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Metal–organic frameworks (MOFs) are unique coordination polymers that have emerged as important candidates for drug delivery in recent years. Herein, we designed a drug delivery system for multi-modal combination therapy (IR-820/DOX@MIL-101-PDA-PEG-F3, simplified as ID@MIL-PPF3). In this study, pH-sensitive nanocarriers MIL-101(Fe) were prepared and loaded with the effective chemotherapy agent doxorubicin (DOX) and the phototherapeutic reagent new indocyanine green (IR-820) using a physical adsorption method. Dopamine was spontaneously polymerized in alkaline solutions to form a hybrid coating on MIL-101(Fe) (denoted as ID@MIL-101-PDA). The surface of ID@MIL-101-PDA was functionalized by the synthesized polymer NH2-PEG-OCH3/F3 to obtain ID@MIL-PPF3. Characterization results show that ID@MIL-PPF3 has a good drug loading rate (27.7%) and photothermal conversion efficiency (28.89%). In addition, Fe3+ released from MIL-101(Fe) can engage in a Fenton-like reaction to generate hydroxyl radicals (˙OH) to realize chemodynamic therapy (CDT). ID@MIL-PPF3 not only demonstrates the ability to intelligently release drugs, but also realizes chemotherapy combined with PDT/PTT/CDT therapy for tumor cells, which was proved by in vitro evaluation. In conclusion, ID@MIL-PPF3 provides a new idea and method for building a multi-modal combination therapy targeted drug delivery platform. [ABSTRACT FROM AUTHOR]

Photoactivated pesticides have many advantages, such as high activity, low toxicity, and no drug resistance. However, poor photostability and a low utilization rate limit their practical application. Herein, the photosensitizer hematoporphyrin (HP) was used as a photoactivated pesticide, covalently linked with pectin (PEC) via ester bonds, to prepare an amphiphilic polymer pro-bactericide, and subsequently self-assembled in aqueous solutions to obtain an esterase-triggered nanobactericide delivery system. The fluorescence quenching effect due to the aggregation of HP in nanoparticles (NPs) enabled the inhibition of photodegradation of HP in this system. Esterase stimulation could trigger HP release and increase its photodynamic activity. Antibacterial assays have shown that the NPs had potent antibacterial capacity, almost completely inactivating bacteria after 60 min of exposure to light. The NPs had good adherence to the leaves. Safety assessment indicated that the NPs have no obvious toxic effects on plants. Antibacterial studies on plants have shown that the NPs have excellent antibacterial effects on infected plants. These results provide a new strategy for obtaining a photoactivated bactericide nanosystem with a high utilization rate and good photostability and targeting ability. [ABSTRACT FROM AUTHOR]

Nanoscale metal–organic framework (nMOF) based nano drug delivery systems show great potential in the biomedical field. In this work, a drug delivery system combined with chemotherapy and phototherapy (DOX/ICG@UiO-66-TK-PEG-F3 or simplified as DI@UiO-TPF3) was designed for the targeted therapy of tumors. The chemotherapeutic drug doxorubicin (DOX) and the photothermal therapeutic agent indocyanine green (ICG) were loaded onto the pH-sensitive UiO-66-NH2 carrier core by physical adsorption, and the surface of UiO-66-NH2 was modified by the multifunctional polymer TK-PEG-F3 to improve the stability and targeting of the drug-loaded core. Characterizations show that the drug delivery system DI@UiO-TPF3 was successfully prepared with an excellent drug loading rate (21.6%) and photothermal conversion efficiency (32.92%). DI@UiO-TPF3 not only shows the ability to stimulate a response to release drugs, but also achieves the synergistic anti-tumor effects of chemotherapy and photothermal/photodynamic therapy (PTT/PDT), which was confirmed by in vitro evaluation. In addition, cell experiments have confirmed that DI@UiO-TPF3 connected with F3 peptide can selectively bind to the nucleolin overexpressed on the surface of tumor cells and reduce the toxicity to normal cells. Therefore, DI@UiO-UTPF3 provided a feasible strategy for constructing a targeted drug delivery platform integrating chemotherapy and phototherapy. [ABSTRACT FROM AUTHOR]

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano‐sized MIL‐101(Fe)‐N3 and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne‐PLA‐PEG was then attached to the F3 peptide (labeled as Alkyne‐PLA‐PEG‐F3), and the surface of DOX/MIL‐101(Fe)‐N3 was covalently modified with it to obtain DOX/MIL‐101‐PLA‐PEG‐F3. Nano‐sized MIL‐101(Fe)‐N3 has high drug loading capacity and the modification of MIL‐101(Fe)‐N3 by polymer Alkyne‐PLA‐PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin‐mediated endocytosis drug delivery system, DOX/MIL‐101‐PLA‐PEG‐F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton‐like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment. [ABSTRACT FROM AUTHOR]

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Persistent high-risk human papillomavirus (hrHPV) infection is confirmed as the major cause of cervical cancer. According to the HPV infection status, cervical cancer could be generalized as following three subgroups: HPV-negative, pure HPV-infection, and HPV-integration. Currently, the impact of HPV status on cervical cancer prognosis remains under dispute. Therefore, we explored the potential correlation between HPV status and the clinical outcome of cervical cancer, by establishing a robust prognostic predicting model based on a cervical cancer cohort using The Cancer Genome Atlas (TCGA) database. We performed an iCluster algorithm incorporating DNA copy number variation, SNP, DNA methylation, mRNA expression, and miRNA expression profile together and classified the cohort into three clusters. According to defined clusters, we established an HPV score system by weighing resultant gene alterations through random forest and COX models. This prediction tool could help to identify cervical cancer prognosis through evaluating individual HPV infection status and subsequent genetic modification, which might provide insights into HPV-related gene driven cervical cancer treatment strategies, yet its predictive power and robustness need to be further verified with independent cohorts. [ABSTRACT FROM AUTHOR]

To improve photostability and enhance utilization rate and reduce pest resistance, a new strategy based on the combination of photodynamic insecticide action and stimulus‐responsive polymer micelles is developed. 4‐(phenylazo)benzoic acid (PBA)‐modified poly(ethylene glycol) monomethyl ether (mPEG) conjugate is prepared by the esterification reaction of mPEG and PBA, and followed by self‐assembly in aqueous solution to obtain polymeric nanoparticles. TEM shows that the nanoparticles have a core‐shell structure and an average diameter of 78 nm. DLS shows that the nanoparticles are stability in water solution but can change their structure in response to UV light and/or esterase stimulation. The photodegradation of Protoporphyrin IX (PpIX) encapsulated in the nanoparticles can be effectively inhibited because of aggregation‐caused quenching effect, whose maximum photodegradation rate is about 20.54% after 8 h exposure to daylight compared with the complete photodegradation of free PpIX. UV light and/or esterase stimulus can trigger PpIX release and result in a high photodynamic activity. Compared with free PpIX, the PpIX‐loaded nanoparticles show a higher phototoxicity to insect cells and the daylight pretreatment has little influence on the phototoxicity. [ABSTRACT FROM AUTHOR]

A simple strategy was developed to prepare a tough, self-healing, antibacterial and moldable hydrogel by introducing the natural polyphenolic compound tannic acid (TA) as a cross-linking center for hydrogen bonds. Polyvinyl alcohol (PVA)-TA hydrogel was prepared by physical mixing using PVA as a main component and TA as a cross-linker. There were two types of physical cross linking bonds in the PVA-TA hydrogel network, which were weaker hydrogen bonds between PVA molecular chains and stronger hydrogen bonds between PVA and TA molecules. The mechanical properties and self-healing ability could be adjusted by changing the contents of PVA and TA. The hydrogel possessed not only high mechanical strength (305 kPa tensile strength and 864 kPa compressive strength), moldability and excellent self-healing properties (95% self-healing efficiency) but also good antibacterial abilities against S. aureus and E. coli. In addition, after soaking the dried hydrogel in 90 ℃ deionized water for 4 h, they could also regain their self-healing ability to a certain extent. The hydrogels have potential applications in the biomedical fields. [ABSTRACT FROM AUTHOR]

A novel quaternary ammonium chitosan hydrogel modified by poly(amidoamine) (PAMAM) dendrimer was prepared by using glutaraldehyde as a cross-linker. The hydrogel was characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results confirmed its highly porous three-dimensional network structure. The swelling test of hydrogel proved that it had excellent swelling and pH-sensitive properties. The increasing PAMAM content or quaternization degree led to the increase in swelling properties. And the hydrogel with lower cross-linking agent concentration or quaternary ammonium chitosan concentration exhibited better swelling properties. The antibacterial results indicated that with the increase in the PAMAM content, quaternary ammonium chitosan concentration or cross-linking agent concentration, the hydrogels showed better antibacterial activities against both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Thus, the hydrogel could serve as a promising antibacterial material in the future. [ABSTRACT FROM AUTHOR]

Superabsorbent hydrogels were prepared successfully from N-succinyl chitosan grafted poly(acrylic acid- co-acrylamide). The potassium persulfate (KPS), N, N'-methylenebisacrylamide (MBA) were used as the initiator and crosslinker, respectively. Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) were used to confirm the porous network structure of superabsorbent hydrogel. The effects of reaction parameters on the swelling behaviors of the superabsorbent hydrogels were investigated. The results indicated that water absorbency increased first, and then decreased gradually with the increase in the contents of monomer (AA+AM), KPS, MBA or acrylamide. The product had excellent water absorbency of 1375 g/g in distilled water and 83 g/g in 0.9wt% NaCl solution. Simultaneously, the superabsorbent hydrogels were pH sensitive. The antibacterial activities of the hydrogels against Escherichia coli ( E. coli) were improved effectively because of polyamidoamine (PAMAM) dendrimer absorbed in the hydrogels. [ABSTRACT FROM AUTHOR]

In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition–elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile – glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days.In vitrodrug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV–vis spectrophotometer.In vitromacrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs. [ABSTRACT FROM AUTHOR]

In this study,O-carboxymethyl chitosan (O-CMCS) was synthesized from chitosan and monochloroacetic acid. ThenO-CMCS hydrogel was prepared by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) andN-hydroxysuccinimide (NHS) in which the lincomycin was packaged. The Fourier transform infrared spectrum and scanning electron microscopy were adopted to characterize the structure and morphology of the product. The influences of dosage of EDC/NHS and concentration ofO-CMCS on the swelling properties of the hydrogels were investigated. The hydrogels performed good swelling capacities and obvious pH-sensitive properties. The antibacterial activities of the hydrogels were tested against Gram-negativeEscherichia coli(E. coli) and Gram-positiveStaphylococcus aureus(S. aureus). Compared with pureO-CMCS hydrogels, the antibacterial activities ofO-CMCS/lincomycin hydrogels were significantly improved with the increase in the concentration of lincomycin againstE. coliandS. aureus. With the increase in dosage of crosslinking agent or concentration ofO-CMCS, the antibacterial activities both decreased gradually against the two bacteria.O-CMCS/lincomycin hydrogel was expected to be used for antibacterial material in view of its significant antibacterial activities. [ABSTRACT FROM AUTHOR]

Ras homology GTPase activation protein 6 (Arhgap6), as a member of the rhoGAP family of proteins, performs vital functions on the regulation of actin polymerization at the plasma membrane during several cellular processes. The role of Arhgap6 in the progression and development of cancer remains nearly unknown. This study aimed at exploring the effects of Arhgap6 on cervical carcinoma. Human cervical cancer cells HeLa and SiHa were transduced with a lentivirus targeting Arhgap6 (Arhgap6+), while CaSki and C4-1 cells were transfected with miRNA. Cell proliferation was identified by Cell Counting Kit-8 (CCK-8). Cell cycle distribution and cell apoptosis were identified by flow cytometry. The capacity of cell migration, invasion, and adhesion were detected by Transwell assay. Further, quantitative real-time PCR (qRT-PCR) and western blot were used to analyze the expression levels of Arhgap6 and several tumor-related genes. Co-immunoprecipitation assay was performed to validate the interaction between Arhgap6 and Rac3 (Ras-related C3 botulinum toxin substrate 3). Results showed that Arhgap6 inhibited cell proliferation, migration, invasion, and adhesion of cervical carcinoma, induced cell apoptosis, and caused cell cycle arrest in the G0/G1 phase ( n = 3, p < 0.05). Expression of the tumor suppressor genes and oncogenes were up- and down-regulated respectively by Arhgap6, and Rac3 was proved to be the target of Arhgap6. Besides, in in vivo assays, tumor size and weight were destructed in Arhgap6+ athymic nude mouse. This study indicated that Arhgap6 may play a role in the treatment of cervical cancer as a tumor supressor. [ABSTRACT FROM AUTHOR]

A series of novel water soluble chitosan derivatives as gene vectors was synthesized. The delivery systems were tested for their ability to form complexes with plasmid DNA by utilizing agarose gel electrophoresis, particle size analysis, zeta potential measurement and scanning electron microscopy. Furthermore, cytotoxicity of chitosan derivatives and transfection efficiency of polyplexes were evaluated in vitro. The experimental results showed that the novel chitosan derivatives had lower cytotoxicity, good DNA condensation, and higher transfection efficiencies compared to chitosan in both 293T and HeLa cell lines. It was indicated that these chitosan derivatives were promising candidates for non-viral gene vectors [ABSTRACT FROM AUTHOR]

Osteomyelitis is a bone infection disease which is caused by bacteria or other germs, and could cause serious impact on the health and working capacity of the patients. Alendronate (ALN) can chelate strongly with the calcium ion of hydroxyapatite (HA) which is commonly used to treat osteoporosis. Nanomedicine has attracted a lot of attention in that the nano-sized carrier can deliver drug molecules to specific site of interest with the aid of targeting moiety and achieve sustained release, resulting in improved therapeutic effect and reduced side effect. In this study, micelles self-assembled from poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-alendronate (PLGA-PEG-ALN) copolymer were prepared for bone-targeted delivery of vancomycin (Van). The chemical structure of PLGA-PEG-ALN was confirmed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. The formation of the nanoparticles was characterized by dynamic light scattering, transmission electronic microscopy as well as the critical micelle concentration measurement. Release profiles from the micelles revealed that the conjugation of ALN to the surface of micelle did not pose adverse effect on the drug-loading capacity and release behaviors. The cytotoxicity of Van-loaded PLGA-PEG-ALN micelles as well as the blank micelles was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay toward rat bone marrow stromal cells (rBMSCs) and human embryonic hepatocytes (L02 cells), and results showed that this Van-loaded micelle possesses appropriate cytotoxicity and is safe in the potential treatment of osteomyelitis. Thein vitroaffinity of PLGA-PEG-ALN micelles to the HA was also confirmedin vitro. The antibacterial effect of Van-loaded PLGA-PEG-ALN micelles was tested againstStaphylococcus aureus(SA) which is the main pathogenic bacteria in osteomyelitis, and the results showed that the Van-loaded micelles can effectively inhibit the growth of SA. These results demonstrated that the PLGA-PEG-ALN micelles may be potentially used for the bone targeted delivery of Van. [ABSTRACT FROM PUBLISHER]

The use of methotrexate (MTX), an anticancer drug for the treatment of hematologic malignancies, has been limited in the clinical application due to its poor water solubility, high clearance rate, and lack of target specificity. To solve these problems, O, N-carboxymethyl chitosan-dipeptide-MTX conjugates have been synthesized and characterized by fourier transform infrared radiation spectroscopy and proton nuclear magnetic resonance (H NMR). All polymeric conjugates showed satisfactory water solubility. The results of the study revealed that drug release and toxicity were affected by employing polymeric conjugation strategy and dipeptide spacers [glycylglycine (Gly-Gly), glycyl- l-phenylalanine (Gly-Phe), glycyl- l-tyrosine (Gly-Tyr)]. It has been found that drugs could be effectively loaded and released when polymeric prodrugs were combined with a dipeptide spacer. In conclusion, O, N-CMCS-dipeptide-MTX polymeric prodrugs could potentially be used as responsive drug delivery systems. [ABSTRACT FROM AUTHOR]

Though previous studies investigated the association between glutathione S-transferase M 1 (GSTM1) null genotype and ovarian cancer risk, the effect of GSTM1 null genotype on ovarian cancer risk was still unclear. To comprehensively quantify the association between GSTM1 null genotype and ovarian cancer risk, we performed a meta-analysis. Eleven studies from ten publications were identified from PubMed database. The pooled odds ratio (OR) with its 95 % confidence interval (CI) was used to assess the association. Meta-analysis of the total 11 studies showed that GSTM1 null genotype was not associated with ovarian cancer risk (OR = 1.03, 95 % CI 0.92–1.14, P = 0.625). The cumulative meta-analyses showed a trend of no association between GSTM1 null genotype and ovarian cancer risk as information accumulated by year. There was no evidence of publication bias in the meta-analysis. Meta-analysis of the 11 available studies shows that GSTM1 null genotype is not associated with ovarian cancer risk. [ABSTRACT FROM AUTHOR]

A series of cross-linked hydrogels for colon-specific drug delivery were synthesized by graft copolymerization of Chitosan and acrylic acid using N, N′-methylene-bis-(acrylamide) as a cross-linker. Their swelling behavior in different pH buffer solutions and colonic enzymatic degradability were studied. The obtained results show that these hydrogels have good pH sensitivity which can avoid drug release in stomach, and their swelling kinetics in stimulant intestinal environment follow second-order swelling kinetics equation. The factors influencing the swelling kinetics include the degree of cross-linking and the composition, which may control no release or a little amount release of drug inside the hydrogels in the small intestine by tailoring these factors. The gels are degradable by colonic enzymes and there is a correlativity between the degradation of networks and the swelling degree of the gels, which may trigger the release of drug in the colon. The hydrogels show a great potential for their application in oral colon-specific drug delivery system. [ABSTRACT FROM AUTHOR]

A series of cross-linked gels of Poly(N-isopropylacrylamide) [P(NIPAAm)] and Poly(methacr-ylic acid)[P(MAA)] homopolymers and P(NIPAAm-co-MAA) random copolymers were synthesized based on NIPAAm and MAA using 4,4-Bis-(methacryloylamino) azobenzene (BMAAB) as a cross-linker. The swelling behavior of these hydrogels in different pH buffer solutions was studied. The influential factors of the gels including composition of NIPAAm and MAA, pH and temperature upon swelling behavior were investigated. The obtained gels not only hold pH and thermometrical sensitivity, but also take on enzymatic sensitivity due to the cross-linker could be degraded by enzymes of colon. Swelling equilibrium degree of copolymers was very low in acidic medium, which could avoid drug releasing due to biggish swelling of carrier in stomach. Hydrogels would partly swell owing to higher pH value in small intestine. When arrived in colon, hydrogels completely swelled, meanwhile, azoenzymes located would degrade azo-bonds of polymeric network and then drug released in colon. [ABSTRACT FROM AUTHOR]

Biopolymeric hollow nanospheres with stabilized structure have been prepared by self-assembly of amphiphatic photocrosslinkable carboxymethyl chitosans in a water medium into hollow nanocapsules and subsequent in situphoto-crosslinking of the photoreactive functional groups in the shells of the nanocapsules. [ABSTRACT FROM AUTHOR]

Biopolymeric hollow nanospheres with stabilized structure have been prepared by self-assembly of amphiphatic photocrosslinkable carboxymethyl chitosans in a water medium into hollow nanocapsules and subsequent in situphoto-crosslinking of the photoreactive functional groups in the shells of the nanocapsules. [ABSTRACT FROM AUTHOR]

For enhanced intracellular accumulation of 6-mercaptopurine (6-MP) in leukemia, a folate receptor-targeted and glutathione (GSH)-responsive polymeric prodrug nanoparticle was made. The nanoparticles were prepared by conjugating 6-MP to carboxymethyl chitosan via a GSH-sensitive carbonyl vinyl sulfide linkage, ultrasonic self-assembly and surface decoration with folate. The TEM graphs shows that the as-synthesized nanoparticles are spherical with a particle size of 170~220 nm. In vitro drug release of nanoparticles demonstrated acceptable stability in PBS containing 20 μM GSH at pH 7.4. However, the cumulative drug release rate of the samples containing 20 mM and 10 mM GSH medium reached 78.9% and 64.8%, respectively, in pH 5.0 at 20 h. This indicated that this nano-sized system is highly sensitive to GSH. The inhibition ratio of folate-modified nanoparticles compared to unmodified nanoparticles was higher in cancer cells (human promyelocytic leukemia cells, HL-60) while their cytotoxicity was lower in normal cells (mouse fibroblast cell lines, L929). Furthermore, in vitro cancer cell incubation studies confirmed that folate-modified nanoparticles therapeutics were significantly more effective than unmodified nanoparticles therapeutics. Our results suggest that folate receptor-targeting and GSH-stimulation can significantly elevate tumour intracellular drug release. Therefore, folate-modified nanoparticles containing chemoradiotherapy is a potential treatment for leukemia therapy. [ABSTRACT FROM AUTHOR]