Near‐Infrared Light‐Mediated Photoactivation of a Platinum Antitumor Prodrug and Simultaneous Cellular Apoptosis Imaging by Upconversion‐Luminescent Nanoparticles

Platinum‐based drugs are among the most active antitumor reagents in clinical practice; their application is limited by side effects and drug resistance. A novel and personalized near‐infrared (NIR) light‐activated nanoplatform is obtained by combining a photoactivatable platinum(IV) prodrug and a caspase imaging peptide conjugated with silica‐coated upconversion‐luminescent nanoparticles (UCNPs) for the remote control of antitumor platinum prodrug activation, and simultaneously for real‐time imaging of apoptosis induced by activated cytotoxicity. Upon NIR light illumination, the Pt^IV prodrug complex is activated at the surface of the nanoparticle and active components are selectively released which display cytotoxicity against human ovarian carcinoma A2780 cells and its cisplatin‐resistant variant A2780cis cells. More importantly, the caspases enzymes triggered by cytotoxicity would effectively cleave the probe peptide, thereby allowing the direct imaging of apoptosis in living cells.     

Why is Rose Bengal More Phototoxic to Fibroblasts In Vitro Than In Vivo?

Photosensitized protein cross‐linking has been recently developed to seal wounds and strengthen tissue. Although the photosensitizing dye, Rose Bengal (RB), is phototoxic to cultured cells, cytotoxicity does not accompany RB‐photosensitized tissue repair in vivo. We investigated whether the environment surrounding cells in tissue or the high irradiances used for photo–cross‐linking inhibited RB phototoxicity. Fibroblasts (FB) grown within collagen gels to mimic a tissue environment and monolayer cultured FB were treated with RB (0.01–1 mm ) and the high 532 nm laser irradiances used in vivo for tissue repair (0.10–0.50 W cm^?2). Monolayer FB were substantially more sensitive to RB photosensitization: the LD₅₀ was >200‐fold lower than that in collagen gels. Collagen gel protection was associated with increased Akt phosphorylation, a prosurvival pathway. RB phototoxicity in collagen gels was 25‐fold greater at low (0.030 W cm^?2) that at high (0.50 W cm^?2) irradiances. Oxygen depletion at high irradiance only partially accounted for the irradiance dependence of phototoxicity as replacing air with nitrogen only increased the LD₅₀ by four‐fold in monolayers. These results indicate that the lack of RB phototoxicity during in vivo tissue repair results from upregulation of prosurvival pathways in tissue cells, oxygen depletion and irradiance‐dependent RB photochemistry.     

Peptide‐Coated Platinum Nanoparticles with Selective Toxicity against Liver Cancer Cells

Peptide‐stabilized platinum nanoparticles (PtNPs) were developed that have significantly greater toxicity against hepatic cancer cells (HepG2) than against other cancer cells and non‐cancerous liver cells. The peptide H‐Lys‐Pro‐Gly‐d Lys‐NH₂ was identified by a combinatorial screening and further optimized to enable the formation of water‐soluble, monodisperse PtNPs with average diameters of 2.5 nm that are stable for years. In comparison to cisplatin, the peptide‐coated PtNPs are not only more toxic against hepatic cancer cells but have a significantly higher tumor cell selectivity. Cell viability and uptake studies revealed that high cellular uptake and an oxidative environment are key for the selective cytotoxicity of the peptide‐coated PtNPs.     

Multifunctional Uniform Core–Shell Fe3O4@mSiO2 Mesoporous Nanoparticles for Bimodal Imaging and Photothermal Therapy

Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging‐guided focused tumor therapy. In this study, indocyanine green (ICG), a near‐infrared (NIR) imaging agent and perfect NIR light absorber for laser‐mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe₃O₄@mSiO₂ core–shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG‐loaded nanoparticles. The relatively high r₂ value (171.6 mM ^?1 s^?1) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG‐loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells.     

Facile Synthesis of Three‐Dimensional Pt‐TiO2 Nano‐networks: A Highly Active Catalyst for the Hydrolytic Dehydrogenation of Ammonia–Borane

Three‐dimensional (3D) porous metal and metal oxide nanostructures have received considerable interest because organization of inorganic materials into 3D nanomaterials holds extraordinary properties such as low density, high porosity, and high surface area. Supramolecular self‐assembled peptide nanostructures were exploited as an organic template for catalytic 3D Pt‐TiO₂ nano‐network fabrication. A 3D peptide nanofiber aerogel was conformally coated with TiO₂ by atomic layer deposition (ALD) with angstrom‐level thickness precision. The 3D peptide‐TiO₂ nano‐network was further decorated with highly monodisperse Pt nanoparticles by using ozone‐assisted ALD. The 3D TiO₂ nano‐network decorated with Pt nanoparticles shows superior catalytic activity in hydrolysis of ammonia–borane, generating three equivalents of H₂.     

Stimulus‐Induced Conformational Transformation of a Cyclic Peptide for Selective Cell‐Targeting On–Off Gatekeeper for Mesoporous Nanocarriers

α_vβ₃ Integrin is upregulated on many cancer cells. We designed a dual functional cyclic peptide gatekeeper with a capability of stimuli‐responsive conformational transformation which could serve as a selective cell‐targeting on–off gatekeeper for mesoporous nanocarriers. The advantage of employing the motif of stimuli‐induced conformational transformation of cyclic peptides is that they could be utilized not only as an on–off gatekeeper for the triggered release of cargo drugs but also as a targeting ligand of the carriers to desired cells with their respective binding receptors. The peptide gatekeepers on the surface of nanocarriers exhibited on–off gatekeeping via conformational transformation triggered by intracellular glutathione levels of the cancer cells. The cyclic RGD sequence of the peptide gatekeepers enhanced the intracellular uptake into tumor cells (A549) and the therapeutic efficacy of the nanocarrier.     

NIR‐II Fluorescent Self‐Assembled Peptide Nanochain for Ultrasensitive Detection of Peritoneal Metastasis

Fluorescence‐guided cytoreductive surgery is one of the most promising approaches for facile elimination of tumors in situ, thereby improving prognosis. Reported herein is a simple strategy to construct a novel chainlike NIR‐II nanoprobe (APP‐Ag₂S‐RGD) by self‐assembly of an amphiphilic peptide (APP) into a nanochain with subsequent chemical crosslinking of NIR‐II Ag₂S QDs and the tumor‐targeting RGD peptide. This probe exhibits higher capability for cancer cell detection compared with that of RGD‐functionalized Ag₂S QDs (Ag₂S‐RGD) at the same concentration. Upon intraperitoneal injection, superior tumor‐to‐normal tissue signal ratio is achieved and non‐vascularized tiny tumor metastatic foci as small as about 0.2 mm in diameter could be facilely eliminated under NIR‐II fluorescent imaging guidance. These results clearly indicate the potential of this probe for fluorescence‐guided tumor staging, preoperative diagnosis, and intraoperative navigation.     

Synthesis of a Photostable Near‐Infrared‐Absorbing Photosensitizer for Selective Photodamage to Cancer Cells

A new class of near‐infrared (NIR)‐absorptive (>900 nm) photosensitizer based on a phenothiazinium scaffold is reported. The stable solid compound, o‐DAP, the oxidative form of 3,7‐bis(4‐methylaminophenyl)‐10H‐phenothiazine, can generate reactive oxygen species (ROS, singlet oxygen and superoxide) under appropriate irradiation conditions. After biologically evaluating the intracellular uptake, localization, and phototoxicity of this compound, it was concluded that o‐DAP is photostable and a potential selective photodynamic therapy (PDT) agent under either NIR or white light irradiation because its photodamage is more efficient in cancer cells than in normal cells and is without significant dark toxicity. This is very rare for photosensitizers in PDT applications.     

Near‐Infrared‐Emissive Amphiphilic BODIPY Assemblies Manipulated by Charge‐Transfer Interaction: From Nanofibers to Nanorods and Nanodisks

A novel near‐infrared (NIR)‐emissive amphiphilic BODIPY derivative, BBDP, was successfully prepared and thoroughly characterized. The photophysical properties in various organic solvents and THF/H₂O mixtures with different fractions of water were investigated. BBDP self‐assembled into nanofibers in a water environment owing to its amphiphilic properties. Through charge‐transfer interactions, BBDP co‐assembled with a perylene bisimide derivative, PBI, and a viologen derivative, MV, to generate two superamphiphiles. These two superamphiphiles were able to aggregate in water media at appropriate concentrations. The BBDP–PBI charge‐transfer complex formed nanorods, whereas the BBDP–MV aggregates expressed a disk‐like morphology. This research paves the way for us to manipulate the morphology of dye assemblies.     

Gold Nanorods with Phase‐Changing Polymer Corona for Remotely Near‐Infrared‐Triggered Drug Release

Herein, we report a new drug‐delivery system (DDS) that is comprised of a near‐infrared (NIR)‐light‐sensitive gold‐nanorod (GNR) core and a phase‐changing poly(ε‐caprolactone)‐b‐poly(ethylene glycol) polymer corona (GNR@PCL‐b‐PEG). The underlying mechanism of the drug‐loading and triggered‐release behaviors involves the entrapment of drug payloads among the PCL crystallites and a heat‐induced phase change, respectively. A low premature release of the pre‐loaded doxorubicin was observed in PBS buffer (pH 7.4) at 37 °C (<10 % of the entire payload after 48 h). However, release could be activated within 30 min by conventional heating at 50 °C, above the T_m of the crystalline PCL domain (43.5 °C), with about 60 % release over the subsequent 42 h at 37 °C. The NIR‐induced heating of an aqueous suspension of GNR@PCL‐b‐PEG under NIR irradiation (802 nm) was investigated in terms of the irradiation period, power, and concentration‐dependent heating behavior, as well as the NIR‐induced shape‐transformation of the GNR cores. Remotely NIR‐triggered release was also explored upon NIR irradiation for 30 min and about 70 % release was achieved in the following 42 h at 37 °C, with a mild warming (<4 °C) of the surroundings. The cytotoxicity of GNR@PCL‐b‐PEG against the mouse fibroblastic‐like L929 cell‐line was assessed by MTS assay and good compatibility was confirmed with a cell viability of over 90 % after incubation for 72 h. The cellular uptake of GNR@PCL‐b‐PEG by melanoma MEL‐5 cells was also confirmed, with an averaged uptake of 1250(±110) particles cell^?1 after incubation for 12 h (50 μg mL^?1). This GNR@PCL‐b‐PEG DDS is aimed at addressing the different requirements for therapeutic treatments and is envisaged to provide new insights into DDS targeting for remotely triggered release by NIR activation.     

Ag@TiO2 Nanoprisms with Highly Efficient Near‐Infrared Photothermal Conversion for Melanoma Therapy

Melanoma is a primary reason of death from skin cancer and associated with high lethality. Photothermal therapy (PTT) has been developed into a powerful cancer treatment technique in recent years. Here, we created a low‐cost and high‐performance PTT agent, Ag@TiO₂ NPs, which possesses a high photothermal conversion efficiency of ≈65 % and strong near‐infrared (NIR) absorption about 808 nm. Ag NPs were synthesized using a two‐step method and coated with TiO₂ to obtain Ag@TiO₂ NPs by a facile sol‐gel method. Because of the oxide, Ag@TiO₂ NPs exhibit remarkable high photothermal conversion efficiencies and biocompatibility in vivo and in vitro. Cytotoxicity and therapeutic efficiency of photothermal cytotoxicity of Ag@TiO₂ NPs were tested in B16‐F10 cells and C57BL/6J mice. Under light irradiation, the elevated temperature causes cell death in Ag NPs‐treated (100 μg mL^?1) cells in vitro (both p<0.01). In the case of subcutaneous melanoma tumor model, Ag@TiO₂ NPs (100 μg mL^?1) were injected into the tumor and irradiated with a 808 nm laser of 2 W cm^?2 for 1 minute. As a consequence, the tumor volume gradually decreased by NIR laser irradiation with only a single treatment. The results demonstrate that Ag@TiO₂ NPs are biocompatible and an attractive photothermal agent for cutaneous melanoma by local delivery.     

Eliminated Phototoxicity of TiO2 Particles by an Atomic‐Layer‐Deposited Al2O3 Coating Layer for UV‐Protection Applications

We demonstrate the conformal coating of an ultrathin Al₂O₃ layer on TiO₂ nanoparticles through atomic layer deposition by using a specifically designed rotary reactor to eliminate the phototoxicity of the particles for cosmetic use. The ALD reactor is modified to improve the coating efficiency as well as the agitation of the particles for conformal coating. Elemental and microstructural analyses show that ultrathin Al₂O₃ layers are conformally deposited on the TiO₂ nanoparticles with a controlled thickness. Rhodamine B dye molecules on Al₂O₃‐coated TiO₂ exhibited a long life time under UV irradiation, that is, more than 2 h, compared to that on bare TiO₂, that is, 8 min, indicating mitigation of photocatalytic activity by the coated layer. The effect of carbon impurities in the film resulting from various deposition temperatures and thicknesses of the Al₂O₃ layer on the photocatalytic activity are also thoroughly investigated with controlled experimental condition by using dye molecules on the surface. Our results reveal that an increased carbon impurity resulting from a low processing temperature provides a charge conduction path and generates reactive oxygen species causing the degradation of dye molecule. A thin coated layer, that is, less than 3 nm, also induced the tunneling of electrons and holes to the surface, hence oxidizing dye molecules. Furthermore, the introduction of an Al₂O₃ layer on TiO₂ improves the light trapping thus, enhances the UV absorption.     

Promoting self-assembly of collagen-related peptides into various higher-order structures by metal-histidine coordination

Collagen is an important and widely used biomaterial and therapeutic. The construction of large-scale collagen structures via the self-assembly of small collagen-related peptides has been extensively studied in the past decade. Here, we report a highly effective and simple means to assemble small synthetic collagen-related peptides into various higher-order structures by utilizing metal-histidine coordination. In this work, two short collagen-related peptides in which histidine residues were incorporated as metal binding sites were designed and chemically synthesized: HG(PPG)(9)GH (X9) and HG(PPG)(4)(PHG)(PPG)(4)GH (PHG). Circular dichroism measurements indicated that these two peptides form only marginally stable collagen triple helices but that their stability can be increased upon the addition of metal ions. Dynamic light scattering analyses, turbidity measurements, TEM, and SEM results demonstrated the metal ion-dependent self-assembly of X9 and PHG into supramolecular structures ranging from various nanofibrils to microscale spherical, laminated, and granulated assemblies. The topology and size of these higher-order structures depends both on the metal ion identity and the location of the binding sites. Most intriguingly, the assembled fibrils show similar D-periodicity to that of natural collagen. Our results demonstrate that metal-histidine coordination can serve as an effective force to induce the self-assembly of unstable collagen-related peptides into higher-order structures.     

Light‐Induced Chiral Iron Copper Selenide Nanoparticles Prevent β‐Amyloidopathy In Vivo

The accumulation and deposition of β‐amyloid (Aβ) plaques in the brain is considered a potential pathogenic mechanism underlying Alzheimer's disease (AD). Chiral l/d ‐Fe_xCu_ySe nanoparticles (NPs) were fabricated that interfer with the self‐assembly of Aβ42 monomers and trigger the Aβ42 fibrils in dense structures to become looser monomers under 808 nm near‐infrared (NIR) illumination. d ‐Fe_xCu_ySe NPs have a much higher affinity for Aβ42 fibrils than l ‐Fe_xCu_ySe NPs and chiral Cu_2?xSe NPs. The chiral Fe_xCu_ySe NPs also generate more reactive oxygen species (ROS) than chiral Cu_2?xSe NPs under NIR‐light irradiation. In living MN9D cells, d ‐NPs attenuate the adhesion of Aβ42 to membranes and neuron loss after NIR treatment within 10 min without the photothermal effect. In‐vivo experiments showed that d ‐Fe_xCu_ySe NPs provide an efficient protection against neuronal damage induced by the deposition of Aβ42 and alleviate symptoms in a mouse model of AD, leading to the recovery of cognitive competence.     

Monodisperse Magnetite Nanoparticles Coupled with Nuclear Localization Signal Peptide for Cell‐Nucleus Targeting

Functionalization of monodisperse superparamagnetic magnetite (Fe₃O₄) nanoparticles for cell specific targeting is crucial for cancer diagnostics and therapeutics. Targeted magnetic nanoparticles can be used to enhance the tissue contrast in magnetic resonance imaging (MRI), to improve the efficiency in anticancer drug delivery, and to eliminate tumor cells by magnetic fluid hyperthermia. Herein we report the nucleus‐targeting Fe₃O₄ nanoparticles functionalized with protein and nuclear localization signal (NLS) peptide. These NLS‐coated nanoparticles were introduced into the HeLa cell cytoplasm and nucleus, where the particles were monodispersed and non‐aggregated. The success of labeling was examined and identified by fluorescence microscopy and MRI. The work demonstrates that monodisperse magnetic nanoparticles can be readily functionalized and stabilized for potential diagnostic and therapeutic applications.     

A Highly Photostable Near‐Infrared Labeling Agent Based on a Phospha‐rhodamine for Long‐Term and Deep Imaging

Various fluorescence microscopy techniques require bright NIR‐emitting fluorophores with high chemical and photostability. Now, the significant performance improvement of phosphorus‐substituted rhodamine dyes (PORs) upon substitution at the 9‐position with a 2,6‐dimethoxyphenyl group is reported. The thus obtained dye PREX 710 was used to stain mitochondria in living cells, which allowed long‐term and three‐color imaging in the vis‐NIR range. Moreover, the high fluorescence longevity of PREX 710 allows tracking a dye‐labeled biomolecule by single‐molecule microscopy under physiological conditions. Deep imaging of blood vessels in mice brain has also been achieved using the bright NIR‐emitting PREX 710‐dextran conjugate.     

Efficient Gene Transfection through Inhibition of β‐Sheet (Amyloid Fiber) Formation of a Short Amphiphilic Peptide by Gold Nanoparticles

The effect of citrate‐stabilized gold nanoparticles (AuNPs) on the secondary structure of an artificial β‐sheet‐forming cationic peptide has been studied. The AuNPs inhibited β‐sheet formation and led to fragmented fibrils and spherical oligomers with assembled AuNPs on their surface. Besides this structural change, the functional properties of the peptide are also different. Whereas the peptide was unable to act as a vector for gene delivery, formation of a complex with AuNPs allowed successful gene delivery into cells.     

Boron Difluoride Curcuminoid Fluorophores with Enhanced Two‐Photon Excited Fluorescence Emission and Versatile Living‐Cell Imaging Properties

The synthesis of boron difluoride complexes of a series of curcuminoid derivatives containing various donor end groups is described. Time‐dependent (TD)‐DFT calculations confirm the charge‐transfer character of the second lowest‐energy transition band and ascribe the lowest energy band to a “cyanine‐like” transition. Photophysical studies reveal that tuning the donor strength of the end groups allows covering a broad spectral range, from the visible to the NIR region, of the UV–visible absorption and fluorescence spectra. Two‐photon‐excited fluorescence and Z‐scan techniques prove that an increase in the donor strength or in the rigidity of the backbone results in a considerable increase in the two‐photon cross section, reaching 5000 GM, with predominant two‐photon absorption from the S₀–S₂ charge‐transfer transition. Direct comparisons with the hemicurcuminoid derivatives show that the two‐photon active band for the curcuminoid derivatives has the same intramolecular charge‐transfer character and therefore arises from a dipolar structure. Overall, this structure–relationship study allows the optimization of the two‐photon brightness (i.e., 400–900 GM) with one dye that emits in the NIR region of the spectrum. In addition, these dyes demonstrate high intracellular uptake efficiency in Cos7 cells with emission in the visible region, which is further improved by using porous silica nanoparticles as dye vehicles for the imaging of two mammalian carcinoma cells type based on NIR fluorescence emission.     

Fluorescent Coumarin–Artemisinin Conjugates as Mitochondria‐Targeting Theranostic Probes for Enhanced Anticancer Activities

Mitochondria‐targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria‐targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin‐3‐carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin–artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria‐targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells.     

Fabrication of 105Y,Alpha 1‐Anti Trypsin Peptide Conjugated Hybrid Nanoparticles for Biological Applications

In this report, we describe the characterizations and applications of hybrid nanoparticles. These nanoparticles have been synthesized by combination of organometallic, polymerization process and functionalized with a specific peptide for targeting expressed serpin‐enzyme complex (SEC) receptor of human hepatoma HepG2 cells. By using peptide conjugated hybrid nanoparticles, the specific receptor targeting, collections of cells were successfully achieved. The cell collection results indicated that, the maximum up to 95.32% of HepG2 cell were collected. The 5‐dimethylthiazol‐2‐yl‐2,5‐diphenyltetrazolium bromide (MTT) assay of HepG2 cells incubated with these nanoparticles indicated that, the peptide conjugated hybrid nanoparticles did not possess significant cytotoxicity. The rotating magnetic field induced cell death studies indicated that, the HepG2 cell showed up to 70% of cell death was induced by hybrid nanoparticles under magnetic field. Concluding, these studies demonstrate that the hybrid nanoparticles have the capability of effective separation, imaging, targeting and killing of the human hepatoma cells.