Conjugated polyelectrolyte-cisplatin complex nanoparticles for simultaneous in vivo imaging and drug tracking

A molecular brush based on conjugated polyelectrolyte (CPE) grafted with dense poly(ethylene glycol) (PEG) chains was successfully complexed with an anticancer agent, cisplatin, to form cisplatin-loaded nanoparticles (CPE-PEG-Pt). The obtained nanoparticles have high far-red/near-infrared fluorescence and are able to release the drug in a continuous and slow manner. These nanoparticles have not only been used to visualize HepG2 cancer cells, but also served as an in vivo fluorescent imaging probe that simultaneously tracks the in vivo drug distribution in nude mice upon intravenous administration.     

Versatile hybrid polyethyleneimine–mesoporous carbon nanoparticles for targeted delivery

To meet the needs of targeted drug delivery and medical imaging, uniform mesoporous carbon spheres (UMCS) were functionalized using hyperbranched polyethyleneimine (PEI) covalently linked with fluorescein isothiocyanate (FITC) and folic acid (FA). Folate-receptor-positive KB cancer cells internalized five times more nanoparticles than A549 cells deficient in folate receptors in vitro using flow cytometry and confocal microscopy. The in vivo distribution results also confirmed that the FA–PEI–FITC–UMCS nanoparticles could target the FA-positive tumors. In addition, the specifically targeted hybrid carbon nanoparticles exhibited non-cytotoxic and controlled intracellular release (pH dependent) of the loaded agents. The in vivo antitumor effect of the paclitaxel (PTX)-loaded nanoparticles was investigated in Kunming mice harboring a hepatic H22 tumor. PTX-loaded FA–PEI–UMCS nanoparticles displayed superior antitumor effects compared to other PTX formulations, and the tumor growth inhibition rate was 86.53% compared with the control group (saline) for the enhanced targeted accumulation of NPs in tumor cells.     

Therapeutic Potential of Magnetic Nanoparticle-Based Human Adipose-Derived Stem Cells in a Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Several treatments for PD have focused on the management of physical symptoms using dopaminergic agents. However, these treatments induce various adverse effects, including hallucinations and cognitive impairment, owing to non-targeted brain delivery, while alleviating motor symptoms. Furthermore, these therapies are not considered ultimate cures owing to limited brain self-repair and regeneration abilities. In the present study, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASCs) using magnetic nanoparticles in a 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We used the Maestro imaging system and magnetic resonance imaging (MRI) for in vivo tracking after transplantation of magnetic nanoparticle-loaded hASCs to the PD mouse model. The Maestro imaging system revealed strong hASCs signals in the brains of PD model mice. In particular, MRI revealed hASCs distribution in the substantia nigra of hASCs-injected PD mice. Behavioral evaluations, including apomorphine-induced rotation and rotarod performance, were significantly recovered in hASCs-injected 6-OHDA induced PD mice when compared with saline-treated counterparts. Herein, we investigated whether hASCs transplantation using magnetic nanoparticles recovered motor functions through targeted brain distribution in a 6-OHDA induced PD mice. These results indicate that magnetic nanoparticle-based hASCs transplantation could be a potential therapeutic strategy in PD.     

Enhanced immunomodulatory activity of gelatin-encapsulated Rubus coreanus Miquel nanoparticles

The aim of this work was to investigate the immunomodulatory activities of Rubus coreanus Miquel extract-loaded gelatin nanoparticles. The mean size of the produced nanoparticles was 143 ± 18 nm with a bandwidth of 76 nm in the size distribution and a maximum size of ~200 nm, which allows effective nanoparticle uptake by cells. Confocal imaging confirmed this, since the nanoparticles were internalized within 30 min and heterogeneously distributed throughout the cell. Zeta-potential measurements showed that from pH = 5 onwards, the nanoparticles were highly negatively charged, which prevents agglomeration to clusters by electrostatic repulsion. This was confirmed by TEM imaging, which showed a well dispersed colloidal solution. The encapsulation efficiency was nearly 60%, which is higher than for other components encapsulated in gelatin nanoparticles. Measurements of immune modulation in immune cells showed a significant effect by the crude extract, which was only topped by the nanoparticles containing the extract. Proliferation of B-, T- and NK cells was notably enhanced by Rubus coreanus-gelatin nanoparticles and in general ~2-3 times higher than control and on average ~2 times higher than ferulic acid. R. coreanus-gelatin nanoparticles induced cytokine secretion (IL-6 and TNF-α) from B- and T-cells on average at a ~2-3 times higher rate compared with the extract and ferulic acid. In vivo immunomodulatory activity in mice fed with R. coreanus-gelatin nanoparticles at 1 mL/g body weight showed a ~5 times higher antibody production compared to control, a ~1.3 times higher production compared to the extract only, and a ~1.6 times higher production compared to ferulic acid. Overall, our results suggest that gelatin nanoparticles represent an excellent transport vehicle for Rubus coreanus extract and extracts from other plants generally used in traditional Asian medicine. Such nanoparticles ensure a high local concentration that results in enhancement of immune cell activities, including proliferation, cytokine secretion, and antibody production.     

Assessment of the In Vivo Toxicity of Gold Nanoparticles

The environmental impact of nanoparticles is evident; however, their toxicity due to their nanosize is rarely discussed. Gold nanoparticles (GNPs) may serve as a promising model to address the size-dependent biological response to nanoparticles because they show good biocompatibility and their size can be controlled with great precision during their chemical synthesis. Naked GNPs ranging from 3 to 100 nm were injected intraperitoneally into BALB/C mice at a dose of 8 mg/kg/week. GNPs of 3, 5, 50, and 100 nm did not show harmful effects; however, GNPs ranging from 8 to 37 nm induced severe sickness in mice. Mice injected with GNPs in this range showed fatigue, loss of appetite, change of fur color, and weight loss. Starting from day 14, mice in this group exhibited a camel-like back and crooked spine. The majority of mice in these groups died within 21 days. Injection of 5 and 3 nm GNPs, however, did not induce sickness or lethality in mice. Pathological examination of the major organs of the mice in the diseased groups indicated an increase of Kupffer cells in the liver, loss of structural integrity in the lungs, and diffusion of white pulp in the spleen. The pathological abnormality was associated with the presence of gold particles at the diseased sites, which were verified by ex vivo Coherent anti-Stoke Raman scattering microscopy. Modifying the surface of the GNPs by incorporating immunogenic peptides ameliorated their toxicity. This reduction in the toxicity is associated with an increase in the ability to induce antibody response. The toxicity of GNPs may be a fundamental determinant of the environmental toxicity of nanoparticles.     

Targeted Delivery of DNA‐Au Nanoparticles across the Blood–Brain Barrier Using Focused Ultrasound

Nanoparticles have been widely studied as versatile platforms for in vivo imaging and therapy. However, their use to image and/or treat the brain is limited, as they are often unable to cross the blood–brain barrier (BBB). To overcome this problem, herein we report the use of focused ultrasound in vivo to successfully deliver DNA‐coated gold nanoparticles to specific locations in the brains of mice.     

Intestinal absorption and biological effects of orally administered amorphous silica particles

Although amorphous silica nanoparticles are widely used in the production of food products (e.g., as anticaking agents), there is little information available about their absorption and biological effects after oral exposure. Here, we examined the in vitro intestinal absorption and in vivo biological effects in mice of orally administered amorphous silica particles with diameters of 70, 300, and 1,000 nm (nSP70, mSP300, and mSP1000, respectively) and of nSP70 that had been surface-modified with carboxyl or amine groups (nSP70-C and nSP70-N, respectively). Analysis of intestinal absorption by means of the everted gut sac method combined with an inductively coupled plasma optical emission spectrometer showed that the intestinal absorption of nSP70-C was significantly greater than that of nSP70. The absorption of nSP70-N tended to be greater than that of nSP70; however, the results were not statistically significant. Our results indicate that silica nanoparticles can be absorbed through the intestine and that particle diameter and surface properties are major determinants of the degree of absorption. We also examined the biological effects of the silica particles after 28-day oral exposure in mice. Hematological, histopathological, and biochemical analyses showed no significant differences between control mice and mice treated with the silica particles, suggesting that the silica nanoparticles evaluated in this study are safe for use in food production.     

Pharmacokinetics of Single Domain Antibodies and Conjugated Nanoparticles Using a Hybrid near Infrared Method

Iron oxide nanoparticles and single domain antibodies from camelids (VHHs) have been increasingly recognized for their potential uses for medical diagnosis and treatment. However, there have been relatively few detailed characterizations of their pharmacokinetics (PK). The aim of this study was to develop imaging methods and pharmacokinetic models to aid the future development of a novel family of brain MRI molecular contrast agents. An efficient near-infrared (NIR) imaging method was established to monitor VHH and VHH conjugated nanoparticle kinetics in mice using a hybrid approach: kinetics in blood were assessed by direct sampling, and kinetics in kidney, liver, and brain were assessed by serial in vivo NIR imaging. These studies were performed under “basal” circumstances in which the VHH constructs and VHH-conjugated nanoparticles do not substantially interact with targets nor cross the blood brain barrier. Using this approach, we constructed a five-compartment PK model that fits the data well for single VHHs, engineered VHH trimers, and iron oxide nanoparticles conjugated to VHH trimers. The establishment of the feasibility of these methods lays a foundation for future PK studies of candidate brain MRI molecular contrast agents.     

Biodistribution of co-exposure to multi-walled carbon nanotubes and nanodiamonds in mice

ABSTRACT: In this work, technetium-99 (99mTc) was used as the radiolabeling isotope to study the biodistribution of oxidized multi-walled carbon nanotubes (oMWCNTs) and/or nanodiamonds (NDs) in mice after intravenous administration. The histological impact of non-radiolabeled oMWCNTs or NDs was investigated in comparison to the co-exposure groups. 99mTc-labeled nanomaterials had high stability in vivo and fast clearance from blood. After a single injection of oMWCNTs, the highest distribution was found in the lungs, with lower uptake in the liver/spleen. As for NDs injected alone, high distribution in the liver, spleen, and lungs was observed right after. However, uptake in the lungs was decreased obviously after 24 h, while high accumulation in the liver or spleen continued. After co-injection of oMWCNTs and NDs, oMWCNTs significantly affected the distribution pattern of NDs in vivo. Meanwhile, the increasing dose of oMWCNTs decreased the hepatic and splenic accumulation of NDs and gradually increased lung retention. On the contrary, the NDs had no significant effects on the distribution of oMWCNTs in mice. Histological photographs showed that oMWCNTs were mainly captured by lung macrophages, and NDs were located in the bronchi and alveoli after co-administration. oMWCNTs and NDs had different modes of micro-cells. In conclusion, the behavior and fate of NDs in mice depended strongly on oMWCNTs, but NDs had a small influence on the biodistribution and excretion pattern of oMWCNTs.     

The first step into the brain: uptake of NIO-PBCA nanoparticles by endothelial cells in vitro and in vivo, and direct evidence for their blood-brain barrier permeation

By using fluorescent polysorbate 80 coated poly(n-butylcyanoacrylate) (PBCA) nanoparticles in an in vivo study, direct evidence was found for the presence of nanoparticles entering the brain and retina of rats. The nanoparticles, prepared with a miniemulsion process, were labeled in situ with a fluorescent dye and coated with polysorbate 80. After preparation the particle size, zeta potential, and the molecular weight distribution were determined. BMEC cells were used as an in vitro model for the BBB. The cells showed significant uptake of the particles, but no transcytosis could be observed in vitro. After applying the particles to the animals at two concentrations, cryosections of the brains and retinas were prepared. Regarding the sections of the rats that received the lower dose, co-localization of the applied fluorescent particles and the stained endothelial cells could be detected in the brain and retina, indicating particle internalization in the endothelial cells. Applied at higher doses, the particles could be detected within the brain and retina with few co-localized signals, suggesting passage through the blood-brain and blood-retina barriers.     

Both FA- and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution

Both folic acid (FA)- and methoxypoly(ethylene glycol) (mPEG)-conjugated chitosan nanoparticles (NPs) had been designed for targeted and prolong anticancer drug delivery system. The chitosan NPs were prepared with combination of ionic gelation and chemical cross-linking method, followed by conjugation with both FA and mPEG, respectively. FA-mPEG-NPs were compared with either NPs or mPEG-/FA-NPs in terms of their size, targeting cellular efficiency and tumor tissue distribution. The specificity of the mPEG-FA-NPs targeting cancerous cells was demonstrated by comparative intracellular uptake of NPs and mPEG-/FA-NPs by human adenocarcinoma HeLa cells. Mitomycin C (MMC), as a model drug, was loaded to the mPEG-FA-NPs. Results show that the chitosan NPs presented a narrow-size distribution with an average diameter about 200 nm regardless of the type of functional group. In addition, MMC was easily loaded to the mPEG-FA-NPs with drug-loading content of 9.1%, and the drug releases were biphasic with an initial burst release, followed by a subsequent slower release. Laser confocal scanning imaging proved that both mPEG-FA-NPs and FA-NPs could greatly enhance uptake by HeLa cells. In vivo animal experiments, using a nude mice xenograft model, demonstrated that an increased amount of mPEG-FA-NPs or FA-NPs were accumulated in the tumor tissue relative to the mPEG-NPs or NPs alone. These results suggest that both FA- and mPEG-conjugated chitosan NPs are potentially prolonged drug delivery system for tumor cell-selective targeting treatments.     

Comparison of In vitro Nanoparticles Uptake in Various Cell Lines and In vivo Pulmonary Cellular Transport in Intratracheally Dosed Rat Model

In present study, the potential drug delivery of nanoformulations was validated via the comparison of cellular uptake of nanoparticles in various cell lines and in vivo pulmonary cellular uptake in intratracheally (IT) dosed rat model. Nanoparticles were prepared by a bench scale wet milling device and incubated with a series of cell lines, including Caco-2, RAW, MDCK and MDCK transfected MDR1 cells. IT dosed rats were examined for the pulmonary cellular uptake of nanoparticles. The processes of nanoparticle preparation did not alter the crystalline state of the material. The uptake of nanoparticles was observed most extensively in RAW cells and the least in Caco-2 cells. Efflux transporter P-gp did not prevent cell from nanoparticles uptake. The cellular uptake of nanoparticles was also confirmed in bronchoalveolar lavage (BAL) fluid cells and in bronchiolar epithelial cells, type II alveolar epithelial cells in the intratracheally administrated rats. The nanoparticles uptake in MDCK, RAW cells and in vivo lung epithelial cells indicated the potential applications of nanoformulation for poorly soluble compounds. The observed limited direct uptake of nanoparticles in Caco-2 cells suggests that the improvement in oral bioavailability by particle size reduction is via increased dissolution rate rather than direct uptake.     

Multifunctional mesoporous silica nanocomposite nanoparticles for theranostic applications

Clever combinations of different types of functional nanostructured materials will enable the development of multifunctional nanomedical platforms for multimodal imaging or simultaneous diagnosis and therapy. Mesoporous silica nanoparticles (MSNs) possess unique structural features such as their large surface areas, tunable nanometer-scale pore sizes, and well-defined surface properties. Therefore, they are ideal platforms for constructing multifunctional materials that incorporate a variety of functional nanostructured materials. In this Account, we discuss recent progress by our group and other researchers in the design and fabrication of multifunctional nanocomposite nanoparticles based on mesoporous silica nanostructures for applications to simultaneous diagnosis and therapy. Versatile mesoporous silica-based nanocomposite nanoparticles were fabricated using various methods. Here, we highlight two synthetic approaches: the encapsulation of functional nanoparticles within a mesoporous silica shell and the assembly of nanoparticles on the surface of silica nanostructures. Various nanoparticles were encapsulated in MSNs using surfactants as both phase transfer agents and pore-generating templates. Using MSNs as a scaffold, functional components such as magnetic nanoparticles and fluorescent dyes have been integrated within these systems to generate multifunctional nanocomposite systems that maintain their individual functional characteristics. For example, uniform mesoporous dye-doped silica nanoparticles immobilized with multiple magnetite nanocrystals on their surfaces have been fabricated for their use as a vehicle capable of simultaneous magnetic resonance (MR) and fluorescence imaging and drug delivery. The resulting nanoparticle-incorporated MSNs were then tested in mice with tumors. These in vivo experiments revealed that these multifunctional nanocomposite nanoparticles were delivered to the tumor sites via passive targeting. These nanocomposite nanoparticles served as successful multimodal imaging probes and also delivered anticancer drugs to the tumor site. With innumerable combinations of imaging modalities and drug delivery available within these vehicles, multifunctional nanocomposite nanoparticles provide new opportunities for clinical diagnostics and therapeutics.     

以纳米球形聚电解质刷为载体原位还原制备贵金属纳米粒子的研究

以具有核壳结构的纳米球形聚电解质刷为载体,通过吸附不同种类的贵金属离子并将其原位还原,得到分布和粒径不同的贵金属纳米粒子。采用动态光散射(DLS)研究了金属离子浓度和pH对壳层聚电解质链长的影响,使用透射电镜(TEM)观察了贵金属粒子在纳米球形聚电解质刷中的分布,并测量了金属粒子的尺寸。结果表明:金属离子浓度增大,聚电解质链长减小;pH>5时,负载金属粒子之后的聚电解质链长度均大于负载前的长度。不同金属粒子的负载情况相差较大:相同温度下,纳米金属粒子的尺寸符合Ni>Ag>Co的顺序;较高温下制得的金属粒子尺寸要高于低温下制得的金属粒子尺寸;三种纳米金属粒子中,Co纳米粒子具有最好的分布和最小的尺寸。     

Preparation of OVA-loaded γ-PGA/CS nanocomposite delivery vector and its immune response

To improve the stability and immunization of proteins or peptides after vaccination, choosing biodegradable and biocompatible materials to encapsulate protein ovalbumin (OVA) is necessary. In this study, we aim to construct OVA-loaded γ-polyglutamic acid (γ-PGA)/chitosan (CS) nanoparticles (NPs) using ionic cross-linking and poly-electrolyte composite methods and to explore its immune effect in mice. The as-constructed γ-PGA/CS/OVA NPs, with a positive charge on the surface, were uniformly round. Additionally, the particle size range of the as-constructed γ-PGA/CS/OVA NPs was 200–400 nm. Furthermore, the sodium dodecyl sulfate (SDS)-PAGE analysis showed that OVA in γ-PGA/CS/OVA NPs had high structural integrity. The conditions of preparing γ-PGA/CS/OVA NPs were optimized in detail, and it was found that the resultant loading capacity of NPs achieved 207.7 ± 11.1 μg/mg. MTT assay showed that γ-PGA/CS NPs have good biocompatibility. The results of immune experiments in mice showed that compared with OVA not wrapped with γ-PGA/CS composite carrier, γ-PGA/CS/OVA NPs can induce a stronger immune response through humoral immunity in vivo. Overall, these findings demonstrated that γ-PGA/CS NPs can be regarded as a good protein delivery system to enhance the immune response in vivo.     

单克隆抗体免疫结合物~(125)Ⅰ—3A_1在裸鼠淋巴瘤模型体内示踪研究

本文报道利用~(125)I 标记的抗 CD_7抗原决定簇的单抗 3A_1,在人 T 淋巴瘤裸鼠模型及人鼻咽癌裸鼠模型体内进行生物学分布和显像研究。注射标记抗体26小时后,淋巴瘤裸鼠模型中出现肿瘤显像。96小时后处死裸鼠,测定肿瘤及各器官中的放射性分布,结果表明 McAb 3A_1在 CEM 荷瘤裸鼠的肿瘤组织中有特异性的浓集。~(125)I 标记的对照抗体,鼠抗乙型肝炎病毒核心抗原抗体,在 T 淋巴瘤裸鼠模型的肿瘤部位无明显浓集。     

TiN nanoparticles: small size-selected fabrication and their quantum size effect

Size-selected TiN nanoclusters in the range of 4 to 20 nm have been produced by an ionized cluster beam, which combines a glow-discharge sputtering with an inert gas condensation technique. With this method, by controlling the experimental conditions, it was possible to produce nanoparticles with a high control in size. The size distribution of TiN nanoparticles was determined before deposition by mass spectroscopy and confirmed by atomic force microscopy. The size distribution was also analyzed using a high-resolution transmission electron micrograph. The photoluminescence [PL] spectra of TiN nanoparticles at different sizes were also experimentally investigated. We reported, for the first time, the strong visible luminescence of TiN nanoparticles on Si (111) wafer due to the reduced size. We also discussed the PL intensity as a function of the nanoparticle size distribution.     

In vitro and in vivo antitumor study of folic acid-conjugated carboxymethyl chitosan and phenylboronic acid–based nanoparticles

Folic acid-modified carboxymethyl chitosan was polymerized with N-3-acrylamidophenylboronic acid monomer to prepare tumor-targeting nanoparticles (NPs). Nanoparticles’ size was characterized by dynamic light scattering, while the micromorphology was observed through transmission electron microscopy (TEM) and scanning electronic microscope (SEM). Doxorubicin was then loaded into prepared nanoparticles. The cellular uptake of these NPs was investigated in monolayer cell model and multicellular spheroids. The results revealed that FA-modified nanoparticles possess excellent ability of accumulation and penetration in 2D and 3D cell models. It was also found that these nanoparticles enhanced drug accumulation in tumor, which finally increased antitumor efficiency in H22 tumor-bearing mice.     

Photosensitizer-doped conjugated polymer nanoparticles for simultaneous two-photon imaging and two-photon photodynamic therapy in living cells

Photosensitizer doped conjugated polymer nanoparticles have been prepared by incorporating polyoxyethylene nonylphenylether (CO-520) into the nanoparticles using a re-precipitation method. The conjugated polymer, poly[9,9-dibromohexylfluorene-2,7-ylenethylene-alt-1,4-(2,5-dimethoxy)phenylene] (PFEMO), was used as the host matrix to disperse tetraphenylporphyrin (TPP) and an energy donor to enhance the two-photon excitation properties of TPP. These CO-520 incorporated, TPP-doped PFEMO nanoparticles are stable and have low cytotoxicity in the dark. The TPP emission of the nanoparticles was found to be enhanced by about 20 times by PFEMO under two-photon excitation. The nanoparticles showed significantly enhanced two-photon excitation singlet oxygen generation efficiency and two-photon photodynamic therapy activity in cancer cells. These composite nanoparticles display features required for ideal photosensitizers, such as low cytotoxicity in the dark and efficient two-photon photodynamic activity under laser radiation. In addition, these novel nano-photosensitizers allow simultaneous in vivo monitoring by two-photon fluorescence imaging during two-photon photodynamic treatment. These photosensitizer-doped conjugated polymer nanoparticles can act as novel photosensitizing agents for two-photon photodynamic therapy and related applications.     

Liposomes: from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine

For decades, clinicians have used liposomes, self-assembled lipid vesicles, as nanoscale systems to deliver encapsulated anthracycline molecules for cancer treatment. The more recent proposition to combine liposomes with nanoparticles remains at the preclinical development stages; however, such hybrid constructs present great opportunities to engineer theranostic nanoscale delivery systems, which can combine simultaneous therapeutic and imaging functions. Many novel nanoparticles of varying chemical compositions are being developed in nanotechnology laboratories, but further chemical modification is often required to make these structures compatible with the biological milieu in vitro and in vivo. Such nanoparticles have shown promise as diagnostic and therapeutic tools and generally offer a large surface area that allows covalent and non-covalent surface functionalization with hydrophilic polymers, therapeutic moieties, and targeting ligands. In most cases, such surface manipulation diminishes the theranostic properties of nanoparticles and makes them less stable. From our perspective, liposomes offer structural features that can make nanoparticles biocompatible and present a clinically proven, versatile platform for further enhancement of the pharmacological and diagnostic efficacy of nanoparticles. In this Account, we describe two examples of liposome-nanoparticle hybrids developed as theranostics: liposome-quantum dot hybrids loaded with a cytotoxic drug (doxorubicin) and artificially enveloped adenoviruses. We incorporated quantum dots into lipid bilayers, which rendered them dispersible in physiological conditions. This overall vesicular structure allowed them to be loaded with doxorubicin molecules. These structures exhibited cytotoxic activity and labeled cells both in vitro and in vivo. In an alternative design, lipid bilayers assembled around non-enveloped viral nanoparticles and altered their infection tropism in vitro and in vivo with no chemical or genetic capsid modifications. Overall, we have attempted to illustrate how alternative strategies to incorporate nanoparticles into liposomal nanostructures can overcome some of the shortcomings of nanoparticles. Such hybrid structures could offer diagnostic and therapeutic combinations suitable for biomedical and even clinical applications.