Fabrication of a polypseudorotaxane nanoparticle with synergistic photodynamic and chemotherapy

Polypseudorotaxane (PPR) nanoparticles were fabricated by the self-assembly of mPEG-protoporphyrin IX (PpIX) conjugate and a-CDs via the hostguest interaction for achieving synergistic photodynamic and chemotherapy.     

Dual-targeted nanoformulation with Janus structure for synergistic enhancement of sonodynamic therapy and chemotherapy

The accurate delivery of nanoparticles and organic small molecule drugs remains a serious challenge in nanoparticle-based tumor therapy. Dual-targeted therapy combining tumor cell targeting and organelle targeting is an effective solution. Here, an anticancer nanoformulation accurate delivery system was prepared using hyaluronic acid (HA) targeting CD44 receptors on the surface of tumor cells and IR780 iodine (IR780) targeting mitochondrial for delivery. The system is based on an ultra-small Janus structured inorganic sensitizer TiO_2-x@NaGdF₄ nanoparticles (TN NPs) prepared by one-step pyrolysis, further loaded with organic small molecule acoustic sensitizer IR780 and mitochondrial hexokinase II inhibitor lonidamine (LND), followed by encapsulation of HA. Ultra-small size nanoparticles exhibit strong tissue penetration, tumor inhibition and in vivo metabolism. Under ultrasound radiation, TN NPs and IR780 could produce a synergistic effect, effectively increased the efficiency of reactive oxygen species (ROS) production. Meanwhile, the released IR780 could smoothly target the mitochondria, and the ROS produced by IR780 can destroy the mitochondrial structure and disrupt the mitochondrial respiration. LND could inhibit the energy metabolism of tumor cells by reducing the activity of hexokinase II (HK II), which further accelerates the process of apoptosis. Furthermore, since the Janus structure allows the integration of multifunctional components into a single system, TN NPs can not only serve as an acoustic sensitizer to generate ROS, but the Gd element contained can also act as the nuclear magnetic resonance (MR) imaging contrast agent, suggesting that the nanoformulation can enable imaging-guided diagnosis and therapy. In conclusion, a new scheme to enhance sonodynamic therapy (SDT) and chemotherapy synergistically is proposed here based on ultra-small dual-targeted nanoformulation with Janus structure in the ultrasound radiation environment.     

Dual drug delivery system with flexible and controllable drug ratios for synergistic chemotherapy

Determination of whether multidrug nanocarriers can deliver and release loaded drugs at a predefined synergistic ratio to target cancer cells is crucial. Although there are many successful applications for delivery of multiple drugs, most current carriers are unable to achieve coordinated loading and release, leading to a drug release ratio that disagrees with the predefined loading ratio.In this work, a simple dual-drug delivery system with a flexible and controllable drug release ratio was constructed to deliver two anticancer drugs, doxorubicin(DOX) and curcumin(CUR). The drug ratio of DOX and CUR can be easily tuned for an enhanced synergistic effect, and the drugs can be released at predesigned ratios due to synchronous drug activation and nanoparticle collapse. Drug release at predefined ratios for synergistic anticancer therapy was demonstrated via in vitro and in vivo experiments. Therefore, the dual drug delivery system developed here provides a simple and efficient strategy for combination chemotherapy.     

Biointerface engineering of self-protective bionic nanomissiles for targeted synergistic chemotherapy

Erythrocyte membrane(EM)-camouflaged chemotherapeutic delivery nanovehicles hold promise for solid tumor therapy because of their excellent biostability and biocompatibility. However, it is accompanied with insufficient targeting effect and deficient pharmacokinetic behavior due to the lack of a regulated biointerface to navigate and overcome biological transportation obstacles in solid tumor therapy.Herein, an anti-epidermal growth factor receptor(EGFR) aptamer(EApt) modified and EM-cloaked che...     

Near-infrared light (NIR)-responsive nanoliposomes combining photodynamic therapy and chemotherapy for breast tumor control

Light-responsive carriers have been used for the controlled release of antitumor drugs in recent years. However, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug release, and ultraviolet light would cause cellular damage. Near-infrared light has a deeper tissue-penetration depths and minimal harm to tissues, but it is difficult to cleave the chemical bond directly. The aim of this study is to develop a novel near-infrared light-responsive carrier for local release of antitumor drugs. Unsaturated phospholipids can be oxidized by singlet oxygen to achieve liposomal drug release, and singlet oxygen can be produced by photosensitizer under light irradiation. A new near-infrared light-responsive nanoliposome was designed that imparts light-triggered local drug release. Nanoliposomes, which were composed of matrix phospholipids and unsaturated phospholipids, were prepared by ammonium sulfate gradient method, and loaded with antitumor drug doxorubicin (DOX) and photosensitizer 1,4,8,11,15,18,22,25-octabutoxypalladium phthalocyanine. Under near-infrared light, photosensitizers could produce singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the unsaturated phospholipids were oxidized by singlet oxygen and result in DOX release, causing sustained cell damage by chemotherapy. Near-infrared light-responsive nanoliposomes exhibit enhanced anticancer activity owing to combined treatment of photodynamic therapy and chemotherapy. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy.     

Rational design of iridium–porphyrin conjugates for novel synergistic photodynamic and photothermal therapy anticancer agents

Near-infrared (NIR) emitters are important probes for biomedical applications. Nanoparticles (NPs) incorporating mono- and tetranuclear iridium(iii) complexes attached to a porphyrin core have been synthesized. They possess deep-red absorbance, long-wavelength excitation (635 nm) and NIR emission (720 nm). TD-DFT calculations demonstrate that the iridium–porphyrin conjugates herein combine the respective advantages of small organic molecules and transition metal complexes as photosensitizers (PSs): (i) the conjugates retain the long-wavelength excitation and NIR emission of porphyrin itself; (ii) the conjugates possess highly effective intersystem crossing (ISC) to obtain a considerably more long-lived triplet photoexcited state. These photoexcited states do not have the usual radiative behavior of phosphorescent Ir(iii) complexes, and they play a very important role in promoting the singlet oxygen (¹O₂) and heat generation required for photodynamic therapy (PDT) and photothermal therapy (PTT). The tetranuclear 4-Ir NPs exhibit high ¹O₂ generation ability, outstanding photothermal conversion efficiency (49.5%), good biocompatibility, low half-maximal inhibitory concentration (IC₅₀) (0.057 μM), excellent photothermal imaging and synergistic PDT and PTT under 635 nm laser irradiation. To our knowledge this is the first example of iridium–porphyrin conjugates as PSs for photothermal imaging-guided synergistic PDT and PTT treatment in vivo.

Iridium–porphyrin conjugates assembled in nanoparticles are photosensitizers that exhibit excellent photothermal imaging and synergistic PDT and PTT in vivo.     

siRNA. A guide for RNA silencing

RNAi is routinely used to eliminate gene activity for experimental purposes. However, the precise molecular mechanism of RNAi is unknown. Recent papers partially illuminate this mechanism in human cells, advancing the potential application of RNAi toward the treatment of human disease.     

Multiplex fluorescence imaging-guided programmed delivery of doxorubicin and curcumin from a nanoparticles/hydrogel system for synergistic chemotherapy

Synergistic chemotherapy of doxorubicin and curcumin (CUR) is an important strategy for cancer therapy to compensate for the single drug chemotherapy. Programmed and precise delivery of drugs plays a crucial role for optimizing the mode of administration and revealing the mechanism of synergistic chemotherapy. Herein, multiplex fluorescence imaging-guided programmed delivery of doxorubicin and CUR was achieved by a nanoparticles/hydrogel system for synergistic chemotherapy. CUR-loaded nanoparticles and doxorubicin were co-loaded into hydrogel to construct a synergistic chemotherapy drug delivery system. The hydrogel-nanoparticles combined system can effectively achieve the programmed delivery of hydrophilic drug and hydrophobic drug for the synergistic chemotherapy. They exerted the on-demand spatiotemporal delivery of doxorubicin and CUR. The combined chemotherapy system significantly inhibited the tumor growth compared to single therapy. Moreover, the programmed delivery of doxorubicin and CUR was visualized precisely based on their self-fluorescence instead of extra fluorescent tags at the cellular level and in vivo lever using multiplex fluorescence imaging technology. It afforded an imaging guidance for the controllable synergistic chemotherapy based on programmed delivery.     

A homogeneous fluorescence sensing platform with water-soluble carbon nanoparticles for detection of microRNA and nuclease activity

Based on the high efficiency of fluorescence quenching and the different affinities of water-soluble carbon nanoparticles (CNPs) towards single-stranded DNA (ssDNA) and double-stranded DNA/RNA hybrid, a novel, rapid and cost-effective assay for detection of microRNA and nuclease activity was developed. The fluorescein-labeled ssDNA probe (FAM-P) could be adsorbed on the surface of CNPs through π-π stacking interaction giving rise to fluorescence quenching. By introduction of microRNA complementary to the DNA probe, the double-stranded DNA/miRNA hybrid could be formed and released from the surface of CNPs resulting in the fluorescence recovery. Thus, microRNA was successfully detected in homogenous fashion without any amplification or enzyme-involving reactions. Moreover, we demonstrated that the nuclease activities of RNase H and DNase I could also be sensitively monitored by using CNPs based on the fluorescence changing of the DNA probe. So, the CNPs provide an excellent homogeneous sensing platform for studying molecular diagnosis and therapeutics.     

Characterization of anticancer hypocrellin A encapsulated with silica nanoparticles

Hypocrellins, natural photosensitizers including hypocrellin A (HA) and hypocrellin B (HB), have been used as a traditional Chinese herbal medicine to cure various skin diseases. Hypocrellins have excellent antiviral activity, which can inhibit the growth of human immunodeficiency virus. They also exhibit significant light-induced antitumor property. In this article, thermal analysis technologies (e.g., differential scanning calorimetry and thermogravimetry) are employed to characterize whether the photosensitive hypocrellin A could be encapsulated with silica nanoparticle (SN) material or not, and evaluate the stability of inclusion complex. The results show that the inclusion complex exhibits improved performance in both stability and hydrophilicity than natural hypocrellin A. Fluorescence spectrophotometry studies have also been performed to verify the thermal analysis results. The results suggest that the thermal analysis technology could be used as an effective and rapid tool to characterize the encapsulation properties of the novel anticancer HA–SN complex.     

Synthesis of an AIEgen functionalized cucurbit[7]uril for subcellular bioimaging and synergistic photodynamic therapy and supramolecular chemotherapy

Aggregation-induced emission (AIE) based fluorophores (AIEgens) have attracted increasing attention for biomedical applications due to their unique optical properties. Here we report an AIE photosensitizer functionalized CB[7], namely AIECB[7], which could spontaneously self-assemble into nanoaggregates in aqueous solutions. Interestingly, the carbonyl-lace of CB[7] may potentially act as a proton acceptor in an acidic environment to fine-tune the fluorescence and singlet oxygen generation of AIECB[7] nanoaggregates by regulating the inner stacking of AIEgens. Additionally, benefiting from the guest-binding properties of CB[7], oxaliplatin was included into AIECB[7] nanoaggregates for combined photodynamic therapy and supramolecular chemotherapy. To show the modular versatility of this supramolecular system, a hypoxia-activatable prodrug banoxantrone (AQ4N) was loaded into AIECB[7] nanoaggregates, which exhibited synergistic antitumor effects on a multicellular tumor spheroid model (MCTS). This work not only provides AIECB[7] for versatile theranostic applications, but also offers important new insights into the design and development of macrocycle-conjugated AIE materials for diverse biomedical applications.

An AIEgen-functionalized cucurbit[7]uril was synthesized for the first time and spontaneously self-assembled into nanoaggregates in aqueous solutions and allowed subcellular imaging of the lysosome and photodynamic therapy and chemotherapy of cancer.     

A highly sensitive electrochemical assay for microRNA expression profiling

A simple and highly sensitive electrochemical assay for ligation-free and polymerase chain reaction (PCR)-free microRNA (miRNA) expression profiling is described in this work. The electrode used in the assay was made of a monolayer of stem-looped capture probes (CPs) comprising of a miRNA complementing region at one end and detection probes (DPs) receiving region at the other. It engaged an electrocatalytic reaction between electrochemically activated glucose oxidase (GOx) and glucose to enhance its sensitivity. Briefly, upon hybridizing to its target miRNA, the stem loop is unlocked exposing the DP receiving region. A subsequent hybridization with the DPs brought them together with an amplifier, the activated GOx, onto the electrode. The activated GOx exhibited excellent catalytic activity towards electrooxidation of glucose. MicroRNA detection could therefore be conducted in 60 mM glucose in phosphate-buffered saline. A detection limit of 4.0 fM and a linear calibration curve up to 10 pM were obtained under optimal conditions. The assay was applied to profile human let-7 miRNA expressions in cultured cancer cells.     

A review of Cloud computing technologies for comprehensive microRNA analyses

Cloud computing revolutionized many fields that require ample computational power. Cloud platforms may also provide huge support for microRNA analysis mainly through disclosing scalable resources of different types. In Clouds, these resources are available as services, which simplifies their allocation and releasing. This feature is especially useful during the analysis of large volumes of data, like the one produced by next generation sequencing experiments, which require not only extended storage space but also a distributed computing environment. In this paper, we show which of the Cloud properties and service models can be especially beneficial for microRNA analysis. We also explain the most useful services of the Cloud (including storage space, computational power, web application hosting, machine learning models, and Big Data frameworks) that can be used for microRNA analysis. At the same time, we review several solutions for microRNA and show that the utilization of the Cloud in this field is still weak, but can increase in the future when the awareness of their applicability grows.     

A synergistic organoiron flame-retarding/smoke-suppressing system for ABS

Commercial acrylonitrile butadiene styrene (ABS) polymers are among the most flammable of the currently available range of thermoplastic materials. In addition to having a rather low limiting oxygen index (LOI) value in the range 18.3–18.8, ABS polymers also produce compious amounts of smoke and hazardous gases when burnign in the air. In a recent study directed towards preparing and evaluating compounds which would simultaneously reduce the flammability and smoke produced from burning thermoplastic polymers, a synergistic flame-retarding/smoke-suppressing system based on organoiron compounds has been produced, which when properly compounded into ABS/PVC [poly(vinyl chloride)] blends more than doubles the LOI nad at the same time reduces smoke production significantly.     

A DNAzyme-augmented bioorthogonal catalysis system for synergistic cancer therapy

As one of the representative bioorthogonal reactions, the copper-catalyzed click reaction provides a promising approach for in situ prodrug activation in cancer treatment. To solve the issue of inherent toxicity of Cu(i), biocompatible heterogeneous copper nanoparticles (CuNPs) were developed for the Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. However, the unsatisfactory catalytic activity and off-target effect still hindered their application in biological systems. Herein, we constructed a DNAzyme-augmented and targeted bioorthogonal catalyst for synergistic cancer therapy. The system could present specificity to cancer cells and promote the generation of Cu(i) via DNAzyme-induced value state conversion of DNA-templated ultrasmall CuNPs upon exposure to endogenous H₂O₂, thereby leading to high catalytic activity for in situ drug synthesis. Meanwhile, DNAzyme could produce radical species to damage cancer cells. The synergy of in situ drug synthesis and chemodynamic therapy exhibited excellent anti-cancer effects and minimal side effects. The study offers a simple and novel avenue to develop highly efficient and safe bioorthogonal catalysts for biological applications.

A DNAzyme-augmented and tumor-targeted bioorthogonal catalysis system is constructed for synergistic cancer therapy. It promotes the generation of Cu(i) and ROS using endogenous H₂O₂, thereby achieving in situ drug synthesis and chemodynamic therapy.     

A multiunit catalyst with synergistic stability and reactivity: a polyoxometalate-metal organic framework for aerobic decontamination

A combination of polyanion size and charge allows the Keggin-type polyoxometalate (POM), [CuPW(11)O(39)](5-), a catalyst for some air-based organic oxidations, to fit snuggly in the pores of MOF-199 (HKUST-1), a metal-organic framework (MOF) with the POM countercations residing in alternative pores. This close matching of POM diameter and MOF pore size in this POM-MOF material, [Cu(3)(C(9)H(3)O(6))(2)](4)[{(CH(3))(4)N}(4)CuPW(11)O(39)H] (1), results in a substantial synergistic stabilization of both the MOF and the POM. In addition, this heretofore undocumented POM-MOF interaction results in a dramatic increase in the catalytic turnover rate of the POM for air-based oxidations. While 1 catalyzes the rapid chemo- and shape-selective oxidation of thiols to disulfides and, more significantly, the rapid and sustained removal of toxic H(2)S via H(2)S + 1/2 O(2) → 1/8 S(8) + H(2)O (4000 turnovers in <20 h), the POM or the MOF alone is catalytically slow or inactive. Three arguments are consistent with the catalytic reactions taking place inside the pores. POM activation by encapsulation in the MOF likely involves electrostatic interactions between the two components resulting in a higher reduction potential of the POM.     

A method for quantitative analysis of an anticancer drug in human plasma with CE-ESI-TOF-MS

In this study, the extraction recoveries of an anticancer drug (Imatinib) from human plasma using a common liquid-liquid extraction (LLE) method and a new strong cation exchange (SCX) solid-phase extraction (SPE) column was investigated. The extracts were analyzed with CE coupled on-line to electrospray ionization (ESI) time-of-flight mass spectrometry (TOF-MS) using a monoquaternarized piperazine compound (M7C4I) for capillary coatings. Clean extracts with high and reproducible extraction recoveries ranging between 85 and 91% with % RSD values of 2.5% (n = 3) were obtained using the SCX-SPE columns. This can be compared with the recoveries obtained with the LLE method ranging between 30 and 35%. The CE-ESI-TOF-MS analysis was performed in <10 min with peak efficiencies up to 4.7 × 10? plates/m and an average % RSD for the repeatability of the migration times of the analytes of 1.9% (n = 3) using acidic buffer and adding 5% ACN to the sample. The calibration curves were linear over the range of 0-1500 ng/mL with correlation coefficient (R2 ≥ 0.997 and % RSD values of 0.5% (n=3). The intra-day and inter-day assay variations were lower than 8%. The presented CE-ESI-TOF-MS method with the use of SCX-SPE columns yielded rapid, efficient and high extraction recoveries together with high sensitivity (LOD 5 ng/mL), selectivity and good linearity. Accordingly, the method can readily be used for accurate determination and therapeutic monitoring of the Imatinib blood levels for more effective patient treatment. In addition, it can be applied for the extraction, quantification and clinical assessments of metabolites of Imatinib and other basic pharmaceutical drug molecules in biological fluids or pharmaceutical dosage forms.     

A machine learning framework for predicting synergistic and antagonistic drug combinatorial efficacy

Journal of Mathematical Chemistry - Synergistic drug combinations could achieve increase of therapeutic efficacy and reduce risk of drug resistance and toxicity via targeting multiple genes,...     

A pH-responsive ultrathin Cu-based nanoplatform for specific photothermal and chemodynamic synergistic therapy

Noninvasive tumor therapy requires a new generation of bionanomaterials towards sensitive response to the unique tumor microenvironment to achieve accurate and effective treatment. Herein, we have developed a tumor therapy nanoplatform by immobilizing natural glucose oxidase (GOD) onto Cu-based layered double hydroxide (CuFe-LDH) nanosheets, which for the first time integrates acid-enhanced photothermal therapy (PTT), and pH-responsive and heat-facilitated chemodynamic therapy (CDT) simultaneously. As demonstrated by EXAFS and HRTEM, CuFe-LDH nanosheets possess a considerable number of defects caused by different acid conditions, resulting in a significantly acid-enhanced photothermal conversion efficiency (83.2% at pH 5.4 vs. 46.0% at pH 7.4). Moreover, GOD/CuFe-LDH nanosheets can convert a cascade of glucose into hydroxyl radicals (˙OH) under tumor acid conditions, which is validated by a high maximum velocity (V_max = 2.00 × 10⁻⁷ M) and low Michaelis–Menten constant (K_M = 12.01 mM). With the combination of PTT and CDT, the tumor tissue in vivo is almost eliminated with low-dose drug injection (1 mg kg⁻¹). Therefore, this novel pH-responsive Cu-based nanoplatform holds great promise in tumor-specific CDT/PTT synergistic therapy.

A pH-responsive multifunctional nanosystem was synthesized by loading glucose oxidase (GOD) onto CuFe-layered double hydroxide (LDH) nanosheets, which exhibited synchronous acid-enhanced/responsive photothermal and chemodynamic synergistic therapy.