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Once a nuclear weapon explodes, its power will be devastating. In this paper, we analyze the current situation of nuclear weapons in the world, and firstly, we analyze the relationship between the number of nuclear-armed countries and the year using linear regression to find out the prediction model, from which we get that in 2123, the number of nuclear-armed countries in the world will reach 9. Then, this paper analyzes the Pearson correlation between the number of nuclear weapons of each country and the year and uses lasso regression to model the change in the number of nuclear weapons of each country with the year. Special attention is paid to the fact that the number of nuclear weapons in South Africa in the next 100 years is 0, indicating that the number of nuclear-armed countries will be reduced to 9 in 2123, which is consistent with the prediction of the number of nuclear-armed countries through linear regression. In 2123, the total number of nuclear weapons in the world will reach 29,293. To derive a limited total number of nuclear weapons in the world, a nuclear bomb detonation location destructive force model is developed in this paper to derive the maximum destructive range of nuclear bombs. Combined with the current number of nuclear bombs in the world, the calculation results show that the current number of nuclear bombs in the world is not enough to destroy the earth, and the total number of nuclear bombs in the world should be limited to 44,563.

The selective anti-tumor activity and less toxic nature of hypoxia-activated prodrugs including tirapazamine (TPZ) are harbored by hypoxia levels in tumors, the inadequacy of which leads to failure in clinical trials.

To overcome the limitation of conventional nanodrugs in tumor targeting efficiency, coupling targeting ligands to polymeric nanoparticles can enhance the specific binding of nanodrugs to tumors. Cyclo(Arg-Gly-Asp-d-Phe-Lys) (abbreviated as c(RGDfK)) peptide has been widely adopted due to its high affinity to the tumor marker α

The hybrid hydrogel composed of drug loaded mesoporous silica and pH/glucose-responsive copolymer was used for the healing of diabetic foot ulcers.

A series of eight-arm tapered star copolymers 8[P(I-co-S)x]-POSS were synthesized by the coupling reaction between octavinyl POSS and the tapered living copolymer chains obtained from statistical anionic copolymerization.

The selective anti-tumor activity and less toxic nature of hypoxia-activated prodrugs including tirapazamine (TPZ) are harbored by hypoxia levels in tumors, the inadequacy of which leads to failure in clinical trials. Thus, the development of effective clinical applications of TPZ requires advanced strategies to intensify hypoxia levels in tumors effectively and safely. In this study, we designed and fabricated a paclitaxel (PTX)-loaded dual-response delivery system with a low dose (

This work aims to construct biocompatible, biodegradable core-cross-linked and insulin-loaded nanoparticles which are sensitive to glucose and release insulin via cleavage of the nanoparticles in a high-concentration blood glucose environment. First, a polyphosphoester-based diblock copolymer (PBYP-g-Gluc)-b-PEEP was prepared via ring-opening copolymerization (ROP) and the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in which PBYP and PEEP represent the polymer segments from 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane, respectively, and Gluc comes from 2-azidoethyl-β-d-glucopyranoside (Gluc-N3) that grafted with PBYP. The structure and molecular weight of the copolymer were characterized by 1H NMR, 31P NMR, GPC, FT-IR, and UV-vis measurements. The amphiphilic copolymer could self-assemble into core-shell uncore-cross-linked nanoparticles (UCCL NPs) in aqueous solutions and form core-cross-linked nanoparticles (CCL NPs) after adding cross-linking agent adipoylamidophenylboronic acid (AAPBA). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to study the self-assembly behavior of the two kinds of NPs and the effect of different Gluc group contents on the size of NPs further to verify the stability and glucose sensitivity of CCL NPs. The ability of NPs to load fluorescein isothiocyanate-labeled insulin (FITC-insulin) and their glucose-triggered release behavior were detected by a fluorescence spectrophotometer. The results of methyl thiazolyl tetrazolium (MTT) assay and hemolysis activity experiments showed that the CCL NPs had good biocompatibility. An in vivo hypoglycemic study has shown that FITC-insulin-loaded CCL NPs could reduce blood glucose and have a protective effect on hypoglycemia. This research provides a new method for constructing biodegradable and glucose-sensitive core-cross-linked nanomedicine carriers for controlled insulin release.

A specific emitter identification method based on deep residual network (DRN) is proposed to solve the problem that the traditional expert features relying on artificial extraction are difficult to characterize the subtle differences of specific emitters.The DRN is used to complete the identification task. The in-phase component (I-way) and the quadrature component (Q-way) of signal sample data are inputted into the DRN for training. The performance of the proposed method is evaluated by experiments on datasets containing actual collected ADS-B signals from different planes. The results show that the proposed DRN model achieves high classification accuracy without manual feature selection. Furthermore, data augmentation on signal-to-noise ratio can further improve the performance of the model.

In order to overcome the limitation of traditional active nano-therapeutic drugs on tumor targeting efficiency which cannot reach the receptor/target in sufficient amount in the body, in this work, we developed a monoclonal antibody (mAb) and a polymer-hyd-doxorubicin prodrug conjugate, which enables the self-assembled nanoparticles to have precise targeting, tumor tissue aggregation and pH-sensitive drug release. We first prepared an amphiphilic polymer prodrug, abbreviated as H2N-PEEP-b-PBYP-hyd-DOX, via a combination of ring-opening polymerization (ROP) and “click” chemistry, in which PEEP and PBYP represent two kinds of phosphoester segmemts, -hyd- is hydrazone bond. After self-assembly into prodrug nanoparticles (PDNPs) with a diameter of about 93 nm, CD147 mAb was conjugated onto the PDNPs by EDC/NHS chemistry to form mAb-PDNPs. For the PDNPs and mAb-PDNPs, we also investigated their stability, in vitro drug release behavior and cellular uptake. The results showed that the pH-responsive PDNPs can remain relatively stable under the condition of PB 7.4 buffer solution. However, under acidic conditions or in the presence of phosphodiesterase I (PDE I), both the amount and rate of DOX release increased at the same incubation period. Cytotoxicity assay showed that mAb-PDNPs exhibited higher cytotoxicity (IC50: 1.12 mg·L−1) against HepG2 cells than PDNPs (IC50: 2.62 mg·L−1) without monoclonal antibody. The nanoparticles with antibodies mAb-PDNPs have relatively better stability and can directly achieve the targeting drug delivery through CD147 mAb.

It has been widely recognized that influences of static friction characteristics in a bolted joint on pre-tightening and service reliability. This study proposed a static friction coefficient model of joint surfaces based on the modified three-dimensional fractal model. A method of measuring the static friction coefficient of joint surfaces was investigated to verify the accuracy of model. The results showed that calculated value of the model and measured value of experiment are highly matched. Further, the influential mechanisms of material, pressure and surface topography were investigated. The relative error between experimental results and model calculations are all less than 15%. This research provides a theoretical basis for subsequent research on the friction characteristics of joint surfaces and connection reliability of bolted joints.

A triple stimuli-responsive nanoparticle derived from a noncovalently grafted amphiphilic copolymer was reported. The noncovalent graft copolymer, abbreviated as Dex-β-CD/Fc-PLA, was constructed by the host–guest interactions between β-cyclodextrin (β-CD) grafted dextran (Dex-β-CD) and ferrocene (Fc) terminated poly(lactide) (Fc-PLA). The synthetic Dex-β-CD/Fc-PLA copolymers and precursors were characterized by 1H NMR, FT-IR, UV-Vis, GPC, 2D NOESY 1H NMR and cyclic voltammetry (CV) analyses. The noncovalent amphiphilic copolymers could self-assemble into spherical nanoparticles (NPs) with dextran as the hydrophilic shell and PLA as the hydrophobic core in aqueous solution. The average particle size of Dex-β-CD/Fc-PLA NPs decreased from 118 nm to 79 nm with the increasing amount of hydrophobic PLA segments. Ascribed to the integration of many benzoic imine bonds and Fc groups, the NPs could remain stable at pH 7.4 but decomposed in the acidic and oxidizing (NaClO and positive voltage) media, as indicated by DLS and TEM measurements. The copolymer was used to encapsulate the hydrophobic anticancer drug doxorubicin (DOX) to achieve DOX-loaded NPs, which showed rather low drug release under simulated physiological conditions but significantly enhanced release in the simulated oxidizing and acidic media. MTT assays revealed that the pristine copolymer possessed low toxicity against both normal and cancer cells, but the DOX/Dex-β-CD/Fc-PLA NPs showed much higher selective toxicity on A549 cancer cells than normal HUVEC cells. Furthermore, the results from fluorescence microscopy demonstrated that these NPs could efficiently deliver and release DOX into the nuclei of A549 cells. The present biocompatible copolymers with triple stimuli-sensitivities are promising for the efficient intracellular delivery of hydrophobic anticancer drugs.

In the treatment of tumor-targeted small-molecule anti-cancer drugs, antibody-mediated therapies, especially for antibody-drug conjugates (ADCs), have revealed great latent force. However, the therapeutic drugs provided by ADCs possess limitation. Considering that the combination of antibodies and nano-drugs can broaden their applicability in the field of tumor treatment, herein, we developed an antibody conjugated polymeric prodrug nanoparticles SAE-PEG

The structure and properties of functional nanoparticles are important for stabilizing Pickering emulsion polymerization. Recently, cellulose nanocrystals (CNCs) are increasingly favored as a bio-based stabilizer for Pickering emulsions. In this study, we reported a novel functionalized polyphosphoester-grafted CNCs for the stabilization of oil-in-water Pickering emulsions and the emulsion polymerization of styrene. First, polyphosphoester containing an amino group at one end of the chain, abbreviated as PBYP-NH2, was prepared by ring-opening polymerization (ROP) and hydrolysis reaction, wherein PBYP represents poly[2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane]. Subsequently, CNC-COOH was obtained via 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidation of CNCs. The functionalized nanocrystals CNC-PBYP-COOH with carboxyl groups and polyphosphoester on the surface were obtained by the amidation reaction of PBYP-NH2 with CNC-COOH. Finally, we used CNC-PBYP-COOH as sole particle emulsifiers to stabilize styrene-in-water Pickering emulsions and studied its effects on the emulsions in details by using dynamic light scattering (DLS). The results indicated that the properties of these emulsions depended on the concentration of hydrophobically modified CNCs, volume ratios of oil to water, and pH values. The modified CNCs had higher ability to stabilize the styrene-in-water emulsions relative to the unmodified CNCs, and a stable oil-in-water (o/w) Pickering emulsion with diameter of hundreds of nanometers could be obtained. The resulting emulsions could be polymerized to yield nanosized latexes. The polyphosphoester-modified CNCs as green particle emulsifiers can efficiently stabilize nanoemulsions and latexes, which would promote the development of novel environmentally friendly materials.

PEGylated prodrug, covalent attaching polyethylene glycol (PEG) polymer chains to therapeutic drugs, is one of the most promising techniques to improve the water-solubility, stability, and therapeutic effect of drugs. In this study, three PEGylated acid-sensitive prodrugs DOX-PEG-DOX with different molecular weights, were prepared via Schiff-base reaction between aldehyde-modified PEG and the amino groups of doxorubicin (DOX). This kind of amphiphilic polymeric prodrug could be self-assemble into nanoparticles in aqueous solution. The average particle size and morphologies of the prodrug nanoparticles under different pH conditions were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. It turned out that the nanoparticles could be kept stable in the physiological environment, but degraded in acidic medium. Subsequently, we also investigated in vitro drug release behavior and found that the prodrug had acid-sensitive property. The cytotoxicity and intracellular uptake assays revealed that the prodrugs could rapidly internalized by HeLa or HepG2 cells to release DOX and effectively inhibited the proliferation of the tumor cells, which have the potential for use in cancer therapy.

The syntheses and biological evaluation of GHRH antagonists of AVR series with high anticancer and anti-inflammatory activities are described. Compared to our previously reported GHRH antagonist 602 of MIAMI series, AVR analogs contain additional modifications at positions 0, 6, 8, 10, 11, 12, 20, 21, 29 and 30, which induce greater antitumor activities. Five of nineteen tested AVR analogs presented binding affinities to the membrane GHRH receptors on human pituitary, 2-4-fold better than MIA-602. The antineoplastic properties of these analogs were evaluated in vitro using proliferation assays and in vivo in nude mice xenografted with various human cancer cell lines including lung (NSCLC-ADC HCC827 and NSCLC H460), gastric (NCI-N87), pancreatic (PANC-1 and CFPAC-1), colorectal (HT-29), breast (MX-1), glioblastoma (U87), ovarian (SK-OV-3 and OVCAR-3) and prostatic (PC3) cancers. In vitro AVR analogs showed inhibition of cell viability equal to or greater than MIA-602. After subcutaneous administration at 5 μg/day doses, some AVR antagonists demonstrated better inhibition of tumor growth in nude mice bearing various human cancers, with analog AVR-353 inducing stronger suppression than MIA-602 in lung, gastric, pancreatic and colorectal cancers and AVR-352 in ovarian cancers and glioblastoma. Both antagonists induced greater inhibition of GH release than MIA-602 in vitro in cultured rat pituitary cells and in vivo in rats. AVR-352 also demonstrated stronger anti-inflammatory effects in lung granulomas from mice with lung inflammation. Our studies demonstrate the merit of further investigation of AVR GHRH antagonists and support their potential use for clinical therapy of human cancers and other diseases.

Herein we describe a novel isothermal and enzyme-free electrochemical aptasensor for protein detection via the employment of polymeric ferrocene nanoparticles (PFcNPs) and target-catalyzed hairpin assembly amplification. The synthesized PFcNPs not only load numerous Fc molecules for enhanced electrochemical output but also possess plenty of amino groups, which increase the water solubility and facilitate the conjugation with the aptamer toward the recognition of target protein. After the formation of an aptamer/protein complex, the conformation of the DNA probe changes, which further triggers hairpin assembly on top of DNA tetrahedral structures modified on the electrode interface. The process can be recycled, and multiple PFcNPs are localized on the electrode. Thus, an amplified electrochemical signal is able to be recorded, which is sufficient to achieve a demonstrated limit of detection as low as 67 fM. This developed aptasensor can also discriminate target protein from other interfering substances with a high selectivity. Furthermore, it has been successfully applied in diluted real blood serum samples. All of these features make the present methodology a promising candidate for ultratrace protein biosensors.

A cross-linked porous polymer membrane using vinyl-functionalized aluminum oxide (Al2O3) nanoparticles was prepared and used as a separator for lithium-ion batteries (LIBs). Poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) was first blended with a mixture solution containing poly(ethylene glycol) methyl ether methacrylate (PEGMEMA), vinyl-functionalized Al2O3 nanoparticles (VTMO@Al2O3) as the cross-linker and poly(vinyl pyrrolidone) (PVP) as the pore-forming agent. Subsequently, the membrane was obtained by free radical copolymerization of the above-mentioned mixture and after-treatment. The preparation and properties of the membranes were investigated. It has been found that, under the action of the pore-forming agent of PVP, the obtained membrane (PMAv) had high ionic conductivity (1.37 mS cm−1) at ambient temperature. On account of the existence of the Al2O3 as cross-linking points, the PMAv membrane showed good mechanical strength of 30.4 MPa and excellent thermal stability at 180 °C. Moreover, comparing with the system without PVP or Al2O3 samples, the cell with the PMAv membrane showed the best discharge capacity and most stable capacity retention and cycle performance, indicating that the PMAv membrane is a good polymer separator for LIBs.

In an effort to achieve a high-efficient fire-resistant coating for the flexible polyurethane (PU) foams, a layer-by-layer assembly technique of polyethylenimine (PEI), graphene oxide (GO) and synthetic melanin nanoparticles (SMNPs) was constructed on the surface of PU foams. The preeminent radical scavenging capacity and high-temperature thermal stability of SMNPs enable it to be applied as a flame retardant for the subsequent coating process. Scanning electron microscope (SEM) images indicate that the as-fabricated PEI/GO/SMNPs coatings are uniformly deposited on the PU foam along the cell walls. In contrast with pure and bilayer-coated (BL-coated) PU foams, thermogravimetric analysis (TGA) reveals that the trilayer-coated (TL-coated) foam exhibits a better thermos-oxidative stability and a lower pyrolysis rate with the deposition of PEI/GO/SMNPs nanocoating. In the torch burn test, the flame of PU-1TL foam coated with only one-trilayer PEI/GO/SMNPs is able to self-extinguish and the original shape of the entire foam is intactly preserved. Cone colorimeter tests indicate that the release amount of heat and smoke can be effectively suppressed in the coated foam, and the formation of the highly graphitized char is beneficial to the improvement of the fire-resistant performance. In addition, thermogravimetric analysis/infrared spectrometry (TG-IR) results demonstrate that the volatilization of organic and toxic gases in gas phase are effectively restrained, which can be attributed to the lamellar shield of GO and radical trapping effect of SMNPs. These results illustrate that synthetic melanin material is one of the promising candidates as efficient additive in fire-resistant polymers, and the PEI/GO/SMNPs coatings play a part in gas-solid phase to improve the flame retardancy of PU foams.

Amphiphilic polymeric prodrugs show improved therapeutic indices with respect to traditional hydrophobic anticancer drugs because these prodrugs can self-assemble into nanoparticles, prolong the circulation of drugs in the blood, improve the accumulation of drugs in the disease site, reduce the side effects of drugs, and achieve therapeutic effect. Here, we describe a novel pH/reduction dual-responsive polymeric prodrug, abbreviated as CPT- ss-poly(BYP- hyd-DOX- co-EEP), with simultaneous conjugating camptothecin (CPT) and doxorubicin (DOX), wherein BYP and EEP represent two cyclic phosphate monomers, respectively, that is, 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane. This prodrug was prepared through a polyphosphoester-DOX conjugate using a CPT derivative (CPT- ss-OH) as the initiator. CPT is linked to the terminal of polyphosphoester via disulfide carbonate, which is easy to break up under intracellular reductive environment and release the parent CPT, whereas DOX was efficiently incorporated onto the pendants of polyphosphoester through a hydrazone bond (- hyd-), which would be cleaved in the intracellular acidic medium. We show that the stable prodrug nanoparticles formed by self-assembly could release CPT and DOX simultaneously in the tumor microenvironment. The results of MTT assay demonstrate that the prodrug, which binds two antitumor drugs simultaneouly, has the properties of dual pH/reduction sensitiveness, biocompatibility, biodegradability, and effective tumor therapy.

As one of the most critical molecular parameters, molecular weight distribution has a profound impact on the structure and properties of polymers. Quantitative and comprehensive understanding, however, has yet to be established, mainly due to the challenge in the precise control and regulation of molecular weight distribution. In this work, we demonstrated a robust and effective approach to artificially engineer the molecular weight distribution through precise recombination of discrete macromolecules. The width, symmetry, and other characteristics of the distribution can be independently manipulated to achieve absolute control, serving as a model platform for highlighting the importance of chain length heterogeneity in structural engineering. Different from their discrete counterparts, each individual component in dispersed samples experiences a varied degree of supercooling at a specific crystallization temperature. Non-uniform crystal nucleation and growth kinetics lead to distinct molecular arrangements. This work could bridge the gap between discrete and dispersed macromolecules, providing fundamental perspectives on the critical role of molecular weight distribution.

Due to the fast phase separation kinetics and small feature size, the self-assembly of giant molecules has attracted lots of attention. However, there is not much study on multicomponent giant surfactants. In this work, through a modular synthetic strategy, different polyhedral oligomeric silsesquioxane (POSS)-based molecular nanoparticles are installed with diverse functionalities (hydrophobic octavinyl POSS (VPOSS), hydrophilic dihydroxyl-functionalized POSS (DPOSS), and omniphobic perfluoroalkyl-chain-functionalized POSS (FPOSS)) on the ends of one polystyrene (PS) chain to build up a series of triblock bola-form giant surfactants denoted as XPOSS-PS

In this work, a new porous cross-linked membrane is prepared and used as the separator for rechargeable lithium-ion batteries. The inorganic zinc oxide nanoparticle (nano-ZnO) was added as a pore-forming agent and filler to the preparation process of membranes composed of poly(vinylidene fluoride-co-hexafluoropropylene) (PVdF-HFP) and a cross-linked polymer by the copolymerization from poly(ethylene glycol methyl ether methacrylate) (PEGMEMA), methyl methacrylate (MMA) and octavinyl-T8-silsesquioxane (OVPOSS). The prepared membrane was firstly swollen by propylene carbonate (PC) and nano-ZnO was then eluted by hydrochloric acid to form the microporous structure. The effects of particle size and additive amount of nano-ZnO on the mechanical and electrochemical properties of microporous membranes were studied. SEM analysis showed that 30 nm nano-ZnO was the most suitable diameter for forming microporous structure. It is generally considered that the ionic conductivity is inversely correlated with the mechanical strength of separator. In our research, we have found that 18% addition of nano-ZnO was the most appropriate amount for the preparation of a microporous membrane (CRZ18) with an ionic conductivity of 1.4 mS cm−1 and a tensile strength of 10.7 MPa. Meanwhile, the LiFePO4/Li half-cell assembled with the CRZ18 membrane as a separator exhibited the best C-rate capacity and cycle charge-discharge performance, indicating that the CRZ18 membrane would be a kind of promising separator for the high-performance lithium-ion batteries.

The effects of the growth hormone-releasing hormone (GHRH) agonist MR409 on various human cancer cells were investigated. In H446 small cell lung cancer (SCLC) and HCC827 and H460 (non-SCLC) cells, MR409 promoted cell viability, reduced cell apoptosis, and induced the production of cellular cAMP in vitro. Western blot analyses showed that treatment of cancer cells with MR409 up-regulated the expression of cyclins D1 and D2 and cyclin-dependent kinases 4 and 6, down-regulated p27kip1, and significantly increased the expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1). Hence, in vitro MR409 exerts agonistic action on lung cancer cells in contrast to GHRH antagonists. However, in vivo, MR409 inhibited growth of lung cancers xenografted into nude mice. MR409 given s.c. at 5 μg/day for 4 to 8 weeks significantly suppressed growth of HCC827, H460, and H446 tumors by 48.2%, 48.7%, and 65.6%, respectively. This inhibition of tumor growth by MR409 was accompanied by the down-regulation of the expression of pGHRH-R and SV1 in the pituitary gland and tumors. Tumor inhibitory effects of MR409 in vivo were also observed in other human cancers, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal. This inhibition of tumor growth parallel to the down-regulation of GHRH-Rs is similar and comparable to the suppression of sex hormone-dependent cancers after the down-regulation of receptors for luteinizing hormone-releasing hormone (LHRH) by LHRH agonists. Further oncological investigations with GHRH agonists are needed to elucidate the underlying mechanisms.

In this study, we report a diblock copolymer based on a polyphosphate backbone and pendant phenylboronic acid with glucose sensitivity. The copolymer, abbreviated as (PBYP-g-MPBA)-b-PEEP, was prepared via a combination of ring-opening copolymerization, "click" chemistry, and amide reaction, in which the PBYP and PEEP blocks, respectively, represent two kinds of polyphosphoester structures and MPBA represents 3-mercaptopropionic acid modified with 3-aminophenylboronic acid. The amphiphilic copolymer (PBYP-g-MPBA)-b-PEEP could self-assemble into core-shell nanoparticles (NPs) in aqueous solutions. The average particle size and morphology of the NPs were measured by dynamic light scattering and transmission electron microscopy, respectively. The phenomenon that the NPs swelled at different glucose concentrations is due to the formation of boronate esters between the diol groups of glucose and boronic acid groups of phenylboronic acid. Fluorescein isothiocyanate (FITC)-insulin was loaded into the NPs and triggered to release in the presence of glucose. The more the glucose in the release media, the more the FITC-insulin released and the faster the release rate. Methyl thiazolyl tetrazolium assays and hemolysis tests proved that the (PBYP-g-MPBA)-b-PEEP copolymers had good biocompatibility. All of these results verify that the glucose-sensitive polyphosphoester diblock copolymer is highly promising for an insulin delivery system.

Click chemistry has increasing applications of the development of polymer materials and modification of drug carriers. The amino-yne click polymerization reacts quickly at room temperature without catalyst, and the enamine bond (-ena-) gained from the reaction is sensitive to acid and can be used to prepare stimulus-responsive polymeric prodrugs. Herein, we report an alkynyl-terminated polymer containing alternately distributed low molecular weight polyethylene glycol (PEG) and hexamethylenediamino (HMDA) linked by enamine bonds, abbreviated as A-P(PEG-alt-HMDA)-A, which was synthesized within 3 h at 35 °C without catalyst. The polymer was verified to have good water solubility, biocompatibility, and acid-sensitive fracturing. Then, a pH-responsive polymeric prodrug (DOX-ena-PPEG-ena-DOX) was further prepared through the amino-yne click reaction between the alkynyl groups of A-P(PEG-alt-HMDA)-A and the amino group of doxorubicin hydrochloride (DOX·HCl). The resulting prodrug can self-assemble into nanoparticles (NPs) in aqueous solution. The pH responsiveness of the prodrug NPs was demonstrated by a stability experiment of NPs and in vitro drug release behavior measurement. The accumulative release of doxorubicin (DOX) was tested with different pH media, which confirmed that the prodrug NPs could effectively dissociate and release drug under a weak acid microenvironment of lysosome/endosome. Subsequently, we investigated cell cytotoxicity and intracellular uptake of the prodrug. It turned out that the prodrug nanoparticles could be internalized into HeLa cells, release original DOX, and efficiently inhibit the proliferation of cancer cells. These results show that the pH-responsive DOX-ena-PPEG-ena-DOX has the potential for use in cancer therapy.

Aminated poly(glycidyl methacrylate)s-based polymers for gene delivery not only can reduce toxicity and improve solubility, but can improve gene transfection efficiency and reduce protein aggregation. In this study, we first prepared poly(glycidyl methacrylate) (PGMA) via reversible addition-fragmentation chain transfer (RAFT) polymerization, and then the obtained PGMA homopolymer was post-modified with ethanol amine (EA), 1-amino-2-propanol (AP), 3-(dibutylamino)propylamine (DA) and N-(2-hydroxyethyl)ethylenediamine (HA), respectively, to yield four kinds of PGMA-based gene vectors containing hydroxyl groups (abbreviated as PGEA, PGAP, PGDA and PGHA). The effects of the different side chains and hydroxyl groups on the biological properties of these four cationic polymers were investigated. We found that the transfection efficiency of the PGHA/p53 complex was higher than those of the other three polymer/gene complexes through MTT assay and laser scanning confocal microscopy. Hence, we chose HA for further post-modification to fabricate a cationic copolymer, PCL-ss-P(PEGMA-co-GHA) (abbreviated as PGHAP), via a combination of ring opening polymerization (ROP) and RAFT copolymerization. The PCL-ss-P(PEGMA-co-GHA) amphiphilic copolymer could self-assemble into nanoparticles, which could be used to encapsulate anticancer drug doxorubicin (DOX) and compress the p53 gene to form the DOX-loaded PCL-ss-P(PEGMA-co-GHA)/p53 complex (abbreviated as DPGHAP/p53). The gel retardation assay showed that p53 gene could be well immobilized and remained stable under the electronegative conditions. MTT assay showed that the DPGHAP/p53 complex had a significant antitumor effect on A549 cells and H1299 cells compared with free DOX or/and p53 gene therapy alone. Furthermore, the test results from live cell imaging systems revealed that the DPGHAP/p53 complexes could effectively deliver DOX and the p53 gene into A549 cells. Therefore, the constructed cationic polymer PCL-ss-P(PEGMA-co-GHA) has potential application prospects as a co-vector of anticancer drugs and genes.

X-ray-responsive nanocarriers for anticancer drug delivery have shown great promise for enhancing the efficacy of chemoradiotherapy. A critical challenge remains for development of such radiation-controlled drug delivery systems (DDSs), which is to minimize the required X-ray dose for triggering the cargo release. Herein, we design and fabricate an effective DDS based on diselenide block copolymers (as nanocarrier), which can be triggered to release their cargo with a reduced radiation dose of 2 Gy due to their sensitivity to both X-ray and the high level of reactive oxygen species (ROS) in the microenvironment of cancer cells. The underlying molecular mechanism is further illustrated by proton nuclear magnetic resonance (1H NMR) experiments and density functional theory (DFT) calculations. In vivo experiments on tumor-bearing mice validated that the loaded drugs are effectively delivered to the tumor site and exert remarkable antitumor effects (minimum tumor volume/weight) along with X-ray. Furthermore, the diselenide nanocarriers exhibit no noticeable cytotoxicity. These findings provide new insights for the de novo design of radiation-controlled DDSs for cancer chemoradiotherapy.

A new kind of reduction-cleavable polymer-camptothecin (CPT) prodrug has been developed, in which the polymer backbone consists of a biodegradable diblock polyphosphoester (PBYP-b-PEEP), and a modified CPT is linked onto the pendant alkynes of PBYP via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to yield the polymeric prodrug, abbreviated as (PBYP-g-ss-CPT)-b-PEEP. The resulting prodrug could self-assemble into uniform prodrug micelles in aqueous solution. Since the releasable disulfide carbonate between the CPT and the polyphosphoester would be disrupted under an intracellular reducing environment, the disassociation of prodrug micelles could result in a rapid release of the CPT parent drug. The chemical structures of the intermediate polymers and a polymeric prodrug have been fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The self-assembly behavior of the prodrug was investigated by the fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The DLS results indicated that these prodrug micelles were relatively stable in neutral pH media, but could be degraded under the reductive conditions. The in vitro drug release studies showed that the CPT release from prodrug micelles was proceeded in a glutathione (GSH)-dependent manner. A methyl thiazolyl tetrazolium (MTT) assay demonstrated that the prodrug micelles could efficiently inhibit the proliferation of HepG2 cells. In addition, the intracellular uptake of prodrug micelles could efficiently release CPT into HepG2 cells, which was observed using a live cell imaging system. All these results indicated that this GSH-responsive polymeric prodrug has high potential for reduction-triggered cancer chemotherapy.

An emerging strategy for synergistic gene and drug therapy is establishing a new paradigm for the synthesis of diversified and functional block copolymers with applications ranging from gene and drug delivery to fluorescence detection. In this paper, we report on a novel amphiphilic block copolymer containing a fluorescent coumarin derivative (CE), an acid-cleavable (acetal group, -a-) linkage between hydrophobic poly(e-caprolactone) (PCL) and hydrophilic poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) and poly[poly(ethylene glycol)methyl ether methacrylate] (PPEGMA) blocks, abbreviated as CE-PCL-a-(PDMAEMA-co-PPEGMA), which was synthesized by a combination of atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP) and CuAAC “click” reaction. The chemical composition and structures of these copolymers were fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The micelles self-assembled from these block copolymers could simultaneously encapsulate anti-cancer drug doxorubicin (DOX) and DNA to form a micelleplex with the hydrophilic brush-type PPEGMA on the surface, and the loaded cargoes could be released after the acetal linkage was cleaved under intracellular acidic conditions. Subsequently, the formed micelles as the drug and gene co-delivery vectors were investigated by employing gel retardation assay, zeta potential, dynamic light scattering (DLS), and transmission electron microscopy (TEM). A fluorescence spectrometer was further used to evaluate the fluorescence of polymers. Finally, in vitro drug release, cytotoxicity and transfection were also studied. All these results indicated that this acid-cleavable and fluorescent block copolymer would hold significant potential as a combined drug and DNA carrier.

Zwitterionic polymers are a class of polymers that acts as both Lewis base and Lewis acid in solution. These polymers not only have excellent properties of hydration, anti-bacterial adhesion, charge reversal and easy chemical modification, but also have characteristics of long-term circulation and suppress nonspecific protein adsorption in vivo. Here, we describe a novel folate-targeted and acid-labile polymeric prodrug under the microenvironment of tumor cells, abbreviated as FA-P(MPC-co-PEGMA-BZ)-g-DOX, which was synthesized via a combination of reversible addition–fragmentation chain transfer (RAFT) copolymerization, Schiff-base reaction, Click chemistry, and a reaction between the amine group of doxorubicin (DOX) and aldehyde functionalities of P(MPC-co-PEGMA-BZ) pendants, wherein MPC and PEGMA-BZ represent 2-(methacryloyloxy)ethyl phosphorylcholine and polyethylene glycol methacrylate ester benzaldehyde, respectively. The polymeric prodrug could self-assemble into nanoparticles in an aqueous solution. The average particle size and morphologies of the prodrug nanoparticles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. We also investigated the in vitro drug release behavior and observed rapid prodrug nanoparticle dissociation and drug release under a mildly acidic microenvironment. The methyl thiazolyl tetrazolium (MTT) assay verified that the P(MPC-co-PEGMA-BZ) copolymer possessed good biocompatibility and the FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticles showed higher cellular uptake than those prodrug nanoparticles without the FA moiety. The results of cytotoxicity and the intracellular uptake of non-folate/folate targeted prodrug nanoparticles further confirmed that FA-P(MPC-co-PEGMA-BZ)-g-DOX could be efficiently accumulated and rapidly internalized by HeLa cells due to the strong interaction between multivalent phosphorylcholine (PC) groups and cell membranes. This kind of multifunctional FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticle with combined target-ability and pH responsiveness demonstrates promising potential for cancer chemotherapy.

Lung cancer is one of the most frequently occurring cancers worldwide and its pathological complexity necessitates combination therapies of various therapeutic elements such as anti-cancer drugs and genes to achieve synergistic treatment. In this study, we designed a co-delivery carrier of the anti-cancer drug doxorubicin (DOX) and the tumor suppressor gene p53 for lung cancer treatment. First, a copolymer precursor (mPEG-b-PBYP) was prepared via ring-opening polymerization of 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (BYP). Subsequently, on the basis of the precursor, a pH-sensitive prodrug (abbreviated as mPEG-b-PBYP-hyd-DOX) and a polycation gene vector (abbreviated as mPEG-b-PBYP-g-DAE) were separately prepared via CuAAC and thiol-yne "click" chemistry, wherein DAE represents 2-dimethylaminoethanethiol hydrochloride. After that, the prodrug and the gene vector copolymers were mixed in an aqueous solution in order to self-assemble into hybrid micelles, which could then condense the p53 gene and finally form DOX prodrug/p53 co-loaded nanoparticles. The average particle size and morphologies of the hybrid micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The gel retardation assay showed that the p53 gene could be well immobilized and maintained stably under the electronegative conditions, similar to those in the blood circulation. A cytotoxicity assay showed the obvious antitumor effect of the hybrid micelle/p53 gene nanoparticles on A549 and H1299 cells when compared to drug or gene therapy applied alone, respectively. Furthermore, the results from the live cell imaging system revealed that the hybrid micelle/p53 gene nanoparticles could effectively deliver and release DOX and the p53 genes into A549 cells. All of the results showed that the hybrid micelles containing the DOX prodrug and p53 genes could be widely used in the treatment of lung cancer.