Energy-storing DNA-based hydrogel remodels tumor microenvironments for laser-free photodynamic immunotherapy.

Photodynamic therapy (PDT) is a promising modality for cancer treatment. However, limited tissue penetration of external radiation and complicated tumor microenvironments (TMEs) restrict the antitumor efficiency of PDT. Herein, we report an energy-storing DNA-based hydrogel, which enables tumor-selective PDT without external radiation and regulates TMEs to achieve boosted PDT-mediated tumor immunotherapy. The system is constructed with two ultralong single-stranded DNA chains, which programmed partial complementary sequences and repeated G-quadruplex forming AS1411 aptamer for photosensitizer loading via hydrophobic interactions and π-π stacking. Then, energy-storing persistent luminescent nanoparticles are incorporated to sensitize PDT selectively at tumor site without external irradiation, generating tumor antigen to agitate antitumor immune response. The system catalytically generates O2 to alleviate hypoxia and releases inhibitors to reverse the IDO-related immunosuppression, synergistically remodeling the TMEs. In the mouse model of breast cancer, this hydrogel shows a remarkable tumor suppression rate of 78.3 %. Our study represents a new paradigm of photodynamic immunotherapy against cancer by combining laser-free fashion and TMEs remodeling.

Persistent luminescent metal-organic framework nanocomposite enables autofluorescence-free dual modal imaging-guided drug delivery.

Molecular imaging-guided therapy was essential for realizing precise cancer intervention, while designing an imaging platform to achieve autofluorescence-free imaging for dual modal imaging-guided drug delivery remains a challenge. Near-infrared persistent luminescence nanoparticles (NIR PLNPs) were promising for tumor imaging due to no background interference from the tissue. Herein, a persistent luminescent metal-organic framework (PLNPs@MIL-100(Fe)) is prepared via a layer-by-layer method for dual-modal imaging-guided drug delivery. The PLNPs@MIL-100(Fe) exhibit NIR persistent luminescence emitting and T2-weighted signal, achieving precise in vivo dual-modal imaging of tumor-bearing mice by providing high spatial resolution MR imaging and autofluorescence-free NIR imaging. The porous MIL-100(Fe) shell provides PLNPs@MIL-100(Fe) with up to 87.1% drug loading capacity and acid-triggered drug release for drug delivery. We envision that the proposed PLNPs@MIL-100(Fe) platform would provide an effective approach for precise tumor imaging and versatile drug delivery.

An Energy-Storing DNA-Based Nanocomplex for Laser-Free Photodynamic Therapy.

Photodynamic therapy (PDT) is a therapeutic strategy that is dependent on external light irradiation that faces a major challenge in cancer treatment due to the poor tissue-penetration depths of light irradiation. Herein, a DNA nanocomplex that integrates persistent-luminescence nanoparticles (PLNPs) is developed, which realizes tumor-site glutathione-activated PDT for breast cancer without exogenous laser excitation. The scaffold of the nanocomplex is AS1411-aptamer-encoded ultralong single-stranded DNA chain with two functions: i) providing sufficient intercalation sites for the photosensitizer, and ii) recognizing nucleolin that specifically overexpresses on the surface of cancer cells. The PLNPs in the nanocomplex are energy-charged to act as a self-illuminant and coated with a shell of MnO2 for blocking energy degradation. In response to the overexpressed glutathione in cancer cells, the MnO2 shell decomposes to provide Mn2+ to catalytically produce O2 , which is essential to PDT. Meanwhile, PLNPs are released and act as a self-illuminant to activate the photosensitizer to convert O2 into cytotoxic 1 O2 . Significant tumor inhibition effects are demonstrated in breast tumor xenograft models without exogenous laser excitation. It is envisioned that a laser-excitation-free PDT strategy enabled by the PLNP-DNA nanocomplex promotes the development of PDT and provides a new local therapeutic approach.

A Synergistic DNA-polydopamine-MnO2 Nanocomplex for Near-Infrared-Light-Powered DNAzyme-Mediated Gene Therapy.

DNAzyme is emerging for gene therapy. The administration of the in vivo catalytic activity of DNAzyme has proven important but challenging for clinical applications. Herein, we report a synergistic DNA-polydopamine-MnO2 nanocomplex, which enables near-infrared (NIR)-light-powered catalytic activity of DNAzyme in vivo. The nanocomplex has a hierarchical structure: a DNA nanoframework as the scaffold and polydopamine-MnO2 (PM) as the coating layer. The DNA nanoframework contains repeated DNAzyme sequences. PM assembles on the surface of the DNA nanoframework. When the nanocomplex accumulates at tumor sites, upon NIR-light radiation, polydopamine induces a temperature elevation at tumor sites via photothermal conversion; meanwhile, glutathione triggers decomposition of PM to release Mn2+ to activate DNAzyme in the cytoplasm for gene regulation. In vitro and in vivo experiments show that the PM-induced temperature elevation enhances the Egr-1 mRNA cleavage activity of DNAzyme, promoting downregulation of the Egr-1 protein in tumor cells. In addition, the temperature elevation induces heat stress, achieving a synergistic tumor ablation effect.

Dual Roles of Metal-Organic Frameworks as Nanocarriers for miRNA Delivery and Adjuvants for Chemodynamic Therapy.

MicroRNA (miRNA) represents a promising class of therapeutic nucleic acid drugs, while delivery challenges remain that impede the advancement of miRNA therapy, largely because of in vivo instability and low delivery efficiency. Herein, we discover the dual roles of metal-organic framework (MOF) nanoparticles (ZIF-8) as nanocarriers for miRNA delivery and adjuvants for chemodynamic therapy. The miR-34a-m@ZIF-8 complex demonstrated efficient cellular uptake and lysosomal stimuli-responsive miRNA release. Zn2+ triggered the generation of reactive oxygen species, which consequently induced apoptosis of tumor cells. Released miR-34a-m led to a remarkable decrease in expression of Bcl-2 at both mRNA and protein levels and enhanced cancer cell apoptosis. In vivo experiments showed high efficacy of using miR-34a-m@ZIF-8 to suppress tumor growth via synergistic gene/chemodynamic therapy in a mouse model of triple-negative breast cancer. Our work demonstrates MOFs as a promising nanoplatform for efficient synergetic gene/chemodynamic therapy.

Enzymatical biomineralization of DNA nanoflowers mediated by manganese ions for tumor site activated magnetic resonance imaging.

DNA nanoflower has been demonstrated as a promising DNA nanostructure for therapeutics and bioimaging primarily because of the programmable DNA sequence and unique structure. Herein, we report manganese ions mediated enzymatic biomineralization to prepare DNA-Mn hybrid nanoflower (DMNF). Paramagnetic Mn2+ was explored as the co-factor of DNA polymerase for the extension of long strand DNA. The biomimetic synthesis of DMNF was performed using the long strand DNA as template via nucleation and growth of Mn2PPi. The morphology and size of DMNF were controllable by tuning reaction time and Mn2+ concentration. The aptamer sequence was encoded into circle template to achieve tumor-targeted DMNF, and cellular uptake assay demonstrated obvious aptamer-mediated internalization. DMNF showed enhanced T1-weighted magnetic resonance (MR) imaging effect in acid environment for high tumor-specific MR imaging, and high spatial resolution imaging of kidneys and liver. Our work provides a facile enzymatically biomineral strategy to integrate multifunctional modules into one DNA structure and promotes the development of DNA nanostructure for precision medicine.

Biosynthetic molecular imaging probe for tumor-targeted dual-modal fluorescence/magnetic resonance imaging.

Molecular imaging enables noninvasive visualization of cancer-related biological processes for tumor diagnostics; engineering molecular probes for accurate and efficient tumor imaging remains challenge. Herein, by using a biosynthetic strategy, we prepared a tumor-targeted fluorescence/magnetic resonance protein-based probe for dual-modal imaging. The probe was biosynthesized by the fusion of targeting peptide (RGD) with fluorescence protein (RFP) and a small peptide (LBT) that had strong affinity with Gd3+. The probe showed excellent RGD-mediated tumor targeting and stable infrared emission, enabling sensitive tumor-specific imaging. Moreover, efficient T1-weighted magnetic resonance imaging was observed both in vitro and at tumor sites, facilitating high spatial resolution tumor imaging. The simultaneous dual-modal imaging provided more complementary information than each imaging modality. Our work demonstrates the capability of biosynthetic strategy to engineer molecular imaging probes for tumor-targeted multimodal bioimaging, and the probes can be customized to precisely localize and monitor other types of diseases.

Persistent Luminescent Nanoparticles Containing Hydrogels for Targeted, Sustained, and Autofluorescence-Free Tumor Metastasis Imaging.

Metastasis is the primary cause of cancer morbidity and mortality. To obtain an effective diagnosis and treatment, precise imaging of tumor metastasis is required. Here we prepared persistent luminescent nanoparticles (PLNPs) containing a hydrogel (PL-gel) for targeted, sustained, and autofluorescence-free tumor metastasis imaging. PLNPs offered renewable long-lasting near-infrared (NIR) emitting without in situ radiation, favoring deep tissue penetration imaging without background interference. PLNPs were conjugated with 4-carboxyphenyl boronic acid (CPBA) to yield PLNPs-CPBA, which specifically recognized metastatic breast cancer cells (MBA-MD-231 cells) and enabled receptor-mediated endocytosis for specific cancer cell labeling. The PLNPs-CPBA-labeled cancer cells enabled sensitive imaging performance and high viability without influencing the migration and invasiveness of cancer cells for long-term tracking. PLNPs-CPBA were further encapsulated inside alginate to generate PL-gel for sustained PLNPs-CPBA release and tumor cell labeling, and the PL-gel showed enhanced renewable persistent luminescence compared to the PLNPs-CPBA suspension. The metastasis in the mouse breast cancer model was continuously tracked by persistent luminescence imaging, showing that PL-gel achieved noninvasive and highly selective imaging of tumor metastasis without background interference. Our PL-gel could be rationally designed to specifically target other types of cancer cells and thus provide a powerful and generic platform for the study of tumor metastasis.

Persistent luminescent metal-organic frameworks with long-lasting near infrared emission for tumor site activated imaging and drug delivery.

Luminescent porous materials have been widely used in biosensing, bioimaging and drug delivery by virtue of the special porous structure and luminescent property. The main obstacle for the application in biosensing and bioimaging is the background interference of external irradiation. Herein, we report a background interference-free persistent luminescent metal-organic framework (PLMOF) with persistent luminescent near infrared (NIR) luminescence for tumor site activated persistent luminescence imaging. The PLMOF (PLNPs@ZIF-8) was prepared by in-situ growth of MOF on the persistent luminescent nanoparticles (PLNPs) via a surface adsorption induced self-assembly method. The PLMOF possessed NIR persistent luminescence and renewable NIR luminescence and thus enabled deep-tissue and long-term imaging without external excitation. Specifically, the PLMOF showed acidic tumor site activated persistent luminescence for in vitro and in vivo tumor imaging, which was also help to reduce the background interference. The mechanism of acidic activation was attributed to the protonation of imidazole that induces disassembly of ZIF-8. In addition, the PLMOF presented a high anti-cancer drug loading capacity, acidity-responsive drug release behavior, and significant anti-tumor effect. All these results indicate that our PLMOF can serve as a promising theranostic platform for precision medicine.

Microwave-Assisted Synthesis of Black Titanium Monoxide for Synergistic Tumor Phototherapy.

Black titanium oxide has attracted tremendous interest in tumor phototherapy via converting light energy to heat and reactive oxygen species (ROS). Nevertheless, current synthesis methods suffer from inert gas shielding, high costs, complicated procedures, and expensive facilities, which are fairly impractical for treatment application. Herein, we propose a one-step strategy for fast facile synthesis of black TiO nanoparticles via a microwave-assisted hydrothermal synthesis approach with Ti power, hydrochloric acid, and hydrofluoric acid without the requirement of an reducing agent and high-temperature calcination. The prepared black TiO nanoparticles with an average size of 52 nm exhibit strong absorbance from ultraviolet (UV) to near-infrared light region, favoring a single agent and single light-induced synergistic phototherapy of tumors. The black TiO nanoparticles shows an excellent performance in phototherapy with a photothermal conversion efficiency up to 50% and a prominent ROS generation under 808 nm laser irradiation. The toxicity and therapeutic effect in vitro and in vivo are investigated, and the results elucidate that black TiO nanoparticles possess good biocompatibility and remarkable synergistic tumor therapeutic efficacy. The proposed microwave-assisted method opens up a novel way for the synthesis of titanium-based material in a simple and fast manner, promoting their applications in the biomedical field.

Fabrication and bioconjugation of BIII and CrIII co-doped ZnGa2O4 persistent luminescent nanoparticles for dual-targeted cancer bioimaging.

Persistent luminescent nanoparticles (PLNPs) show great potential in realizing precision imaging due to the absence of in situ excitation and no background interference. However, the current PLNP-based tumour imaging is usually achieved by single targeting or passive targeting strategies, and thus it lacks high specificity and affinity for efficient persistent luminescence imaging in vivo. Herein we report the bioconjugation of multiple targeting ligands on the surface of PLNPs for dual-targeted bioimaging to improve the specificity and affinity of the PLNP nanoprobe for in vitro and in vivo bioimaging. The PLNPs were prepared by co-doping CrIII and BIII into ZnGa2O4via a hydrothermal-calcination method. While CrIII doped ZnGa2O4 PLNPs possess excellent near-infrared luminescence along with long afterglow and red light renewable near-infrared luminescence, doping of BIII into the PLNPs further improves the persistent luminescence. Conjugation of two targeting ligands, hyaluronic acid and folic acid, which have specificity toward the cluster determinant 44 receptor and folic acid receptor in tumour cells, respectively, provides synergistic targeting effects to enhance the specificity and affinity toward tumour cells. This work provides a dual-targeting strategy for fabricating PLNP-based nanoprobes to realize precision tumour-targeted bioimaging.

Biomineralization of Versatile CuS/Gd2 O3 Hybrid Nanoparticles for MR Imaging and Antitumor Photothermal Chemotherapy.

The versatile application of nanoparticles in integrating imaging and therapy has aroused extensive research interest in precision medicine. Of the various nanoparticles that have been studied, CuS has shown great potential in the construction of multifunctional agents, owing to its excellent photothermal heating properties. Herein, we report a facile one-pot biomineralization approach for the preparation of versatile bovine-serum-albumin-conjugated CuS/Gd2 O3 hybrid nanoparticles (BSA-CuS/Gd2 O3 HNPs), which simultaneously possessed strong longitudinal relaxivity, an outstanding photothermal effect, high drug-loading capacity, and pH/temperature-responsive drug release. The versatile nanoparticles were used for magnetic resonance imaging (MRI) and antitumor photothermal chemotherapy, both in vitro and in vivo. In vivo MRI showed that the BSA-CuS/Gd2 O3 HNPs had a long circulation time and effective passive tumor-uptake ability. More importantly, combined in vitro and in vivo therapy demonstrated that drug-loaded BSA-CuS/Gd2 O3 HNPs offered outstanding synergistic therapeutic efficacy for tumor inhibition.

Theranostic metal-organic framework core-shell composites for magnetic resonance imaging and drug delivery.

Metal-organic frameworks (MOFs) have shown great potential in designing theranostic probes for cancer diagnosis and therapy due to their unique properties, including versatile structures and composition, tunable particle and pore size, enormous porosity, high surface area, and intrinsic biodegradability. In this study, we demonstrate novel MOF-based theranostic Fe3O4@UiO-66 core-shell composites constructed by in situ growth of a UiO-66 MOF shell on a Fe3O4 core for simultaneous drug delivery and magnetic resonance (MR) imaging. In the composites, the UiO-66 shell is devoted for encapsulating the drug, whereas the Fe3O4 core serves as a MR contrast agent. The Fe3O4@UiO-66 core-shell composites show good biocompatibility, high drug loading capacity, sustained drug release, and outstanding MR imaging capability, as well as effective chemotherapeutic efficacy, demonstrating the feasibility of designing theranostic Fe3O4@UiO-66 core-shell composites for cancer diagnosis and therapy.

[Separation of derivatized aliphatic aldehydes in beverage by nonaqueous capillary electrophoresis].

A simple and mild method for the separation of aliphatic aldehydes based on a condensation reaction with 9,10-phenanthrenequinone as labeling reagent with nonaqueous capillary electrophoresis has been developed. The detection was performed with a diode array detector (DAD). A 58.5 cm (50 cm effective length) x 50 microm i.d. untreated fused-silica capillary was used. To optimize the conditions, the background electrolyte concentration, column temperature, voltage and other factors were evaluated. The results indicated that the buffer concentration had a great impact on the separation, but the influences of temperature and added additives on the resolution were not obvious. The optimized conditions were as follows: 80 mmol/L ammonium acetate, 1.4 mol/L acetic acid, voltage of 28 kV, column temperature of 20 degrees C and DAD detection at 254 nm. The samples were introduced atmospherically with the injection at 5 kPa (50 mbar) for 8 s. The results indicate that seven aliphatic aldehyde derivatives and actual samples can be achieved baseline resolution under the proposed conditions.

[A novel fluorescence reagent for the analysis of trace free oestradiol and oestriol in urine by reversed-phase high performance liquid chromatography with fluorescence detection and mass spectrometry identification].

A new fluorescent derivatization reagent, 10-ethyl-9-oxo-9, 10-dihydroacridine-2-sulfonyl chloride (EASC), was synthesized. A pre-column derivatization with EASC and reversed-phase high performance liquid chromatographic (RP-HPLC) method with fluorescence (FL) detection and mass spectrometry (MS) identification was performed for the trace analysis of oestradiol (E2) and oestriol (E3) in urine. This reagent shows higher sensitivities in ultraviolet (UV), FL and MS detection than those of dansyl chloride (DNS-Cl), and the fluorescence intensity of EASC is 1000 times higher than that of DNS-Cl. The results of derivatization indic ted that the derivatives can be obtained by the labeling reaction of EASC with estradiol (E2 and estriol (E3) in the presence of NaHCO3 buffer (pH 10.5) at 60 degrees C for 3 min. The excitation wavelength (lamda ex) and emission wavelength (lamda em) were 270 nm and 430 nm, respectively. The established method exhibited excellent reproducibility and recovery. The calibration curve were linear with regression coefficients over 0.9990, and the detection limits (S/N = 3) w 40, 31 fmol for the studied compounds. The practical applicability of the method was demonstrated by analyzing trace of free oestradiol and oestriol in the urine of root voles.

Application of 10-ethyl-acridine-3-sulfonyl chloride for HPLC determination of aliphatic amines in environmental water using fluorescence and APCI-MS.

A simple, sensitive method for the determination of aliphatic amines based on a sulfonylation reaction using 10-ethyl-acridine-3-sulfonyl chloride (EASC) as pre-column labeling reagent with fluorescence detection and APCI-MS identification has been developed. The labeled derivatives exhibited high stability and were enough to be efficiently analyzed by HPLC with an excitation maximum at lambda(ex) 270 nm and an emission maximum at lambda(em) 430 nm. Identification of derivatives was carried out by online post-column MS in positive-ion mode. Comparing with the widely used 5-dimethylaminonaphthalene-1-sulfonylchloride (Dansyl-Cl), EASC-amine derivatives not only exhibited high fluorescence but also exhibited excellent MS ionizable potential. Detection limits obtained from 0.10 pmol injection, at a S/N of 3, were 4.0-12.7 fmol. The mean intra- and inter-assay precision for all aliphatic amine levels were <3.84 and 3.21%, respectively. Excellent linear responses were observed with coefficients of >0.9995.

A sensitive fluorescence reagent for the determination of aldehydes from alcoholic beverage using high-performance liquid chromatography with fluorescence detection and mass spectrometric identification.

A pre-column derivatization method for the sensitive determination of aldehydes using the tagging reagent 2-[2-(7H-dibenzo[a,g] carbazol-7-yl)-ethoxy] ethyl carbonylhydrazine (DBCEEC) followed by high-performance liquid chromatography with fluorescence detection and APCI-MS identification has been developed. The chromophore of fluoren-9-methoxy-carbonylhydrazine (Fmoc-hydrazine) reagent was replaced by 2-[2-(7H-dibenzo[a,g] carbazol-7-yl)-ethoxy] ethyl functional group, which resulted in a sensitive fluorescence tagging reagent DBCEEC. DBCEEC could easily and quickly labeled aldehydes. The maximum excitation (300nm) and emission (400nm) wavelengths did not essentially change for all the aldehyde derivatives. Derivatives were sufficiently stable to be efficiently analyzed by high-performance liquid chromatography. The derivatives showed an intense protonated molecular ion corresponding m/z [M+(CH(2))(n)](+) in positive-ion mode (M: molecular weight of DBCEEC, n: corresponding aldehyde carbon atom numbers). The collision-induced dissociation of protonated molecular ion formed fragment ions at m/z 294.6, m/z 338.6 and m/z 356.5. Studies on derivatization demonstrated excellent derivative yields in the presence of trichloroacetic acid (TCA) catalyst. Maximal yields close to 100% were observed with a 10 to 15-fold molar reagent excess. Separation of the derivatized aldehydes had been optimized on ZORBAX Eclipse XDB-C(8) column with aqueous acetonitrile as mobile phase in conjunction with a binary gradient elution. Excellent linear responses were observed at the concentration range of 0.01-10nmolmL(-1) with coefficients of >0.9991. Detection limits obtained by the analysis of a derivatized standard containing 0.01nmolmL(-1) of each aldehyde, were from 0.2 to 1.78nmolL(-1) (at a signal-to-noise ratio of 3).