Exceptional removal and immobilization of selenium species by bimetal-organic frameworks.

Binary metallic organic frameworks can always play excellent functions for pollutants removal. One binary MOFs, UiO-66(Fe/Zr)), was newly synthesized and applied to remove aquatic selenite (SeIV) and selenate (SeVI). The adsorption behaviors and mechanisms were investigated using batch experiments, spectroscopic analyses, and theoretical calculations (DFT). The characterization results showed that the material inherited the topological structure of UiO-66 and excellent thermal stability. The large specific surface area (467.52 m2/g) and uniform mesoporous structures of the synthesized MOFs resulted in fast adsorption efficiency and high adsorption capacity for selenium species. The adsorbent kept high adsorption efficiency in a wide pH range from 2 to 11 with good anti-interference ability. The maximum adsorption capacity for Se(IV) and Se(VI) reached as high as 196 mg/g at pH 3 and 258 mg/g at pH 5, respectively. The process was conformed to fit pseudo-second-order kinetics and Langmuir isotherm, and could be explained by the formation of Fe/Zr-O-Se bond on the material surface, which was interpreted by the results of XPS, FTIR and DFT calculation. The regeneration and TCLP experiments demonstrated that UiO-66(Fe/Zr) could be regenerated for five cycles without obvious decrease of efficiencies, and the leaching rate of the adsorbed Se(IV) and Se(VI) in the spent adsorbent were only 4.8% and 2.3%. More than 99% of original Se(IV) and Se(VI) in the lake and tap water samples (1.0 mg/L of Se) could be removed in 2.0 h.

A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals.

Stimuli-responsive nanomaterials are increasingly important in a variety of applications such as biosensing, molecular imaging, drug delivery and tissue engineering. For cancer detection, a paramount challenge still exists in the search for methods that can illuminate tumours universally regardless of their genotypes and phenotypes. Here we capitalized on the acidic, angiogenic tumour microenvironment to achieve the detection of tumour tissues in a wide variety of mouse cancer models. This was accomplished using ultra pH-sensitive fluorescent nanoprobes that have tunable, exponential fluorescence activation on encountering subtle, physiologically relevant pH transitions. These nanoprobes were silent in the circulation, and then strongly activated (>300-fold) in response to the neovasculature or to the low extracellular pH in tumours. Thus, we have established non-toxic, fluorescent nanoreporters that can nonlinearly amplify tumour microenvironmental signals, permitting the identification of tumour tissue independently of histological type or driver mutation, and detection of acute treatment responses much more rapidly than conventional imaging approaches.

Ultra-pH-sensitive nanoprobe library with broad pH tunability and fluorescence emissions.

pH is an important physiological parameter that plays a critical role in cellular and tissue homeostasis. Conventional small molecular pH sensors (e.g., fluorescein, Lysosensor) are limited by broad pH response and restricted fluorescent emissions. Previously, we reported the development of ultra-pH-sensitive (UPS) nanoprobes with sharp pH response using fluorophores with small Stokes shifts (<40 nm). In this study, we expand the UPS design to a library of nanoprobes with operator-predetermined pH transitions and wide fluorescent emissions (400-820 nm). A copolymer strategy was employed to fine tune the hydrophobicity of the ionizable hydrophobic block, which led to a desired transition pH based on standard curves. Interestingly, matching the hydrophobicity of the monomers was critical to achieve a sharp pH transition. To overcome the fluorophore limitations, we introduced copolymers conjugated with fluorescence quenchers (FQs). In the micelle state, the FQs effectively suppressed the emission of fluorophores regardless of their Stokes shifts and further increased the fluorescence activation ratios. As a proof of concept, we generated a library of 10 nanoprobes each encoded with a unique fluorophore. The nanoprobes cover the entire physiologic range of pH (4-7.4) with 0.3 pH increments. Each nanoprobe maintained a sharp pH transition (on/off < 0.25 pH) and high fluorescence activation ratio (>50-fold between on and off states). The UPS library provides a useful toolkit to study pH regulation in many pathophysiological indications (e.g., cancer, lysosome catabolism) as well as establishing tumor-activatable systems for cancer imaging and drug delivery.

Chaotropic-anion-induced supramolecular self-assembly of ionic polymeric micelles.

Traditional micelle self-assembly is driven by the association of hydrophobic segments of amphiphilic molecules forming distinctive core-shell nanostructures in water. Here we report a surprising chaotropic-anion-induced micellization of cationic ammonium-containing block copolymers. The resulting micelle nanoparticle consists of a large number of ion pairs (≈60,000) in each hydrophobic core. Unlike chaotropic anions (e.g. ClO4(-)), kosmotropic anions (e.g. SO4(2-)) were not able to induce micelle formation. A positive cooperativity was observed during micellization, for which only a three-fold increase in ClO4(-) concentration was necessary for micelle formation, similar to our previously reported ultra-pH-responsive behavior. This unique ion-pair-containing micelle provides a useful model system to study the complex interplay of noncovalent interactions (e.g. electrostatic, van der Waals, and hydrophobic forces) during micelle self-assembly.

Molecularly precise dendrimer-drug conjugates with tunable drug release for cancer therapy.

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer-drug conjugates. Current dendrimer-drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer-drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.

Quantification of sources and potential risks of cadmium, chromium, lead, mercury and arsenic in agricultural soils in a rapidly urbanizing region of southwest China: the case of Chengdu.

Rapid urbanization a major factor affecting heavy metal contamination on suburban agricultural soils. In order to assess the dynamic contamination of heavy metals in soil from agricultural land bordering a rapidly urbanizing area and the transfer of human health risks from contaminants in this process, 186 and 293 soil samples from agricultural land in suburban Chengdu were collected in September 2008 and September 2017, respectively. Several indicators, such as the integrated pollution index (PI) and the potential ecological risk index (RI), were employed for analyzing the heavy metal contamination levels, and the APCS-MLR receptor model were applied for analyzing the heavy metal sources. As a result, mean concentrations for five elements did not exceed the national soil pollution risk screening values in the two periods mentioned above. Nemerow's composite contamination index revealed an increase in soil contamination of arable land after 10 years of urbanization, with 3.75 and 1.02% of light and moderate sample plots, respectively, by 2017. The assessment for potential ecological risk indicated an increased level of eco-risk to high for most of the sample plots. Based on the APCS-MLR model, the origin and contribution to the five elements varied considerably between the two periods mentioned above. Among them, soil Pb changed from "industrial source" to "transportation source," soil Cr changed from "natural source" to "transportation source," and As and Hg changed from "industrial source" to "transportation source." As and Hg were associated with agricultural activities in both periods, and Cd was derived from industrial activities in both periods. The study suggests that inhalation has become a major contributor to non-cancer health risks in urbanization, unlike intake routes in previous periods, and that the increase in cancer risk is mainly due to children's consumption of agricultural products with As residues. The change in the main source of As to "transportation" also indicates a decrease in air quality during urbanization and the development of the transportation industry. This study provides a reference for the governments of rapidly urbanizing cities to formulate relevant highway and agricultural policies to safeguard the health of the people based on the current situation.

Acid-active cell-penetrating peptides for in vivo tumor-targeted drug delivery.

Cell-penetrating peptides (CPPs) such as transactivator of transcription (TAT) peptide have long been explored for promoting in vitro cell penetration and nuclear targeting of various cargos, but their positive charges cause strong nonspecific interactions, making them inapplicable for many in vivo applications. In this work, we used TAT to demonstrate a molecular modification approach for inhibiting nonspecific interactions of CPPs in the bloodstream while reactivating their functions in the targeted tissues or cells. The TAT lysine residues' amines were amidized to succinyl amides ((a)TAT), completely inhibiting TAT's nonspecific interactions in the blood compartment; once in the acidic tumor interstitium or internalized into cell endo/lysosomes, the succinyl amides in the (a)TAT were quickly hydrolyzed, fully restoring TAT's functions. Thus, (a)TAT-functionalized poly(ethylene glycol)-block-poly(ε-caprolactone) micelles achieved long circulation in the blood compartment and efficiently accumulated and delivered doxorubicin to tumor tissues, giving rise to high antitumor activity and low cardiotoxicity. This amidization strategy effectively and easily enables in vivo applications of CPPs.

Bioreducible poly(amido amine)s with different branching degrees as gene delivery vectors.

Based on the knowledge that cationic polymers with different topographical structures behave differently in gene transfection process, herein, we synthesized three biodegradable poly(amido amine)s (PAAs) with the same repeating units and molecular weights except for degree of branching: linear PAA (LPAA), low-branched PAA (LBPAA), and high-branched PAA (HBPAA). We found that LBPAA could more effectively compact pDNA into positively charged nanoparticles than both HBPAA and LPAA. LBPAA polyplexes had the highest transfection efficiency among the three PAA polyplexes, and the difference in transfection efficiency is mainly attributed to the endocytosis rate. The cytotoxicity of PAAs was negligible at the transfection doses, probably due to the degradable disulfide bonds. Therefore, we could use branching as a parameter to simply tune a polymer's cellular uptake behavior and transfection efficiency.

Degradable dual pH- and temperature-responsive photoluminescent dendrimers.

Poly(ß-aminoester) dendrimers have been prepared. These systems represent the first degradable dual pH- and temperature-responsive dendrimers displaying photoluminescence. The pH/temperature sensitivities are interrelated; the lower critical solution temperature of the dendrimer decreases as the pH of the solution is increased. The sensitivities are mainly due to phase changes of the surface groups with changes in pH or temperature. These dual-responsive dendrimers are very useful in drug delivery. They may be loaded with a hydrophobic drug at low temperature without using organic solvents. The loaded drug is released very slowly and steadily at 37 °C and physiological pH, but can be quickly released at acidic pH, for example the lysosomal pH (pH 4-5), for intracellular drug release. These dendrimers also display strong photoluminescence, which can be exploited for monitoring drug loading and release. Thus, poly(ß-aminoester) dendrimers constitute ideal drug carriers since their thermal sensitivity allows the loading of drugs without using organic solvents, their pH sensitivity permits fast intracellular drug release, and their photoluminescence provides a means of monitoring drug loading and release.

Facile synthesis of polyester dendrimers from sequential click coupling of asymmetrical monomers.

Polyester dendrimers are attractive for in vivo delivery of bioactive molecules due to their biodegradability, but their synthesis generally requires multistep reactions with intensive purifications. A highly efficient approach to the synthesis of dendrimers by simply "sticking" generation by generation together is achieved by combining kinetic or mechanistic chemoselectivity with click reactions between the monomers. In each generation, the targeted molecules are the major reaction product as detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The only separation needed is to remove the little unreacted monomer by simple precipitation or washing. This simple clicklike process without complicated purification is particularly suitable for the synthesis of custom-made polyester dendrimers.

Digitization of Endocytic pH by Hybrid Ultra-pH-Sensitive Nanoprobes at Single-Organelle Resolution.

A multispectral hybrid nanotransistor consisting of modular fluorescent block copolymers with discrete and sharp pH transitions in one nanoparticluate system is presented. This nanotransistor probe allows digitized reporting of dynamic maturation at single-organelle resolution over time. This nanotechnology platform offers a powerful tool in fundamental studies of organelle biology, cell signaling in diseases characterized by pH dysregulation in the endosomes or lysosomes.

Fabrication of dendrimer-releasing lipidic nanoassembly for cancer drug delivery.

An inherent dilemma in the use of nanomedicines for cancer drug delivery is their limited penetration into tumors due to their large size. We have demonstrated that dendrimer/lipid nanoassemblies can solve this problem by means of tumor-triggered disassembly and the release of small (several nanometers) dendrimers to facilitate tumor penetration. Herein, we report a general strategy for the fabrication of nanoassemblies from hydrophobic and hydrophilic dendrimers with phospholipids. Hydrophobic dendrimers could assemble with lipids via hydrophobic interactions, whereas hydrophilic dendrimers could only assemble with lipids in the presence of anionic surfactants via both electrostatic and hydrophobic interactions. The nanoassemblies of hydrophobic dendrimers/lipids were found to be capable of stripping off their lipid layers via fusion with the cell membrane and then intracellular or extracellular release of dendrimers, whereas the nanoassemblies of hydrophilic dendrimers/lipids were internalized via endocytosis and then released their dendrimers inside the cells. Therefore, these dendrimer/lipid nanoassemblies could be used for the delivery of different cancer drugs.

A Transistor-like pH Nanoprobe for Tumour Detection and Image-guided Surgery.

Because of profound genetic and histological differences in cancerous tissue, it is challenging to detect a broad range of malignant tumours at high resolution. Here, we report the design and performance of a fluorescent nanoprobe with transistor-like responses (transition pH = 6.9) for the detection of the deregulated pH that drives many of the invasive properties of cancer. The nanoprobe amplifies fluorescence signal in the tumour over that in the surrounding normal tissues, resulting in a discretized, binary output signal with spatial resolution smaller than 1 mm. The nanoprobe allowed us to image a broad range of tumours in mouse models using a variety of clinical cameras, and to perform real-time tumour-acidosis-guided detection and surgery of occult nodules (< 1 mm3) in mice bearing head-and-neck or breast tumours, significantly lengthening mice survivability. We also show that the pH nanoprobe can be used as a reporter in a fast, quantitative assay to screen for tumour-acidosis inhibitors. The binary delineation of pH achieved by the nanoprobe promises to improve the accuracy of cancer detection, surveillance and therapy.

Nanotechnology-enabled delivery of NQO1 bioactivatable drugs.

Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. ß-Lapachone (ß-lap) is a novel anticancer agent whose mechanism of action is highly dependent on NAD(P)H: quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of ß-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of ß-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of ß-lap further decreases the crystallization of ß-lap by introducing esterase degradable side chains to the rigid fused ring structure. ß-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of ß-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.

A nanobuffer reporter library for fine-scale imaging and perturbation of endocytic organelles.

Endosomes, lysosomes and related catabolic organelles are a dynamic continuum of vacuolar structures that impact a number of cell physiological processes such as protein/lipid metabolism, nutrient sensing and cell survival. Here we develop a library of ultra-pH-sensitive fluorescent nanoparticles with chemical properties that allow fine-scale, multiplexed, spatio-temporal perturbation and quantification of catabolic organelle maturation at single organelle resolution to support quantitative investigation of these processes in living cells. Deployment in cells allows quantification of the proton accumulation rate in endosomes; illumination of previously unrecognized regulatory mechanisms coupling pH transitions to endosomal coat protein exchange; discovery of distinct pH thresholds required for mTORC1 activation by free amino acids versus proteins; broad-scale characterization of the consequence of endosomal pH transitions on cellular metabolomic profiles; and functionalization of a context-specific metabolic vulnerability in lung cancer cells. Together, these biological applications indicate the robustness and adaptability of this nanotechnology-enabled 'detection and perturbation' strategy.

Esterase-activatable ß-lapachone prodrug micelles for NQO1-targeted lung cancer therapy.

Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, ß-lapachone (ß-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of ß-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of ß-lap prodrug nanotherapeutics consisting of diester derivatives of ß-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of ß-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered ß-lap-dC3 and -dC6 prodrugs were converted to ß-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H: quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of ß-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over ß-lap-dC6 micelles or ß-lap-HPßCD complexes. Improved therapeutic efficacy of ß-lap-dC3 micelles correlated with higher area under the concentration-time curves of ß-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). ß-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.

Prodrug strategy to achieve lyophilizable, high drug loading micelle formulations through diester derivatives of ß-Lapachone.

ß-Lap prodrug micelle strategy improves the formulation properties of ß-lap therapeutics. The resulting micelles yield apparent high ß-lap solubility (>7 mg mL(-1) ), physical stability, and ability to reconstitute after lyophilization. In the presence of esterase, ß-lap prodrugs are efficiently converted into parent drug (i.e., ß-lap), resulting in NQO1-dependent lethality of NSCLC cells.

Integration of nanoassembly functions for an effective delivery cascade for cancer drugs.

A "cluster-bomb"-like lipid-dendrimer nanoassembly synergizes the functions of its components and thereby efficiently accomplishes the drug delivery cascade for high efficacy in treating cancer. The nanoassembly successfully circulates in the blood and accumulates in the tumor. Once in the tumor, it releases small dendrimers that act like "bomblets", enabling tumor penetration, cell internalization, and drug release.

Linear-dendritic drug conjugates forming long-circulating nanorods for cancer-drug delivery.

Elongated micelles have many desirable characteristics for cancer-drug delivery, but they are difficult to obtain since amphiphilic polymers form such nanostructures only within narrow composition ranges depending on their own structures. Herein, we demonstrated a facile fabrication of different nanostructures via drug content-controlled self-assembly of amphiphilic linear-dendritic drug conjugates - using the number of the conjugated hydrophobic drug molecule camptothecin (CPT) to tailor the hydrophobicity of amphiphilic PEG-block-dendritic polylysine-CPT (PEG-xCPT) conjugates and thereby control their self-assembled nanostructures - nanospheres or nanorods of different diameters and lengths. The shape and size of the nanostructures were found to strongly affect their in vitro and in vivo properties, particularly the blood clearance kinetics, biodistribution and tumor targeting. The nanorods with medium lengths (<500 nm) had a much longer blood circulation and faster cellular uptake than the nanospheres or long nanorods. Thus, polymeric nanorods with proper lengths may be ideal nanocarriers capable of uniting the opposite requirements in cancer-drug delivery.