Single Ho3+‐Doped Upconversion Nanoparticles for High‐Performance T2‐Weighted Brain Tumor Diagnosis and MR/UCL/CT Multimodal Imaging

Multimodal bio‐imaging has attracted great attention for early and accurate diagnosis of tumors, which, however, suffers from the intractable issues such as complicated multi‐step syntheses for composite nanostructures and interferences among different modalities like fluorescence quenching by MRI contrast agents (e.g., magnetic iron oxide NPs). Herein, the first example of T₂‐weighted MR imaging of Ho³⁺‐doped upconversion nanoparticles (UCNPs) is presented, which, very attractively, could also be simultaneously used for upconversion luminesence (UCL) and CT imaging, thus enabling high performance multi‐modal MRI/UCL/CT imagings in single UCNPs. The new finding of T₂‐MRI contrast enhancement by integrated sensitizer (Yb³⁺) and activator (Ho³⁺) in UCNPs favors accurate MR diagnosis of brain tumor and provides a new strategy for acquiring T₂‐MRI/optical imaging without fluorescence quenching. Unlike other multi‐phased composite nanostructures for multimodality imaging, this Ho³⁺‐doped UCNPs are featured with simplicity of synthesis and highly efficient multimodal MRI/UCL/CT imaging without fluorescence quenching, thus simplify nanostructure and probe preparation and enable win–win multimodality imaging.     

Enhanced Relaxometric Properties of MRI “Positive” Contrast Agents Confined in Three‐Dimensional Cubic Mesoporous Silica Nanoparticles

Mesoporous silica nanoparticles (MSNs) are of growing interest for the development of novel probes enabling efficient tracking of cells in vivo using magnetic resonance imaging (MRI). The incorporation of Gd³⁺ paramagnetic ions into highly porous MSNs is a powerful strategy to synthesize “positive” MRI contrast agents for more quantitative T₁‐weighted MR imaging. Within this context, different strategies have been reported to integrate Gd chelates to 2D pore network MSNs. As an alternative, we report on the modulation of the pore network topology through the preparation of a 3D pore network hybrid GdSi_xO_y MSN system. In this study, 2D GdSi_xO_y‐MSNs with similar porosity and particle size were also prepared and the relaxometric performances of both materials, directly compared. Both syntheses lead to water‐dispersible MSNs suspensions (particle size < 200 nm), which were stable for at least 48h. 3D GdSi_xO_y‐MSNs provided a significant increase in ¹H longitudinal relaxivity (18.5 s^?1mM^?1; 4.6 times higher than Gd‐DTPA) and low r₂/r₁ ratios (1.56) compatible with the requirements of “positive” contrast agents for MRI. These results demonstrate the superiority of a 3D pore network to host paramagnetic atoms for MRI signal enhancement using T₁‐weighted imaging. Such an approach minimizes the total amount of paramagnetic element per particle.     

Ultrasmall Water‐Soluble and Biocompatible Magnetic Iron Oxide Nanoparticles as Positive and Negative Dual Contrast Agents

Monodispersed water‐soluble and biocompatible ultrasmall magnetic iron oxide nanoparticles (UMIONs, D = 3.3 ± 0.5 nm) generated from a high‐temperature coprecipitation route are successfully used as efficient positive and negative dual contrast agents of magnetic resonance imaging (MRI). Their longitudinal relaxivity at 4.7 T (r₁ = 8.3 mM^?1 s^?1) is larger than that of clinically used T₁‐positive agent Gd‐DTPA (r₁ = 4.8 mM^?1 s^?1), and three times that of commercial contrast agent SHU‐555C (r₁ = 2.9 mM^?1 s^?1). The transversal relaxivity (r₂ = 35.1 mM^?1 s^?1) is six times that of Gd‐DTPA (r₂ = 5.3 mM^?1 s^?1), half of SHU‐555C (r₂ = 69 mM^?1 s^?1). The in vivo results show that the liver signal from T₁‐weighted MRI is positively enhanced 26%, and then negatively decreased 20% after injection of the iron oxide nanoparticles, which is stronger than those obtained from Gd‐DTPA (<10%) using the same dosage. The kidney signal is positively enhanced up to 35%, similar to that obtained from Gd‐DTPA. Under T₂‐weighted conditions, the liver signal is negatively enhanced ?70%, which is significantly higher than that from Gd‐DTPA (?6%). These results demonstrate the great potential of the UMIONs in dual contrast agents, especially as an alternative to Gd‐based positive contrast agents, which have risks of inducing side effects in patients.     

Activated Surface Charge‐Reversal Manganese Oxide Nanocubes with High Surface‐to‐Volume Ratio for Accurate Magnetic Resonance Tumor Imaging

Investigating the surface structure, including crystal surface and surface‐coating ligands, of nanoparticulate T₁ contrast agent may help to understand the T₁ relaxation enhancement in vitro and in vivo. This study presents a novel strategy to develop high‐performance T₁ magnetic resonance imaging (MRI) contrast agents through optimizing the nanocrystal surface and the nanobio interface. Based on the optimized crystal surface, the novel manganese oxide nanocubes (MOCs) show significantly higher surface‐to‐volume ratio and an approximately threefold higher r₁ value compared to traditional manganese oxide nanospheres. Concurrently, transferring MOCs into aqueous media by dopamine derivatization can avoid the oxidation of Mn(II) ions and provide abundant magnetic core. This optimized surface endows MOCs with a high chemical exchange efficiency during T₁ relaxation. Of particular significance, a rationally designed pH‐induced charge‐switchable surfaces can be negatively charged and corona‐free in blood and positively charged surface in tumor sites. This unique feature improves the circulation behavior of this intelligent T₁ contrast agent in blood and increases cancer cell uptake to achieve accurate detection of solid tumor, holding great potential in aiding early and precise tumor diagnosis. This study provides a novel tool for sophisticated design of high‐performance T₁ MRI contrast agents in bioimaging applications.     

Positive and Negative Lattice Shielding Effects Co‐existing in Gd (III) Ion Doped Bifunctional Upconversion Nanoprobes

Gadolinium (Gd) doped upconversion nanoparticles (UCNPs) have been well documented as T₁‐MR and fluorescent imaging agents. However, the performance of Gd³⁺ ions located differently in the crystal lattice still remains debatable. Here, a well‐designed model was built based on a seed‐mediated growth technique to systematically probe the longitudinal relaxivity of Gd³⁺ ions within the crystal lattice and at the surface of UCNPs. We found, for the first time, a nearly 100% loss of relaxivity of Gd³⁺ ions buried deeply within crystal lattices (> 4 nm), which we named a “negative lattice shielding effect” (n‐LSE) as compared to the “positive lattice shielding effect” (p‐LSE) for the enhanced upconversion fluorescent intensity. As‐observed n‐LSE was further found to be shell thickness dependent. By suppressing the n‐LSE as far as possible, we optimized the UCNPs' structure design and achieved the highest r₁ value (6.18 mM^?1s^?1 per Gd³⁺ ion) among previously reported counterparts. The potential bimodal imaging application both in vitro and in vivo of as‐designed nano‐probes was also demonstrated. This study clears the debate over the role of bulk and surface Gd³⁺ ions in MRI contrast imaging and paves the way for modulation of other Gd‐doped nanostructures for highly efficient T₁‐MR and upconversion fluorescent bimodal imaging.     

Novel Redox‐Responsive Polymeric Magnetosomes with Tunable Magnetic Resonance Property for In Vivo Drug Release Visualization and Dual‐Modal Cancer Therapy

Monitoring of in vivo drug release from nanotheranostics by noninvasive approaches remains very challenging. Herein, novel redox‐responsive polymeric magnetosomes (PolyMags) with tunable magnetic resonance imaging (MRI) properties are reported for in vivo drug release monitoring and effective dual‐modal cancer therapy. The encapsulation of doxorubicin (DOX) significantly decreases PolyMags' T₂‐contrast enhancement and transverse relaxation rate R₂, depending on the drug loading level. The T₂ enhancement and R₂ can be recovered once the drug is released upon PolyMags' disassembly. T₂‐ and T₂*‐MRI and diffusion‐weighted imaging (DWI) are utilized to quantitatively study the correlation between MRI signal changes and drug release, and discover the MR tuning mechanisms. The in vivo drug release pattern is visualized based on such tunable MRI capability via monitoring the changes in T₂‐weighted images, T₂ and T₂* maps, and R₂ and R₂* values. Interestingly, the PolyMags possess excellent photothermal effect, which can be further enhanced upon DOX loading. The PolyMags are highly efficacious to treat breast tumors on xenograft model with tumor‐targeted photothermal‐ and chemotherapy, achieving a complete cure rate of 66.7%. The concept reported here is generally applicable to other micellar and liposomal systems for image‐guided drug delivery and release applications toward precision cancer therapy.     

RGD‐Conjugated Nanoscale Coordination Polymers for Targeted T1‐ and T2‐weighted Magnetic Resonance Imaging of Tumors in Vivo

Development of multifunctional nanoscale coordination polymers (NCPs) allowing for T₁‐ and T₂‐weighted targeted magnetic resonance (MR) imaging of tumors could significantly improve the diagnosis accuracy. In this study, nanoscale coordination polymers (NCPs) with a diameter of ≈80 nm are obtained with 1,1′‐dicarboxyl ferrocene (Fc) as building blocks and magnetic gadolinium(III) ions as metallic nodes using a nanoprecipitation method, then further aminated through silanization. The amine‐functionalized Fc‐Gd@SiO₂ NCPs enable the covalent conjugation of a fluorescent rhodamine dye (RBITC) and an arginine‐glycine‐aspartic acid (RGD) peptide as a targeting ligand onto their surface. The formed water‐dispersible Fc‐Gd@SiO₂(RBITC)–RGD NCPs exhibit a low cytotoxicity, as confirmed by MTT assay. They have a longitudinal relaxivity (r₁) of 5.1 mM^?1 s^?1 and transversal relaxivity (r₂) of 21.7 mM^?1 s^?1, suggesting their possible use as both T₁‐positive and T₂‐negative contrast agents. In vivo MR imaging experiments show that the signal of tumor over‐expressing high affinity α_vβ₃ integrin from T₁‐weighted MR imaging is positively enhanced 47±5%, and negatively decreased 33±5% from T₂‐weighted MR imaging after intravenous injection of Fc‐Gd@SiO₂(RBITC)–RGD NCPs.     

Multifunctional Nanoparticles Composed of A Poly( dl‐lactide‐coglycolide) Core and A Paramagnetic Liposome Shell for Simultaneous Magnetic Resonance Imaging and Targeted Therapeutics

A multifunctional nanoscale platform that is self‐assembled from a hydrophobic poly( dl ‐lactide‐coglycolide)(PLGA) core and a hydrophilic paramagnetic‐folate‐coated PEGylated lipid shell (PFPL; PEG=polyethylene glycol) is designed for simultaneous magnetic resonance imaging (MRI) and targeted therapeutics. The nanocomplex has a well‐defined core‐shell structure which is studied using confocal laser scanning microscopy (CLSM). The paramagnetic diethylenetriaminepentaacetic acid‐gadolinium (DTPA‐Gd) chelated to the shell layer exhibits significantly higher spin–lattice relaxivity (r₁) than the clinically used small‐molecular‐weight MRI contrast agent Magnevist^®. The PLGA core serves as a nanocontainer to load and release the hydrophobic drugs. From a drug‐release study, it is found that the modification of the PLGA core with a polymeric liposome shell can be a useful tool for reducing the drug‐release rate. Cellular uptake of folate nanocomplex is found to be higher than that of non‐folate‐nanocomplex due to the folate‐binding effect on the cell membrane. This work indicates that the multifunctional platform with combined characteristics applicable to MRI and drug delivery may have great potential in cancer chemotherapy and diagnosis.     

In vivo Imaging and Drug Storage by Quantum‐Dot‐Conjugated Carbon Nanotubes

A specially designed carbon nanotube (CNT) is developed for use in the early detection and treatment of cancer. The key functionalities for biomedical diagnosis and drug delivery are incorporated into the CNTs. In vivo imaging of live mice is achieved by intravenously injecting quantum dot (QD)‐conjugated CNT for the first time. With near infrared emission around 752 nm, the CNT with surface‐conjugated QD (CNT‐QD) exhibit a strong luminescence for non‐invasive optical in vivo imaging. CNT surface modification is achieved by a plasma polymerization approach that deposited ultra‐thin acrylic acid or poly(lactic‐co‐glycolic acid) (PLGA) films (∼3 nm) onto the nanotubes. The anticancer agent paclitaxel is loaded at 112.5 ± 5.8 µg mg⁻¹ to PLGA‐coated CNT. Cytotoxicity of this novel drug delivery system is evaluated in vitro using PC‐3MM2 human prostate carcinoma cells and quantified by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The in vivo distribution determined by inductively coupled plasma mass spectrometry (ICP‐MS) indicates CNT‐QD uptake in various organs of live animals.     

Time‐Dependent T1–T2 Switchable Magnetic Resonance Imaging Realized by c(RGDyK) Modified Ultrasmall Fe3O4 Nanoprobes

To achieve the accurate diagnosis of tumor with the magnetic resonance imaging (MRI), nanomaterials‐based contrast agents are developed rapidly. Here, a tumor targeting nanoprobe of c(RGDyK) modified ultrasmall sized iron oxide is reported with high saturation magnetization and high T₁‐weighted imaging capability, attributed to a large number of paramagnetic centers on the surface of nanoprobes and rapid water proton exchange rate (inner sphere model), as well as strong superparamagnetism (outer sphere model). These nanoprobes could actively target and gradually accumulate at the tumor site with a time‐dependent T₁–T₂ contrast enhancement imaging effect. In in vivo MRI experiments, the nanoprobes exhibit the best T₁ contrast enhancement at 30 min after intravenous administration, followed by gradually vanishing and generating T₂ contrast enhancement with increasing time at tumor site. This is likely due to time‐dependent nanoprobes aggregation in tumor, in good agreement with in vitro experiment where aggregated nanoprobes display larger r₂/r₁ value (19.1) than that of the dispersed nanoprobes (2.8). This dynamic property is completely different from other T₁‐T₂ dual‐modal nanoprobes which commonly exhibit the T₁‐ and T₂‐weighted enhancement effect at the same time. To sum up, these c(RGDyK) modified ultrasmall Fe₃O₄ nanoprobes have significant potential to improve the diagnostic accuracy and sensitivity in MRI.     

Synthesis of Gadolinium‐Labeled Shell‐Crosslinked Nanoparticles for Magnetic Resonance Imaging Applications

Shell‐crosslinked knedel‐like nanoparticles (SCKs; “knedel” is a Polish term for dumplings) were derivatized with gadolinium chelates and studied as robust magnetic‐resonance‐imaging‐active structures with hydrodynamic diameters of 40 ± 3 nm. SCKs possessing an amphiphilic core–shell morphology were produced from the aqueous assembly of diblock copolymers of poly‐(acrylic acid) (PAA) and poly(methyl acrylate) (PMA), PAA₅₂–b–PMA₁₂₈, and subsequent covalent crosslinking by amidation upon reaction with 2,2′‐(ethylenedioxy)bis(ethylamine) throughout the shell layer. The properties of these materials, including non‐toxicity towards mammalian cells, non‐immunogenicity within mice, and capability for polyvalent targeting, make them ideal candidates for utilization within biological systems. The synthesis of SCKs derivatized with Gd^III and designed for potential use as a unique nanometer‐scale contrast agent for MRI applications is described herein. Utilization of an amino‐functionalized diethylenetriaminepentaacetic acid–Gd analogue allowed for direct covalent conjugation throughout the hydrophilic shell layer of the SCKs and served to increase the rotational correlation lifetime of the Gd. In addition, the highly hydrated nature of the shell layer in which the Gd was located allowed for rapid water exchange; thus, the resulting material demonstrated large ionic relaxivities (39 s^–1 mM^–1) in an applied magnetic field of 0.47 T at 40 °C and, as a result of the large loading capacity of the material, also demonstrated high molecular relaxivities (20 000 s^–1 mM^–1).     

Peptide Materials Obtained by Aggregation of Polyphenylalanine Conjugates as Gadolinium‐Based Magnetic Resonance Imaging Contrast Agents

Peptide materials based on the aggregation of polyphenylalanine conjugates containing gadolinium complexes and acting as potential contrast agents (CAs) in magnetic resonance imaging (MRI) are described. Monomers contain two (F2) or four (F4) phenylalanine residues for self‐assembly, a chelating agent, 1,4,7,10‐tetraazacyclododecane‐N,N,N,N‐tetraacetic acid (DOTA) or diethylenetriaminepentaacetic acid (DTPA), for achieving gadolinium coordination, and ethoxylic linkers at two (L₂) or six (L₆) poly(ethylene glycol) (PEG) units between the chelating group and the peptide region. Both DOTA and DTPA tetraphenylalanine derivatives, and their gadolinium complexes DOTA(Gd)‐L₆‐F4 and DTPA(Gd)‐L₆‐F4, are able to self‐aggregate at very low concentration. Structural characterization, obtained by circular dichroism and infrared measurements, confirms the amyloid type fibril formation in which an antiparallel peptide alignment is preferred. Amyloid type fibril formation is also observed, in solid state, by transmission electron microscopy images and X‐ray diffraction patterns. The relaxivity values of DOTA(Gd)‐L₆‐F4 and DTPA(Gd)‐L₆‐F4 and their ability to enhance the MRI cellular response on the J774A.1 mouse macrophages cell line indicate that these peptide materials are promising candidate as a new class of supramolecular gadolinium based MRI contrast agents.     

Multifunctional Graphene Oxide‐based Triple Stimuli‐Responsive Nanotheranostics

Construction of multifunctional stimuli‐responsive nanosystems intelligently responsive to inner physiological and/or external irradiations based on nanobiotechnology can enable the on‐demand drug release and improved diagnostic imaging to mitigate the side‐effects of anticancer drugs and enhance the diagnostic/therapeutic outcome simultaneously. Here, a triple‐functional stimuli‐responsive nanosystem based on the co‐integration of superparamagnetic Fe₃O₄ and paramagnetic MnO_x nanoparticles (NPs) onto exfoliated graphene oxide (GO) nanosheets by a novel and efficient double redox strategy (DRS) is reported. Aromatic anticancer drug molecules can interact with GO nanosheets through supramolecular π stacking to achieve high drug loading capacity and pH‐responsive drug releasing performance. The integrated MnO_x NPs can disintegrate in mild acidic and reduction environment to realize the highly efficient pH‐responsive and reduction‐triggered T₁‐weighted magnetic resonance imaging (MRI). Superparamagnetic Fe₃O₄ NPs can not only function as the T₂‐weighted contrast agents for MRI, but also response to the external magnetic field for magnetic hyperthermia against cancer. Importantly, the constructed biocompatible GO‐based nanoplatform can inhibit the metastasis of cancer cells by downregulating the expression of metastasis‐related proteins, and anticancer drug‐loaded carrier can significantly reverse the multidrug resistance (MDR) of cancer cells.     

Cover Picture: Synthesis of Gadolinium‐Labeled Shell‐Crosslinked Nanoparticles for Magnetic Resonance Imaging Applications (Adv. Funct. Mater. 8/2005)

Robust, amphiphilic core–shell nanoparticles that are selectively labeled with gadolinium in the hydrophilic and water‐swollen shell layer are depicted in the cover picture. These well‐defined nanostructured materials exhibit high relaxivity, a large loading capacity, and are based upon a biocompatible platform for ultimate function in magnetic resonance imaging (MRI) applications, as reported by Wooley and co‐workers on p. 1248. Shell‐crosslinked knedel‐like nanoparticles (SCKs; “knedel” is a Polish term for dumplings) were derivatized with gadolinium chelates and studied as robust magnetic‐resonance‐imaging‐active structures with hydrodynamic diameters of 40 ± 3 nm. SCKs possessing an amphiphilic core–shell morphology were produced from the aqueous assembly of diblock copolymers of poly‐(acrylic acid) (PAA) and poly(methyl acrylate) (PMA), PAA₅₂–b–PMA₁₂₈, and subsequent covalent crosslinking by amidation upon reaction with 2,2′‐(ethylenedioxy)bis(ethylamine) throughout the shell layer. The properties of these materials, including non‐toxicity towards mammalian cells, non‐immunogenicity within mice, and capability for polyvalent targeting, make them ideal candidates for utilization within biological systems. The synthesis of SCKs derivatized with Gd^III and designed for potential use as a unique nanometer‐scale contrast agent for MRI applications is described herein. Utilization of an amino‐functionalized diethylenetriaminepentaacetic acid–Gd analogue allowed for direct covalent conjugation throughout the hydrophilic shell layer of the SCKs and served to increase the rotational correlation lifetime of the Gd. In addition, the highly hydrated nature of the shell layer in which the Gd was located allowed for rapid water exchange; thus, the resulting material demonstrated large ionic relaxivities (39 s^–1 mM^–1) in an applied magnetic field of 0.47 T at 40 °C and, as a result of the large loading capacity of the material, also demonstrated high molecular relaxivities (20 000 s^–1 mM^–1).     

PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium Chelates for Dual‐Modal MRI/Photoacoustic Imaging Guided Photothermal Therapy of Cancer

Polypyrrole nanoparticles conjugating gadolinium chelates were successfully fabricated for dual‐modal magnetic resonance imaging (MRI) and photoacoustic imaging guided photothermal therapy of cancer, from a mixture of pyrrole and pyrrole‐1‐propanoic acid through a facile one‐step aqueous dispersion polymerization, followed by covalent attachment of gadolinium chelate, using polyethylene glycol as a linker. The obtained PEGylated poly­pyrrole nanoparticles conjugating gadolinium chelates (Gd‐PEG‐PPy NPs), sized around around 70 nm, exhibited a high T₁ relaxivity coefficient of 10.61 L mm ^?1 s^?1, more than twice as high as that of the relating free Gd³⁺ complex (4.2 L mm ^–1 s^?1). After 24 h intravenous injection of Gd‐PEG‐PPy NPs, the tumor sites exhibited obvious enhancement in both T₁‐weighted MRI intensity and photoacoustic signal compared with that before injection, indicating the efficient accumulation of Gd‐PEG‐PPy NPs due to the introduction of the PEG layer onto the particle surface. In addition, tumor growth could be effectively inhibited after treatment with Gd‐PEG‐PPy NPs in combination with near‐infrared laser irradiation. The passive targeting and high MRI/photo­acoustic contrast capability of Gd‐PEG‐PPy NPs are quite favorable for precise cancer diagnosing and locating the tumor site to guide the external laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. Therefore, Gd‐PEG‐PPy NPs may assist in better monitoring the therapeutic process, and contribute to developing more effective “personalized medicine,” showing great potential for cancer diagnosis and therapy.     

Furin‐Controlled Fe3O4 Nanoparticle Aggregation and 19F Signal “Turn‐On” for Precise MR Imaging of Tumors

For cancer diagnosis, ¹H magnetic resonance imaging (MRI) is advantageous in sensitivity but lacks selectivity. Endogenous ¹⁹F MRI signal in humans is barely detectable and thus ¹⁹F MRI has very high selectivity. A combination of ¹H and ¹⁹F MRI is ideal for precise tumor imaging but a protease‐controlled strategy of simultaneous T₂ ¹H MRI enhancement and ¹⁹F MRI “Turn‐On” has not been reported. Here, used is a click condensation reaction to rationally project a dual‐functional fluorine probe 4‐(trifluoromethyl)benzoic acid (TFMB)‐Arg‐Val‐Arg‐Arg‐Cys(StBu)‐Lys‐CBT ( 1 ), which is further utilized to functionalize Fe₃O₄ nanoparticle ( IONP ) to achieve IONP@1 . As such, the IONP aggregation can be activated by furin addition, thereby enhancing the T₂ ¹H MRI signal and switching the ¹⁹F NMR/MRI signal “On”. Using this strategy, IONP@1 is successfully applied to detect the activity of the furin enzyme with “Turn‐On” ¹⁹F NMR/MRI and T₂ ¹H MRI signals are enhanced. Moreover, IONP@1 is also applied for precise dual‐mode (¹H and ¹⁹F) MR imaging of tumors in zebrafish under 14.1 T. The current approach, therefore, provides a feasible and robust means to reconcile the dilemma between selectivity and sensitivity of conventional MRI probes. More importantly, it is envisioned that, by substituting the TFMB moiety in 1 with a perfluorinated compound, this “smart” method could be of potential use for precise ¹H MR and ¹⁹F MR imaging of tumor in mouse or in bigger rodents in near future.     

Unprecedented “All‐in‐One” Lanthanide‐Doped Mesoporous Silica Frameworks for Fluorescence/MR Imaging and Combination of NIR Light Triggered Chemo‐Photodynamic Therapy of Tumors

Designing a single multifunctional nanoparticle that can simultaneously impart both diagnostic and therapeutic functions is considered to be a long‐lasting hurdle for biomedical researchers. Conventionally, a multifunctional nanoparticle can be constructed by integrating organic dyes/magnetic nanoparticles to impart diagnostic functions and anticancer drugs/photosensitizers to achieve therapeutic outcomes. These multicomponents systems usually suffer from severe photobleaching problems and cannot be activated by near‐infrared (NIR) light. Here, it is demonstrated that all‐in‐one lanthanide‐doped mesoporous silica frameworks (EuGdOx@MSF) loaded with an anticancer drug, doxorubicin (DOX) can facilitate simultaneous bimodal magnetic resonance (MR) imaging with approximately twofold higher T₁‐MR contrast as compared to the commercial Gd(III)‐DTPA complex and fluorescence imaging with excellent photostability. Upon a very low dose (130 mW cm^?2) of NIR light (980 nm) irradiation, the EuGdOx@MSF not only can sensitize formation of singlet oxygen (¹O₂) by itself but also can phototrigger the release of the DOX payload effectively to exert combined chemo‐photodynamic therapeutic (PDT) effects and destroy solid tumors in mice completely. It is also discovered for the first time that the EuGdOx@MSF‐mediated PDT effect can suppress the level of the key drug resistant protein, i.e., p‐glycoprotein (p‐gp) and help alleviate the drug resistant problem commonly associated with many cancers.     

Nitroxide Radicals@US‐Tubes: New Spin Labels for Biomedical Applications

The encapsulation of nitroxide radicals within ultrashort (ca. 50 nm) single‐walled carbon nanotubes (US‐tubes) is achieved. Tempo‐ and Iodo‐Tempo@US‐tubes are characterized by thermogravimetric analysis (TGA), X‐ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Electron paramagnetic resonance (EPR) spectra display characteristic signals due to the detection of the spin probes within the US‐tubes. Longitudinal proton relaxivities (r₁) of both nitroxide@US‐tubes samples are 7 to 13 times greater than the free nitroxide radicals in solution, giving relaxivities comparable to the clinical contrast agent (CA) Magnevist. In addition, transverse proton relaxivities (r₂) show unprecedented proton relaxation enhancement in comparison to any other reported nitroxide radical‐based system or the clinically approved T₂ CA, Resovist, under the same conditions. T₂‐weighted magnetic resonance imaging (MRI) phantom images show that the encapsulation of nitroxide radicals within the US‐tubes produces good contrast enhancement due to their high r₂ relaxivities. The nitroxide radicals@US‐tube agents are a new promising class of spin probes for MRI and electronic paramagnetic resonance imaging (EPRI) labeling, tracking, and diagnosis.     

A General and Efficient Route to Fabricate Carbon Nanotube‐Metal Nanoparticles and Carbon Nanotube‐Inorganic Oxides Hybrids

Novel pyrenyl‐moieties‐decorated hyperbranched polyglycidol (pHBP) is synthesized and utilized for the functionalization of carbon nanotubes (CNTs) via a non‐covalent (non‐destructive) process. Mediated by a pHBP layer on the CNT sidewall, Au, Ag and Pt nanoparticles and uniform SiO₂, GeO₂ and TiO₂ coatings are generated in situ and deposited onto the as‐prepared CNT/pHBP hybrids, forming versatile homogeneous CNT‐based nanohybrid sols. The coverage of metal nanoparticles and oxide coatings is controllable simply by changing the employed amount of precursors. This easy synthetic strategy provides a general and convenient route to efficiently assemble a wide range of metal nanoparticles and inorganic oxide components on the sidewalls of CNTs, and enables the construction of heterogeneous nanostructures with novel functionalities. As a means of demonstrating the versatility of the fabricated hybrid materials, the catalytic function of CNT/pHBP/Pt hybrids towards the reduction of 4‐nitrophenol and the incorporation of dye molecules into the CNT/pHBP/SiO₂ matrix resulting in fluorescent nanofibers are investigated.     

Targeted Tumor Hypoxia Dual‐Mode CT/MR Imaging and Enhanced Radiation Therapy Using Dendrimer‐Based Nanosensitizers

The efficacy of radiation therapy (RT) is often limited by the poor response of hypoxia inside most solid tumors. The development of a theranostic nanoplatform for precision‐imaging‐guided sensitized RT for tumor hypoxia is still challenging. Herein, the creation of hypoxia‐targeted dendrimer‐entrapped gold nanoparticles complexed with gadolinium(III) (Gd‐Au DENPs‐Nit) for dual‐mode CT/MR imaging and sensitized RT of hypoxic tumors is reported. In this work, generation 5 poly(amidoamine) dendrimers are partially conjugated with Gd(III) chelator, entrapped with Au nanoparticles, and conjugated with hypoxia‐targeting agent nitroimidazole via a polyethylene glycol linker, and ending with chelation of Gd(III) and conversion of their leftover amine termini to acetamides. The designed dendrimer‐based nanohybrids with 3.2 nm Au cores exhibit an excellent X‐ray attenuation effect, acceptable r₁ relaxivity (1.32 mM^?1 s^?1), and enhanced cellular uptake in hypoxic cancer cells, affording efficient dual‐mode CT/MR imaging of tumor hypoxia. Under X‐ray irradiation, the Gd‐Au DENPs‐Nit nanohybrids can produce reactive oxygen species, promote DNA damage, and prevent DNA repair, facilitating sensitized RT of hypoxic cancer cells in vitro and tumor hypoxia in vivo. The developed hypoxia‐targeted dendrimer‐based nanohybrids may be employed as both contrast agents and nanosensitizers for precision tumor hypoxia imaging and sensitized tumor RT.