs were injected into the tumor-bearing mouse model, the absorption at the tumor site did not change for 12 h.

This method is more efficient and simple to determine the localized surface plasmon resonances LSPR absorption intensity in molecular imaging. NIR laser-driven photothermal therapy, which converts NIR laser energy to heat energy, has attracted much interest due to its minimally invasive and potentially effective results compared with the conventional approaches, such as surgery, radiation therapy, chemotherapy, hormone therapy, immunotherapy, etc. In order to promote the photothermal conversion efficiency and particularly improve laser discrimination for targeted cancers, the photothermal agents are generally indispensable [ 83 , 84 , 85 ].

Among various photothermal therapy agents, the strong absorption properties of the gold nanorods from the visible region to the near-infrared region allows light energy to be efficiently converted to thermal energy under near-infrared laser irradiation, making it possible to perform laser-selective heating at a local range [ 52 , 86 ]. Moreover, the gold nanorods with diameters smaller than 10 nm are dominated by absorption, which could minimize the impact of the scattering cross-section [ 30 , 33 ]. Thus, the small gold nanorod-assisted laser thermal method has great applications in bio-imaging and cancer therapy, which can selectively destroy cancer cells and not damage benign cells [ 87 , 88 ].

Utilizing the prepared absorption-dominant small gold nanorods, Jia et al. They found the internalized number of large Au nanorods was much larger than that of small nanorods in U MG lines. These results indicate that both the particle size and cell type influence the cellular uptake of gold nanorods. The photothermal therapy PTT efficiency per unit amount of the internalized Au nanorods was defined as the cell viability reduction divided by the intracellular Au content in each cell line.

Compared with the values of 0. These results demonstrate that the small Au nanorods show a higher photothermal therapeutic efficacy on these cancer cells than the large Au nanorods at the same internalized Au amount, and suggest that the absorption-dominant small Au nanorods are promising for plasmonic photothermal conversion-based biomedical applications.

The uptake of gold nanorods was observed through dark-field DF microscopy Figure 9 A. A nm NIR laser with power of 5. These results indicated that the AuNRs-NLS can accurately target the nucleus and enhance plasmonic photothermal therapy. Recently, theranostic nanomaterials for real-time diagnosis and cancer PTT has been an attractive method for the treatment of solid tumors as it has the advantages of high efficiency, concurrent accurate diagnosis and efficient in situ therapy of tumors [ 89 ].

However, these imaging-guided therapy patterns still suffer from a low signal to noise ratio [ 90 ]. Based on this background, Zhang et al. The CTAB-coated ultrasmall GNRs were first placed in cysteamine, and a near-infrared dye Cy5 conjugated onto the ultrasmall gold nanorods as the fluorescent component. Cy5 was highly quenched by the GNRs in a normal tissue, while being activated in the tumor cells.

For the existence of glutathione GSH , a highly reactive thiol were found in the cytoplasm of tumor cells. GSH can competitively replace the Cy5 and conjugate with the gold nanorods, and the fluorescence of Cy5 can recover rapidly. The study provided a new strategy for clinical tumor theranostics with image-guided photothermal cancer therapy. Concerning the balance of higher tumor accumulation efficiency and rapid clearance from the body after therapy [ 91 , 92 , 93 ], a vesicle assembled by ultra-small gold nanorods was developed by Chen et al.

The higher temperature will induce irreversible tissue damage, which is necessary for the photothermal therapy. The tracked curative effect Figure 11 D further supports this conclusion, as all the tumors were completely ablated and no reoccurrence was observed when treated with AuNR Ve with a nm laser, compared with the AuNR and laser irradiation group.

The tumor sections stained with hematoxylin and eosin for the AuNR Ve plus laser-treated group showed an intensive necrosis area, while highly pleomorphic nuclei and many mitoses, which are the features of the infiltrating tumor cells, was observed for the PBS or laser-only treatment group. Most importantly, most of the vesicles were cleared from the body after ten days post-injection, due to most of the vesicles being disassembled into single polyethylene glycol-modified Au nanorods as triggered by the hydrolysis of PLGA, which is very essential and beneficial for meeting the requirements of the US Food and Drug Administration [ 94 ].

These results suggest that the newly-developed ultra-small gold nanorod vesicles provide opportunities for further clinical translation. In vivo photothermal ablation of tumor after intravenous injection of Au nanorod vesicles followed by laser irradiation. In order to overcome the drawback that the injected nanoparticles cannot penetrate the tumor mass, leading to incomplete ablation and disease recurrence [ 95 ], the cell-mediated delivery of nanoparticles, which can cross the nearly-impermeable biological barriers to reach many areas in the body [ 96 , 97 , 98 ], was developed to improve agent delivery in vivo and enhance photothermal agent efficiency.

Based on this, the macrophage delivery system was used by Chu et al. They first investigated macrophage uptake, which is important for photothermal conversion. Compared with the commonly used 14 nm diameter gold nanorods, the small gold nanorods showed much higher macrophage uptake and negligible cytotoxicity due to their small size.

The macrophages could deliver small gold nanorods to the entire tumor after intratumoral injection, resulting in photothermal conversion being greatly improved almost everywhere in the tumor, with tumor recurrence rates minimized compared to free BSA-coated small gold nanorods. Their findings not only provided an effective approach to improving photothermal therapy efficiency by delivering the agents to whole tumors, but also expedited the clinical application of nanotechnology for cancer treatment.

A Diagram highlighting the difference between the treatment of free small gold nanorods and macrophage-loaded small gold nanorods; B temperature profile of tumor under nm light irradiation for 10 min; and C growth of tumors in the different groups of mice after the irradiation treatments [ 99 ]. Reduced graphene oxide rGO nanoparticles with a large surface area for drug loading and photothermal effects for photothermal therapy have been widely explored for theranostic applications [ ].

Although rGO can absorb light from the UV to NIR and subsequently release it as heat by nonradioactive decay, the broad absorption spectrum and low quantum efficiency of rGO means that it has relatively low photothermal conversion efficiency [ ]. The nanorod vesicle can avoid rGO-DOX to interact with normal tissue and also enhance the photothermal effect.

Additionally, the inside of a plasmonic metal shell can behave as a cavity where electromagnetic radiation is concentrated, leading to increased light absorption efficiency of the encapsulated rGO [ ]. Schematic illustration of sequential DOX release triggered by i remote NIR laser irradiated photothermal effect and ii acidic environment of the cancer cell [ ]. The safety profile of gold nanorods remains largely undefined. Generally speaking, it is considered biocompatible. Several studies [ , ] have indicated no significant short-term toxicity of gold nanoparticles over three months.

However, there are also some other studies [ ] that have reported that the presence of gold nanoparticles causes cytotoxicity or inflammation in mouse livers [ ]. Particularly, gold nanorods may cause cytotoxicity if they are not completely purified of surfactant CTAB.

Gold nanoparticles enlighten the future of cancer theranostics

Additionally, the ideal agents in diagnosis and therapy should be completely cleared from the human body within a reasonable period. Therefore, it is essential to understand the organ uptake, biodistribution, longer-term fate, and toxicity of AuNRs, and to provide a strong framework for their clinic translation. The histopathology of tissues from the liver, spleen, lung, and kidney of mice was evaluated by a pathologist at one month and 15 months after single intravenous injection of AuNR PEG.

There were no histopathological abnormalities in any of the mouse organs. AuNRs PEG remained inside the cells without any structure over a long period, from visual observation of the organ tissue microstructure. During the whole treatment, gold nanorods accumulated in mouse organs without any evidence of toxicities. Similarly, Yu et al. Therefore, small-sized gold nanorods are more suitable for in vivo imaging and tumor therapy. The unique surface plasma optical properties and their ultra-small size make ultra-small gold nanorods able to be widely used in the bio-imaging and cancer treatment.

At the same time, ultra-small gold nanorod synthesis, surface modification, and functional applications have also made great progress. However, two aspects still need to be further improved: first, the yield of ultra-small gold nanorods needs to be improved, which may require further understanding of the process of growth of gold nanorods in solution; and, second, the extinction coefficient, which is related with the photothermal conversion efficiency, of small gold nanorods prepared by the seedless method is smaller than those prepared using the seeded technique.

Thus, it is necessary to develop new methods to modify the small gold nanorods, thus, obtaining higher extinction coefficients and subsequently higher photothermal conversion efficiencies, which is of benefit to cancer treatment. With the advancement of modern science and technology, greater drawbacks for small gold nanorods will be overcome. We believe that the clinical application of small gold nanorods will be achieved in the future.

National Center for Biotechnology Information , U. Journal List Materials Basel v. Materials Basel. Published online Nov Author information Article notes Copyright and License information Disclaimer. Received Oct 20; Accepted Nov This article has been cited by other articles in PMC. Abstract Over the past few decades, the synthetic development of ultra-small nanoparticles has become an important strategy in nano-medicine, where smaller-sized nanoparticles are known to be more easily excreted from the body, greatly reducing the risk caused by introducing nano-theranostic agents.

Keywords: small gold nanorods, seedless, biological imaging, cancer therapy. Introduction In recent years, near-infrared light-mediated multifunctional platforms based on inorganic nanomaterials for cancer diagnosis and treatment have been explored widely [ 1 , 2 , 3 ], including carbon [ 4 , 5 , 6 ], semiconductors [ 7 , 8 , 9 ], and noble metals [ 10 , 11 , 12 , 13 ]. Synthesis of Small Gold Nanorods The synthesis of monodispersed small gold nanorods has attracted much attention for their optical properties and biomedical applications. Seed-Mediated Method The seed mediated method is the typical and more commonly used method for preparing gold nanorods due to the high quality and yield of nanorods, and their tunable size.

Open in a separate window. Figure 1. Figure 2. High-Temperature Seedless Method Many groups have reported methods for synthesizing gold nanorods at room temperature. Figure 3. Ligand Exchange Method The ligand exchange method is another commonly used method to remove the CTAB on the surface of the gold nanorods. Figure 4. Biological Imaging In the field of non-invasive diagnostic and therapeutic fields for cancer, real-time imaging of cancer is a goal that people have been pursuing [ 53 , 54 , 55 ]. Photoacoustic Imaging Photoacoustic tomography PAT , which is based on the NIR laser, developed quickly recently as a non-destructive medical imaging method [ 60 , 61 , 62 ], which combines the high contrast characteristics of optical imaging and the high penetration depth characteristics of ultrasound imaging [ 63 , 64 , 65 ].

Figure 5. Figure 6.

NIR-Absorbing Imaging NIR light — nm for NIR optical imaging [ 79 ] can penetrate several centimeters into tissue, because hemoglobin and water, the primary absorbers of visible and infrared light, experience their lowest absorptions in the NIR region. Figure 7. Cancer Therapy 5. Photothermal Therapy NIR laser-driven photothermal therapy, which converts NIR laser energy to heat energy, has attracted much interest due to its minimally invasive and potentially effective results compared with the conventional approaches, such as surgery, radiation therapy, chemotherapy, hormone therapy, immunotherapy, etc.

Figure 8. Figure 9. Image-Guided Photothermal Therapy Recently, theranostic nanomaterials for real-time diagnosis and cancer PTT has been an attractive method for the treatment of solid tumors as it has the advantages of high efficiency, concurrent accurate diagnosis and efficient in situ therapy of tumors [ 89 ]. Figure Cell-Mediated Photothermal Therapy In order to overcome the drawback that the injected nanoparticles cannot penetrate the tumor mass, leading to incomplete ablation and disease recurrence [ 95 ], the cell-mediated delivery of nanoparticles, which can cross the nearly-impermeable biological barriers to reach many areas in the body [ 96 , 97 , 98 ], was developed to improve agent delivery in vivo and enhance photothermal agent efficiency.

Photothermal-Chemo Combination Therapy Reduced graphene oxide rGO nanoparticles with a large surface area for drug loading and photothermal effects for photothermal therapy have been widely explored for theranostic applications [ ]. Cytotoxicity and Metabolizable Ability of Small Gold Nanorods The safety profile of gold nanorods remains largely undefined. Future Challenges and Prospects The unique surface plasma optical properties and their ultra-small size make ultra-small gold nanorods able to be widely used in the bio-imaging and cancer treatment.

Conflicts of Interest The authors declare no conflict of interest. References 1. Gao Z. Tumor microenvironment-triggered aggregation of antiphagocytosis 99m Tc-labeled Fe 3 O 4 nanoprobes for enhanced tumor imaging in vivo. ACS Nano.

Polymeric Nanoparticles Loaded with Organic Dye for Optical Bioimaging in Near-Infrared Range

Cheng L. Functional nanomaterials for phototherapies of cancer. Liu Z. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Cite this article: Lee I. Yolk-shell structure for upconverting nanoparticles: Bioimaging, drug delivery, and photodynamic therapy. J Nanomed. Upconverting Nanoparticle UCNP has recently received many attentions from theranostics and nanomedicine fields because it can be designed for multi-functional targeted nanomedicines with multi-modal imaging. Lantanides doping enhances upconversion luminescence and enable magnetic resonance imaging.

In addition IR-regulating drug release reaches deep without harm. Core-shell nanostructures have been applied for the most of UCNP applications, but the therapeutic efficacy is still far away from the desired levels in nanomedicine. Thicker shell is better for higher loading, but a bigger particle size is unavoidable. Second, only outer shell surface is offered for surface modifications to specific binding or properties, which is critical of targeted therapy. In addition, both inner and outer surfaces can be modified as any desired purposes.

Third, the movable yolk UCNP has more chance to contact with photo triggers and photosensitizers in the void. All the benefits with yolk-shell structure are resulted in high therapeutic efficacy. In this mini review, some of yolk-shell UCNP examples are introduced for in vivo multimodal bioimaging with high contrast, IR-regulated drug release, and high efficacy in photodynamic therapy. Recently upconverting nanoparticle UCNP has been one of promising platforms, where nanomedicine meets theranostics and improves its therapeutic level. UCNPs exhibit the photon upconversion that convert two incident lower energy photons to one higher energy photon [2].

They are commonly composed of lanthanide or actinide-doped transition metals, because they have multiple 4f electrons with long enough excitations for upconversion [2]. Ytterbium-erbium or ytterbium-thulium are sensitizers and doped to NaLnF 4 nanoparticles for absorbing infrared IR and releasing visible Vis or ultraviolet UV light [2,5,6]. Their synthesis has been already reviewed in many literatures [1,4,7]. For the practical applications such as water soluble or binding to functional groups, core UCNPs need to be coated with inorganic materials or capping polymers [8,9].

UCNP silica core-shell nanostructure is one of popular forms because of easy preparation [10], water-soluble, and biocompatible features. Titania, [11] drug-conjugated, [12] and capping ligands [13] are also available for the shell materials. No matter what the material is, the main challenge would be the loading ability to deliver drugs, photo triggers, or photosensitizers to targets. The therapeutic efficacy with core-shell nanostructures is limited by the loading space in the shell. Simply thicker shell or larger dose is required for higher loading, but a bigger particle size or any side effect caused by heavy doses would be inevitable.

Figure 5: Graphical Abstract. First, the void can be filled with anything to deliver or carry. It is a much larger amount than any loading in core-shell structures. Second, both inner and outer surfaces can be modified as desired e. It is quite useful when keeping undesired chemicals inside of the shell, but releasing drugs only to outside targets.

Core-shell has an option at outer surface only. Third, yolk is movable and can have more chance of contact with anything in void. For the applications in nanomedicine, UCNP is commonly placed at yolk position, and mesoporous silica has been one of frequent materials for shell. Photo trigger-conjugated drug or photosensitize can be stored in both void and pores of shell, which are better than only pores of core-shell structure. In addition, much higher energy transfer efficiency in photodynamic therapy is available with movable UCNP yolk.

Both inner and outer surfaces of shell are modified with desired surface properties, or tethered to any specific binding to tumor or cancer cell surfaces. When UCNPs meet yolk-shell nanostructure, theranostics can be achieved as multimodal imaging, target specificity, and multifunctional therapeutic properties. Radiotherapy and chemotherapy have been widely used in cancer treatments [17,18].

However, radiotherapy fails to eradicate hypoxic tumors and high doses of irradiation unavoidably because damage to normal cells [19]. Chemotherapy is limited for drug resistant cells [20]. Its efficacy may be improved by high doses, but side effects would cause other diseases. In photodynamic therapy, [21,22] cytotoxic singlet oxygen 1 O 2 can be more efficient at killing cancer cells, as it inhibits DNA repair and elicits to cell death.

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In addition, NIR lights penetrate deeply into tissues with no harm. In this mini review, only some of selected UCNP examples built in yolk-shell nanostructures are introduced to prospect for practical applications in nanomedicine. Chlorambuchil drug release is regulated by IR light and amino-coumarin phototrigger [24]. Various technologies using ultrasonic, optical, luminescent, magnetic, or X-ray sources are available for bioimaging. Recently rare-earth UCNPs have being considered as promising fluorescent imaging probes [26]. In addition, neither harm nor auto fluorescence in bioimaging.

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MRI has a much deeper penetration depth and a much better contrast. If magnetization recovers before MR measurement, the image weighting is denoted by T 1. If it decays before the measurement, that is denoted by T 2. Tumor signal is high in T 2 -weighted, but low in T 1 -weighted MR images [27]. CT images are preferred when high special resolution is required [28]. Figure 1 shows one of examples [32]. High signal intensity at the tumor site indicates not only targeting folate receptors in HeLa tumor cells [33], but also enhanced MRI.

Reproduced with permission from ref. Zhu et al. Fe 3 O 4 nanoparticles are yolks for the magnetic manipulation without shielding UCL signal. High contrast of tumor area was also observed well in volume-rendered and coronal CT images. Volume rendering is a computer technique to get a 2-D projection of a 3-D sample. Trimodal imaging is applicable with yolk-shell structured UCNPs, although further research is required for smaller particle sizes, better sensitivity and deeper penetration depth. Drug release can be triggered by photolysis, [34] pH responses, [35,36] redox, [37] enzymes [38] or temperature [39].

Among them, NIR light trigger using UCNPs has been succeeded in drug delivery with convenient manipulation and improved therapeutic efficacy. Traditional photo-regulated drug release uses UV light, which has a shorter penetration depth and is harmful to living tissues. Zhao et al.

Lipase is blocked by the mesoporous shell, hence enzymolysis is not allowed in yolkshell nanostructures. Amino-coumarin is the phototrigger that releases chlorambuchil an anticancer drug, denoted as ACCh upon photolysis under UV adsorption at nm. The phototrigger has hydrophobic two octanyl chains, which prevent from being released together with the drug.

Without light, the drug release stops. Kunming mice bearing S tumor were used for photo-regulated drug delivery experiments. UCNPs can be applied for photodynamic therapy using photosensitizers under NIR light to produce cytotoxic singlet oxygen 1 O 2 that treat tumor cells in both in vivo and vitro. One of challenges for practical use is the efficacy of PDT, which depends on the efficiency of energy transfer from UCNPs to photosensitizers. Lu et al. H human lung cancer cells were used to evaluate in vitro PDT efficacy.