**6. Hybrid nanostructures for biomedical diagnosis and therapy**

### **6.1. Plasmonic-magnetic hybrid nanostructures**

Magnetic nanoparticles with unique magnetic properties are a direct consequence of the behaviour of electrons within the particle. The electrons are similar to tiny bar magnets, with a surrounding magnetic field that corresponds to the electron spin in an applied field. When electrons move between different energy levels, they absorb energy and can generate light or heat.[13] Because of their low toxicity and good sensitivity, the magnetic particles conjugated with biomolecules are widely studied and applied in biomedicine, where these particles are used as magnetic carriers that could travel to targeted cancer tumors under orientation of an external magnetic field. The magnetic carriers then absorb externally magnetical energy and convert them to heat to kill the cancer cells. Magnetic resonance imaging (MRI) is presently one of the most powerful diagnosis tools for imaging the central nervous system and for detecting tumors and cancer cells. The paramagnetic gadolinium chelate complexes (e.g., Gd-DTPA) were widely used for MRI contrast agents.[70] The porous/hollow iron oxide nanocapsules made by wrap-bake-peel process from FeOOH nanorods via silica coating were used for this goal.[14]

The plasmonic-magnetic nanohybrids retain plasmonic properties and strong response to magnetic fields, where scattering of the plasmon alongside with magnetic contrast could be envisioned. Many researchers have recently developed the plasmonic-magnetic nanohybrids to improve the contrasting abilities with extra functions. As a typical material for cancer diagnostics and therapeutics, the Au/Fe3O4 nanohybrids as a bifunctional probe offer two functional surfaces for attachment of the plasmonic and magnetic particles.[71] The Au and Fe3O4 particles both in a hybrid system are known to be highly compatible with biomedicine and a consequence of extending for diagnostics and therapeutics. The Au and Fe3O4 interfaces result in drastically change the local electronic structure, leading to an enhancement of their synergistic properties. The plasmonic and magnetic properties of the nanohybrids could be optimized by adjusting the size of the two particles. In comparison with the single Au and Fe3O4 particles, the Au/Fe3O4 hybrids possessing simultaneous plasmonic and magnetic detection facilitate for cancer diagnosis and therapy. When the biomolecules-conjugated Au/Fe3O4 hybrids are dispersed in body, they could travel to the targeted cancer tumors by influence of external magnetic field. The Au and Fe3O4 particles in the hybrid system adsorb energy from irradiating laser light and from exposing external magnetic field, respectively, and convert them into heat to kill the cancer cells. By using these bifunctional materials, an abundant amount of synergistic heating within the cancer tumors is created by a simultaneous adsorption-conversion of Au and Fe3O4 species facilitating the heating of the cancer cells.

328 Practical Applications in Biomedical Engineering

The gold species conjugated to antibodies can be selectively targeted to cancer cells without significant binding to healthy cells. In general, the routes to nanoparticle delivery are mainly based on an "active" mechanism and a "passive" mechanism.[67] In the active mode, the molecule ligands of antibodies, DNA, and peptides are used to recognize specific receptors on the tumor cell surface. In the passive mode, the nanoparticles without targeting ligands are accumulated and retained in the tumor interstitial space mainly. In both mechanisms, the nanoparticles in the bloodstream must first move across the tumor blood vessels. Some reports were used PEG ligand to attach the lysine-capped Au nanoparticles through lysineterminated PEG link.[68] The targeted delivery of the gold nanoparticles to solid tumors is one of the most important and challenging problems in cancer nanomedicine. It was recently observed that the colloidal gold nanoparticles were found in dispersed and aggregated forms within the cell cytoplasm and provided anatomic labeling information. The anti-EGFR antibody-conjugated nanoparticles homogeneously bind to the surface of the cancer type cells with greater affinity than to the noncancerous cells. These results were detected by using SPR scattering imaging and SPR absorption spectroscopy, in which a relatively sharper SPR absorption band with a red shifted maximum compared to that observed on noncancerous cells.[69] We recently reviewed the aqueous-based synthetic

pathways of the metal nanocrystals potential in biomedical applications.[67]

**6.1. Plasmonic-magnetic hybrid nanostructures** 

nanorods via silica coating were used for this goal.[14]

**6. Hybrid nanostructures for biomedical diagnosis and therapy** 

Magnetic nanoparticles with unique magnetic properties are a direct consequence of the behaviour of electrons within the particle. The electrons are similar to tiny bar magnets, with a surrounding magnetic field that corresponds to the electron spin in an applied field. When electrons move between different energy levels, they absorb energy and can generate light or heat.[13] Because of their low toxicity and good sensitivity, the magnetic particles conjugated with biomolecules are widely studied and applied in biomedicine, where these particles are used as magnetic carriers that could travel to targeted cancer tumors under orientation of an external magnetic field. The magnetic carriers then absorb externally magnetical energy and convert them to heat to kill the cancer cells. Magnetic resonance imaging (MRI) is presently one of the most powerful diagnosis tools for imaging the central nervous system and for detecting tumors and cancer cells. The paramagnetic gadolinium chelate complexes (e.g., Gd-DTPA) were widely used for MRI contrast agents.[70] The porous/hollow iron oxide nanocapsules made by wrap-bake-peel process from FeOOH

The plasmonic-magnetic nanohybrids retain plasmonic properties and strong response to magnetic fields, where scattering of the plasmon alongside with magnetic contrast could be envisioned. Many researchers have recently developed the plasmonic-magnetic nanohybrids to improve the contrasting abilities with extra functions. As a typical material for cancer diagnostics and therapeutics, the Au/Fe3O4 nanohybrids as a bifunctional probe offer two functional surfaces for attachment of the plasmonic and magnetic particles.[71] **Figure 8** shows the use of S6 aptamer-conjugated plasmonic-magnetic Au-Fe3O4 nanohybrids for the targeted diagnosis, isolation, and photothermal destruction of human breast cancer cells.[72] Cy3-modified S6 aptamers were attached to magnetic/plasmonic nanoparticles through -SH linkage. In the multifunctional nanoparticles, gold plasmonic shells were used as both a photothermal agent and a nanoplatform; the magnetic core was used for cell isolation. The S6 aptamer-conjugated magnetic/plasmonic nanoparticles attached to the cancer cells due to the S6 aptamer-cancer cell interaction. The bioconjugated magnetic/plasmonic nanoparticles highly selectively bind to the cells, which can be used for targeted imaging and magnetic separation of a specific kind of cell from a mixture of different cancer cells. The photothermal destruction results showed a selective irreparable cellular damage to most of the cancer cells, due to the absorption of 670 nm continuous NIR irradiation of the hybrid nanostructures.

Sun et al.[10] was achieved the thermolysis of Fe(CO)5 on the surface of the Au nanoparticles in octadecene to produce Au-Fe3O4 dumbbells followed by coupling with Herceptinand Pt complex. The cisplatin complex was linked to Au surface by reacting Au-S-CH2CH2N(CH2COOH)2 with cisplatin. The coating of Herceptin antibody on Fe3O4 particles was performed by PEG3000-CONH-Herceptin. Cisplatin-Au-Fe3O4-Herceptin nanohybrids were tested to HER2-positive breast cancer cells and HER2-negative breast cancer cells. The cisplatin-Au-Fe3O4-Herceptin hybrids revealed a high efficiency in the killing of HER2 positive cancer cells. The presence of the hollow inside the nanohybrids was witnessed as an efficient carrier for targeted delivery and controlled release of cisplatin. These materials illustrated the possibility of acting as a multifunctional platform for target-specific platin delivery. Besides, other plasmon-magnetic materials of FePt/Fe2O3 yolk-shells[6] and mesoporous silica-coated Au-Fe3O4 core shells[73] were also synthesized and extensively studied for strong MRI contrast agent enhancement and carriers for anticancer drug delivery.

Functional Inorganic Nanohybrids for Biomedical Diagnosis 331

brightness, resistance to photobleaching, and broad absorption spectra for simultaneous excitation of multiple fluorescence colours. In order to establish the utility of the quantum dots for biological sensing application, the quantum dots are injected into desired cells of animals (e.g., mouse), emitted green and red labels are spectrally resolved to the eye clearly under the excitation of a single light source by a laser scanning microscope. For example, Liu et al.[74] used the synthesized triantennary dendritic galactoside-capped ZnS/CdSe nanohybrids as a hydrophilic, fluorescent, multivalent probe for detecting metastatic lung cancer cells. The water-soluble nanohybrids were selectively uptaken by lung cancer cells enriched with membrane-bound asialoprotein receptors. The results suggested the stronger interaction between polyhydroxylended nanohybrids in the membrane composition and cancer cells.

Nevertheless, the use of the quantum dots for biosensor application still has some limitations. Namely, the quantum dots are frequently emitted at UV and visible regions, meanwhile biological samples (water and tissues) also induce autofluorescence by the absorption of ultraviolet and visible light, possibly leading to an inexact diagnosis. Moreover, if the biological samples are prolonged exposure to UV radiation, it would cause the photo-damage and mutation. Therefore, the use of the quantum dots emitted in the near-infrared spectrum is an alternative approach for the imaging of tumour structures in vivo. The fluorescent emission peaks of these desired nanoparticles are in the low-energy NIR (800-1000 nm), distant from the typical UV-vis spectrum (400-600 nm) of tissue autofluorescence. This unique properties of the near-infrared quantum dots makes probes easily recognisable under near-infrared light, even in the tissues with high fluorescent

To overcome this barrier, one novel approach is based on the conjugation of two components in a fluorescent particle. The fluorescent emission peaks of the quantum dots could be shifted from ultraviolet to near-infrared region, arising from particle-particle interface. Because the quantum dots did not show the magnetism, consequently, the quantum dots coupled with superparamagnetic particles could provide the two-in-one multimodal fluorescent-magnetic nanohybrids, which could act as multi-targeting, multifunctional and multi-treating tools. The bifunctional magnetic-fluorescent nanoprobe allows for a preoperative diagnosis via MRI owing to the magnetic-fluorescent properties. They ally the high sensitivity and resolution of the fluorescence phenomenon to the high spatial resolution and noninvasiveness of MRI. Furthermore, the interaction between quantum dots

and magnetic particles could result in NIR fluorescent emission of the nanohybrids.

Visual sorting and manipulation of tumor cells through using fluorescent-magneticbiotargeting multifunctional nanobioprobes were reported by Pang et al.[75] Avidinconjugated fluorescent CdSe/ZnS-magnetic γ-Fe2O3 nanohybrids synthesized were used to perform detection and extraction of multiple types of cancer cells via high affinity between antigens and antibodies. **Figure 9** presents the synthetic procedure for these materials. CdSe/ZnS and γ-Fe2O3 were coupled together in the chloroform/butanol suspension containing hydrazine-treated poly-(styrene/acrylamide) copolymer. Avidin-coupled fluorescent-magnetic nanohybrids were then obtained by incubating aldehyde-containing

background.

**Figure 8.** Plasmonic-magnetic Au-Fe3O4 shell cores for targeted diagnostics, isolation, and photothermal destruction of tumor cells. (a) Scheme showing the synthesis of S6 aptamer-conjugated core shells. (b) Scheme showing the separation of breast cancer cells using S6 aptamer-conjugated plasmonic-magnetic nanoparticles. (c) Scheme showing the selective uorescence imaging and targeted photothermal destruction of breast cancer cells. Reproduced with permission from ref. [72]. Copyright 2012, American Chemical Society.

#### **6.2. Fluorescent-magnetic hybrid nanostructures**

In comparison with conventional organic dyes and fluorescent proteins, the quantum dots have unique optoelectronic properties with size-tunable light emission, superior signal brightness, resistance to photobleaching, and broad absorption spectra for simultaneous excitation of multiple fluorescence colours. In order to establish the utility of the quantum dots for biological sensing application, the quantum dots are injected into desired cells of animals (e.g., mouse), emitted green and red labels are spectrally resolved to the eye clearly under the excitation of a single light source by a laser scanning microscope. For example, Liu et al.[74] used the synthesized triantennary dendritic galactoside-capped ZnS/CdSe nanohybrids as a hydrophilic, fluorescent, multivalent probe for detecting metastatic lung cancer cells. The water-soluble nanohybrids were selectively uptaken by lung cancer cells enriched with membrane-bound asialoprotein receptors. The results suggested the stronger interaction between polyhydroxylended nanohybrids in the membrane composition and cancer cells.

330 Practical Applications in Biomedical Engineering

2012, American Chemical Society.

**6.2. Fluorescent-magnetic hybrid nanostructures** 

**Figure 8.** Plasmonic-magnetic Au-Fe3O4 shell cores for targeted diagnostics, isolation, and

photothermal destruction of tumor cells. (a) Scheme showing the synthesis of S6 aptamer-conjugated core shells. (b) Scheme showing the separation of breast cancer cells using S6 aptamer-conjugated plasmonic-magnetic nanoparticles. (c) Scheme showing the selective uorescence imaging and targeted photothermal destruction of breast cancer cells. Reproduced with permission from ref. [72]. Copyright

In comparison with conventional organic dyes and fluorescent proteins, the quantum dots have unique optoelectronic properties with size-tunable light emission, superior signal Nevertheless, the use of the quantum dots for biosensor application still has some limitations. Namely, the quantum dots are frequently emitted at UV and visible regions, meanwhile biological samples (water and tissues) also induce autofluorescence by the absorption of ultraviolet and visible light, possibly leading to an inexact diagnosis. Moreover, if the biological samples are prolonged exposure to UV radiation, it would cause the photo-damage and mutation. Therefore, the use of the quantum dots emitted in the near-infrared spectrum is an alternative approach for the imaging of tumour structures in vivo. The fluorescent emission peaks of these desired nanoparticles are in the low-energy NIR (800-1000 nm), distant from the typical UV-vis spectrum (400-600 nm) of tissue autofluorescence. This unique properties of the near-infrared quantum dots makes probes easily recognisable under near-infrared light, even in the tissues with high fluorescent background.

To overcome this barrier, one novel approach is based on the conjugation of two components in a fluorescent particle. The fluorescent emission peaks of the quantum dots could be shifted from ultraviolet to near-infrared region, arising from particle-particle interface. Because the quantum dots did not show the magnetism, consequently, the quantum dots coupled with superparamagnetic particles could provide the two-in-one multimodal fluorescent-magnetic nanohybrids, which could act as multi-targeting, multifunctional and multi-treating tools. The bifunctional magnetic-fluorescent nanoprobe allows for a preoperative diagnosis via MRI owing to the magnetic-fluorescent properties. They ally the high sensitivity and resolution of the fluorescence phenomenon to the high spatial resolution and noninvasiveness of MRI. Furthermore, the interaction between quantum dots and magnetic particles could result in NIR fluorescent emission of the nanohybrids.

Visual sorting and manipulation of tumor cells through using fluorescent-magneticbiotargeting multifunctional nanobioprobes were reported by Pang et al.[75] Avidinconjugated fluorescent CdSe/ZnS-magnetic γ-Fe2O3 nanohybrids synthesized were used to perform detection and extraction of multiple types of cancer cells via high affinity between antigens and antibodies. **Figure 9** presents the synthetic procedure for these materials. CdSe/ZnS and γ-Fe2O3 were coupled together in the chloroform/butanol suspension containing hydrazine-treated poly-(styrene/acrylamide) copolymer. Avidin-coupled fluorescent-magnetic nanohybrids were then obtained by incubating aldehyde-containing

Functional Inorganic Nanohybrids for Biomedical Diagnosis 333

fluorescence imaging probes, along with their potential as drug delivery vehicles made them

The surface functionalization of the nanohybrids consisted of a polymer-coated maghemite superparamagnetic core and a CdSe/ZnS quantum dot shell, with anticycline E antibodies was permitted the separation of MCF-7 breast cancer cells from serum solution. The surface immobilised anticycline E antibodies bound specifically to cyclin, a protein which is expressed on the surface of breast cancer cells. The separated cells were monitored by fluorescence imaging microscopy, due to the strong luminescence of these nanohybrids.[42] An interesting external magnetic motor effect on floating cells, treated with fluorescentmagnetic nanocomposites, was reported by Lee et al.[77] In an another report, CdS:Mn/ZnS fluorescent-magnetic core-shells were prepared by using water-in-oil microemulsion. The peptide-conjugated fluorescent-magnetic core-shells possessing fluorescent, radio-opacity, and paramagnetic properties were used to label and visualise brain tissue without manipulating the blood-brain-barrier. The fluorescent visualisation of the whole rat brain was achieved using a simple low power handheld UV lamp, indicating that these materials

**Figure 10.** In vivo photodynamic therapy using mesoporous silica-coated NaYF4:Yb,Er upconversion fluorescent nanoparticles (UCNs) as remote-controlled nanotransducers. (a) TEM image of the

mesoporous silica-coated UCNs, scale bar = 100 nm. (b) Change in tumor size as a function of time after treatment to assess the effectiveness of UCN-based mediated targeted PDT in tumor-bearing mice intravenously injected with folic acid (FA)-PEG-UCNs. (c) Photograph showing showing UCN-based targeted conventional photodynamic therapy (PDT) in a mouse model of melanoma injected with UCNs surface modified with FA and PEG moieties. Reproduced with permission from ref. [82].

One of the main problems in the preparation of the fluorescent-magnetic nanohybrids is the risk of quenching of the fluorophore on the surface of the particle by the magnetic core. This quenching process could be occurred because of the fluorophore contact with the particle surface, resulting in an energy transfer process. The problem of quenching can be partially resolved by coating of a stable shell (e.g., coating of a thin silica layer) on the magnetic nanoparticles prior to the introduction of the fluorescent molecules. As a proof-of-concept, Ying et al.[79] employed the silanization in a reverse microemulsion to produce a thin silica coating on the bare quantum dots or magnetic particles with surface NH2 groups. The

novel candidates for simultaneous cancer diagnosis and therapy.

are potentially applicable for advanced multimodal detection.[78]

Copyright 2012, Nature.

**Figure 9.** Fluorescent-magnetic biotargeting nanobioprobes for detecting and isolating tumor cells. (a) Scheme of avidin-coupled fluorescent-magnetic nanohybrids. Fluorescent-magnetic nanohybrids were covalently coupled with avidin and then coated with biotinylated goat anti-mouse IgG via biotin-avidin interaction. Mouse monoclonal antibody (mAb) was then attached to the nanohybrids via binding to goat antibody; (b) Fluorescence microscopic images of anti-CD3 mAb-coupled red nanobioprobes; (c) Anti-prostate-specific membrane antigen mAb-coupled yellow nanobioprobes. Reproduced with permission from ref. [75]. Copyright 2011, American Chemical Society.

avidin with fluorescent-magnetic nanohybrids. The authors demonstrated that the avidincoupled fluorescent-magnetic nanobioprobes detected and extracted two different types of tumor cells from complex samples containing both normal cells and the target cancer cells and the capture efficiencies were of about 96% and 97%, respectively. Upon exposing magnet and fluorescence microscopes, these multifunctional materials were sensitively detect and isolate target tumor cells at low concentration of 0.01% in the mixed cells. Shi et al. [76] synthesized fluorescent-magnetic nanospheres by co-embedding quantum dots and magnetite nanoparticles into hydrazide-functionalized copolymer nanospheres followed by coupled on the surface with IgG, avidin and biotin to form the fluorescent-magnetic bio-targeting trifunctional nanospheres. The nanoscale biocomposites can selectively link to apoptotic cells, allowing their visualisation and isolation. The fluorescent-magnetic particles were inert with respect to cell proliferation and tumour formation and served as both a negative contrast agent for in vivo MRI, as well as a fluorescent tumour marker for optical imaging in vivo and in vitro. The multifunctional capability of the nanocomposite nanoparticles as MRI and fluorescence imaging probes, along with their potential as drug delivery vehicles made them novel candidates for simultaneous cancer diagnosis and therapy.

332 Practical Applications in Biomedical Engineering

**Figure 9.** Fluorescent-magnetic biotargeting nanobioprobes for detecting and isolating tumor cells. (a) Scheme of avidin-coupled fluorescent-magnetic nanohybrids. Fluorescent-magnetic nanohybrids were covalently coupled with avidin and then coated with biotinylated goat anti-mouse IgG via biotin-avidin interaction. Mouse monoclonal antibody (mAb) was then attached to the nanohybrids via binding to goat antibody; (b) Fluorescence microscopic images of anti-CD3 mAb-coupled red nanobioprobes; (c) Anti-prostate-specific membrane antigen mAb-coupled yellow nanobioprobes. Reproduced with

avidin with fluorescent-magnetic nanohybrids. The authors demonstrated that the avidincoupled fluorescent-magnetic nanobioprobes detected and extracted two different types of tumor cells from complex samples containing both normal cells and the target cancer cells and the capture efficiencies were of about 96% and 97%, respectively. Upon exposing magnet and fluorescence microscopes, these multifunctional materials were sensitively detect and isolate target tumor cells at low concentration of 0.01% in the mixed cells. Shi et al. [76] synthesized fluorescent-magnetic nanospheres by co-embedding quantum dots and magnetite nanoparticles into hydrazide-functionalized copolymer nanospheres followed by coupled on the surface with IgG, avidin and biotin to form the fluorescent-magnetic bio-targeting trifunctional nanospheres. The nanoscale biocomposites can selectively link to apoptotic cells, allowing their visualisation and isolation. The fluorescent-magnetic particles were inert with respect to cell proliferation and tumour formation and served as both a negative contrast agent for in vivo MRI, as well as a fluorescent tumour marker for optical imaging in vivo and in vitro. The multifunctional capability of the nanocomposite nanoparticles as MRI and

permission from ref. [75]. Copyright 2011, American Chemical Society.

The surface functionalization of the nanohybrids consisted of a polymer-coated maghemite superparamagnetic core and a CdSe/ZnS quantum dot shell, with anticycline E antibodies was permitted the separation of MCF-7 breast cancer cells from serum solution. The surface immobilised anticycline E antibodies bound specifically to cyclin, a protein which is expressed on the surface of breast cancer cells. The separated cells were monitored by fluorescence imaging microscopy, due to the strong luminescence of these nanohybrids.[42] An interesting external magnetic motor effect on floating cells, treated with fluorescentmagnetic nanocomposites, was reported by Lee et al.[77] In an another report, CdS:Mn/ZnS fluorescent-magnetic core-shells were prepared by using water-in-oil microemulsion. The peptide-conjugated fluorescent-magnetic core-shells possessing fluorescent, radio-opacity, and paramagnetic properties were used to label and visualise brain tissue without manipulating the blood-brain-barrier. The fluorescent visualisation of the whole rat brain was achieved using a simple low power handheld UV lamp, indicating that these materials are potentially applicable for advanced multimodal detection.[78]

**Figure 10.** In vivo photodynamic therapy using mesoporous silica-coated NaYF4:Yb,Er upconversion fluorescent nanoparticles (UCNs) as remote-controlled nanotransducers. (a) TEM image of the mesoporous silica-coated UCNs, scale bar = 100 nm. (b) Change in tumor size as a function of time after treatment to assess the effectiveness of UCN-based mediated targeted PDT in tumor-bearing mice intravenously injected with folic acid (FA)-PEG-UCNs. (c) Photograph showing showing UCN-based targeted conventional photodynamic therapy (PDT) in a mouse model of melanoma injected with UCNs surface modified with FA and PEG moieties. Reproduced with permission from ref. [82]. Copyright 2012, Nature.

One of the main problems in the preparation of the fluorescent-magnetic nanohybrids is the risk of quenching of the fluorophore on the surface of the particle by the magnetic core. This quenching process could be occurred because of the fluorophore contact with the particle surface, resulting in an energy transfer process. The problem of quenching can be partially resolved by coating of a stable shell (e.g., coating of a thin silica layer) on the magnetic nanoparticles prior to the introduction of the fluorescent molecules. As a proof-of-concept, Ying et al.[79] employed the silanization in a reverse microemulsion to produce a thin silica coating on the bare quantum dots or magnetic particles with surface NH2 groups. The silanized particles were conjugated to oleyl-O-poly(ethylene glycol)succinyl-Nhydroxysuccinimidyl ester through binding of the surface amine groups with heterofunctional polyethylene glycol. The biocompatible silica-coated can effectively target the cell membranes of HepG2 human liver cancer cells, NIH-3T3 mouse fibroblast cells, and 4T1 mouse breast cancer cells. These results demonstrated that these materials have potential for drug loading and delivery into cancer cells to induce cell death.

Functional Inorganic Nanohybrids for Biomedical Diagnosis 335

in materials science. In the multicomponent system, one can expect unique properties originated from collective interactions between the constituents. The outstanding understanding of how growth joining of two individual materials could allow for controlling the nanohybrid geometries with unexpected properties. In this Chapter, we review theranostic biomedical applications of diverse types of the colloidal inorganic nanohybrids synthesized using seed-mediated growth. The structure and shape of the nanohybrids are predominantly dependent on the crystal structure and lattice parameter of each component and seed-toprecursor ratio in heterogeneous growth. A major goal in nanomedicine is the coherent implementation of multifunctional platforms within a single targeted nanodelivery system, which would simultaneously perform diagnosis, targeted delivery and efficient therapy. With the goal of creating synergistic properties, multifunctional hybrid materials with combined plasmonic-magnetic, plasmonic-fluorescent, fluorescent-magnetic structures are reviewed. These hybrid structures were then functionalized with either silica or amphiphilic polymer layers to convert water-soluble particles compatible with biomedical applications, while retaining their individual functional characteristics. For theranostic biomedical applications, the water-soluble nanomaterials were conjugated with biomolecules (antibody, DNA, peptide). The resulting bioconjugated hybrid nanoparticles show to be viable not only as dualfunctional probes for imaging but also as an anticancer drug delivery vehicle even orientation of NIR excitation and external magnetic field. Through in vitro experiments demonstrated that these conjugated hybrid nanoparticles were actively delivered and targeted to the tumor sites

Since recent efforts on the synthesis of the multifunctional hybrid materials and studies them on animal species for theranostic biomedical applications, however it still presents major challenges for transferring into the clinical practices. Integrated collaborations of materials scientists with biologists and clinicians to be interdisciplinary teams should be established to systematic demonstrate and evaluate specific properties of the preformed hybrid nanomaterials, such as long-term toxicity, pharmacokinectics, and disinfection byproduct effects. In the future, the unexpected properties of these materials effective to human cancer cells are conducted by medical doctors, the multifunctional hybrid nanomaterials will provide powerful tools for simultaneous diagnosis and therapy of

*Department of Chemistry, Faculty of Sciences, Hue University, Hue 84054, Vietnam* 

*Department of Chemical Engineering, Laval University, Quebec G1K 7P4, Canada* 

in alive organs.

cancer diseases.

**Author details** 

Thanh-Dinh Nguyen**\***

Corresponding Author

Thai-Hoa Tran

 \*

The biological applications of the down-conversion luminescent materials are currently restricted because they frequently emit at UV and visible regions, given the autofluorescence from biological tissues. These limitations would be breakthrough if we discover an alternate materials emitted in near-infrared (NIR)-to-vis upconversion.[80] This expectation was proved by Stucky et al.[81] who recently developed the new mesoporous multifunctional materials based on the combination of both up-converting luminescent and magnetic properties. Nanorattle hollow spheres consisted of the rare-earth-doped NaYF4 shells with a SiO2-coated Fe3O4 inner particle fabricated through ion-exchange process. The silica coating of the Fe3O4 nanoparticles were carried out by hydrolysis of TEOS in reverse-microemulsion system. The Fe3O4@SiO2@Y2O3/Yb,Er magnetic upconversion oxide nanospheres were prepared by coating with the layer of Y/Yb,Er(OH)CO3.H2O via homogeneous precipitation in the aqueous solution of yttrium nitrate and urea and subsequent calcination at 550 oC for 2 h. The Fe3O4@SiO2@α-NaYF4/Yb,Er magnetic upconversion uoride nanorattles were formed via ion-exchange of the Fe3O4@SiO2@Y2O3/Yb,Er particles in HF and NaF solution. To demonstrate the material's potential use as a drug delivery system, the magnetic upconversion uoride nanorattles were conjugated with antitumor drug doxorubicin. Through in vitro experiments in mice cells, the authors demonstrated that the material emits visible luminescence upon NIR excitation and can be directed by external magnetic field to specific target, making it an attractive system for targeted chemotherapy. **Figure 10** shows the use of mesoporous silica-coated NaYF4:Yb,Er upconversion fluorescent nanoparticles (UCNs) as a remote-controlled nanotransducer for photodynamic therapy reported by Zhang et al.[82] The nanoparticle matrix can efficiently upconvert the energy of penetrating near-infrared light to visible light and transfer it to the encapsulated photosensitizers. The UCN materials exhibited a spectral overlap between the emitted visible light and the maximum absorption wavelengths of the photosensitizers to generate cytotoxic singlet oxygen in water. The authors discovered that the inhibition of tumor-cell growth in mice as a result of singlet oxygen generation from the UCNs, even at a very low 980-nm laser powers. This enabled selective fluorescent labelling, imaging and potentially sorting of the cells opening new prospects in cancer diagnostics and therapy.

#### **7. Conclusions and outlooks**

Most strategies of conjugating functional surfaced nanoparticles with biomolecule imaging agents produce antibody-conjugated particles that are considered as efficient biomedical diagnosis agents and universal platforms for engineering of multifunctional nanodevices. Inorganic nanohybrids containing more than one component have drawn considerable interest in materials science. In the multicomponent system, one can expect unique properties originated from collective interactions between the constituents. The outstanding understanding of how growth joining of two individual materials could allow for controlling the nanohybrid geometries with unexpected properties. In this Chapter, we review theranostic biomedical applications of diverse types of the colloidal inorganic nanohybrids synthesized using seed-mediated growth. The structure and shape of the nanohybrids are predominantly dependent on the crystal structure and lattice parameter of each component and seed-toprecursor ratio in heterogeneous growth. A major goal in nanomedicine is the coherent implementation of multifunctional platforms within a single targeted nanodelivery system, which would simultaneously perform diagnosis, targeted delivery and efficient therapy. With the goal of creating synergistic properties, multifunctional hybrid materials with combined plasmonic-magnetic, plasmonic-fluorescent, fluorescent-magnetic structures are reviewed. These hybrid structures were then functionalized with either silica or amphiphilic polymer layers to convert water-soluble particles compatible with biomedical applications, while retaining their individual functional characteristics. For theranostic biomedical applications, the water-soluble nanomaterials were conjugated with biomolecules (antibody, DNA, peptide). The resulting bioconjugated hybrid nanoparticles show to be viable not only as dualfunctional probes for imaging but also as an anticancer drug delivery vehicle even orientation of NIR excitation and external magnetic field. Through in vitro experiments demonstrated that these conjugated hybrid nanoparticles were actively delivered and targeted to the tumor sites in alive organs.

Since recent efforts on the synthesis of the multifunctional hybrid materials and studies them on animal species for theranostic biomedical applications, however it still presents major challenges for transferring into the clinical practices. Integrated collaborations of materials scientists with biologists and clinicians to be interdisciplinary teams should be established to systematic demonstrate and evaluate specific properties of the preformed hybrid nanomaterials, such as long-term toxicity, pharmacokinectics, and disinfection byproduct effects. In the future, the unexpected properties of these materials effective to human cancer cells are conducted by medical doctors, the multifunctional hybrid nanomaterials will provide powerful tools for simultaneous diagnosis and therapy of cancer diseases.
