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It is a tough task in the clinic to remove and refresh dressings. Inspired by the chemical structure of mussel adhesive proteins (MAP), an injectable dopamine (DOPA)-based adhesive hydrogel was constructed as a wound-healing dressing that could be easily replaced by spraying zinc ions. A hyperbranched polymer named HB-PBAE was synthesized by a Michael addition reaction between dopamine (DOPA), poly(ethylene glycol) diacrylate (PEGDA700), and pentaerythritol triacrylate (PETA). The DOPA-based adhesive hydrogel was fabricated by mixing HB-PBAE, poly(1-vinylimidazole) (PVI) and gelatin solution, followed by adding Fe3+. Intriguingly, spraying Zn2+ solution resulted in rapidly reduced adhesive strength and sharply increased strength. Importantly, the adhesive dressing reduced damage during changing the dressing in a rat wound bed and accelerated the wound-healing process. This metal ion-facilitated dressing change might provide a novel concept in the design of wound dressings.

Aspidopterys obcordata vine is a Chinese Dai ethnic herb used to treat urolithiasis. However, the material basis and underlying mechanisms remain undefined. In this study, a 2.3 kD inulin-like A. obcordata fructan (AOFOS) was isolated by size exclusion column chromatography and characterized by ultrahigh-performance liquid chromatography-ion trap-time of flight mass spectrometry (UPLC-IT-TOF-MS), nuclear magnetic resonance (NMR) spectroscopy, gas chromatography mass spectrometry (GC-MS) and high-performance gel permeation chromatography (HGPC). In addition, AOFOS showed unique anti-urolithiasis activity in Drosophila kidney stone models. Mechanism study indicated that AOFOS reduced the size of calcium oxalate crystals by inhibiting the formation of large size crystals and the generation rate of calcium oxalate crystals as well as the crystal form conversion from calcium oxalate monohydrate (COM) to calcium oxalate dihydrate (COD).

In this paper, adamantane (Ad) substituted reduction-sensitive polyethylenimine (Ad-b-SS-PEI600) was used as cationic polymer gene vector for DNA loading. And then the α,β CD dimers were applied as the bridges between the Ad-b-SS-PEI600/DNA polyplexes and the functional moieties, i.e. targeting moiety and fluorescent probe through effective host–guest interactions. Located in the surface of the assemblies, the postdecorated functional moieties can efficiently exert their own function. It was found that gene delivery platforms thus obtained exhibited promising DNA compaction capability, rapid stimuli responsiveness, and good biocompatibility, and moreover they can mediate efficient gene transfection, targeting, and imaging both in vitro and in vivo.

Cancer is considered to be the leading factor which threatens human lives nowadays, and 90% of cancer-related deaths are attributed to the metastasis of cancer. Thus an effective and simultaneous separation and therapeutic method for circulating tumor cells is crucial for improving the diagnosis, prognosis, and treatment of cancer. Here, we report the design of theranostic magnetic nanoparticles conjugated with the targeting peptide SP94 and the anticancer drug doxorubicin (DOX) (symbolized as Fe3O4–DOX/SP94) for the targeted isolation of the human hepatocellular carcinoma cell line (HepG2), followed by the in situ chemotherapy of cancer cells upon capture. It was found that the capture efficiencies of 400 μg Fe3O4–DOX/SP94 for HepG2 cells and human embryonic kidney transformed 293 cells (293T) were around 75% and 5% respectively after 15 min incubation. Furthermore, it is worth mentioning that DOX was covalently conjugated via pH-sensitive hydrazone bonds, and the in vitro release studies demonstrated that DOX was released much faster at pH 5.0 than at pH 7.4. According to the in vitro cytotoxicity assays, significantly reduced cell viability was observed in HepG2 cells when the concentration of Fe3O4–DOX/SP94 nanoparticles was 300 μg mL−1. Such a rapid and facile approach has considerable potential for the targeted capture as well as effective chemotherapy of circulating tumor cells, in an attempt to improve the curative effects against metastatic diseases.

Taking advantage of the special nucleophilic addition reaction with aldehyde, a “switching-on” fluorescent probe (C1) for hydrogen sulfite was synthesized using intramolecular charge transfer (ICT) as a signal mechanism. Upon the addition of HSO3− ions, the probe displayed apparent fluorescence changes from non-emission to strong green fluorescence. C1 gave response to hydrogen sulfite with high sensitivity and the detection limit was determined to be as low as 3.0 μM. In addition to its high selectivity for hydrogen sulfite rather than other common anions, C1 was successfully applied to the detection of hydrogen sulfite in HeLa cells with turn-on fluorescent methods.

Cell membrane-camouflaged nanoparticles for cancer therapy have received a burgeoning interest over the past years. However, the low drug loading and intratumoral release efficiency, and lack of precise targeting remains a big challenge; in addition, foreign carriers used may pose an expected burden in the course of metabolism. In this study, we designed and fabricated a novel NIR-responsive highly targeted carrier-free nanosystem by coating the exactly identical source of cracked cancer cell membranes (CCCMs) specifically derived from the homologous tumors onto the surface of the co-assembly nanoparticles of doxorubicin (DOX) and FDA-approved photothermal agent, indocyanine green (ICG). The nanosystems exhibited a high drug loading capacity (89.8%), cancer cell self-recognized ability and immune escape function. Further, the nanodrugs could be efficiently released for the membrane disturbance triggered by photothermal effect of ICG under NIR irradiation. The tumor-bearing mice model demonstrated that the self-carried DOX NPs@ICG@CCCM nanoparticles possessed a strong synergistic chemo-/photothermal therapeutic efficacy against tumors in vivo. The present strategy could be developed as a universal approach for designing and constructing carrier-free theranostic nanovehicles by intentionally selecting specific cancer cell membrane and the inner loading cargoes.

Nature-inspired nanoparticles, from pathogens to mammalian cells, have attracted increasing attention, for their specific functions and unparalled features that are often desired in designing drug/gene delivery nonviral vectors. However, the applications of nonviral vectors are still suffering from the limits of low drug loading efficiency and/or low gene transfection efficiency. Herein, a novel carrier-free nanodrug-based virus-surface-mimicking gene delivery nanosystem is designed by condensing doxorubicin nanoparticles (DNPs) onto the surface of the PEI/DNA nanocomplex through electrostatic force, which would prolong the blood circulation time of PEI/DNA and confer high drug loading characteristics to the PEI/DNA nanosystem. Meanwhile, the gene transfection efficiency of DNA can also be enhanced for the increased roughness of coated DNPs. The in vitro and in vivo results demonstrate that carrier-free nanodrug-based gene delivery nanosystems with high drug loading efficiency (97.5%) as well as a rough surface can enhance the endocytosis of the nanoparticles, and consequently enhance the chemo/gene co-therapy of cancers. This is the first time soft materials are used to design virus-surface-mimicking nanocarriers, avoiding the side effects of inorganic materials caused by their non-degradable property. Importantly, our delicate design opens a new pathway to develop nature-inspired nanoparticles for cancer synergistic therapy.

The insufficient endocytosis and the low expression efficiency of the transfected gene in the lesion are still the main challenge for gene therapy. Herein, a novel bilirubin (BR)-based ROS responsive hydrophobicity/hydrophilicity switchable BR-grafted polylysine (PLL)/DNA nanosystem is designed by condensing indocyanine green (ICG) onto the surface of vector through electrostatic interaction between ICG and PLL, which can prolong the blood circulation time of nanocomplexes, and thus enhance the gene transfection efficiency due to the favorable solubility exchange of BR from hydrophobicity to hydrophilicity under ROS stimulus and the increased roughness of coated ICG. The in vitro and in vivo results demonstrate that the BR-based ROS responsive hydrophobicity/hydrophilicity switchable nanosystem with a rough surface can enhance the endocytosis of the nanoparticles, and consequently facilitate the gene therapy in an inflammatory environment. Our delicate design concept can expand to develop an anti-inflammation nanocarrier for efficient gene therapy in an inflammatory setting.

Acute myelocytic leukemia (AML) is the most common type of acute leukemia. Long non‑coding RNAs (lncRNAs) serve an important role in regulating gene expression through chromatin modification, transcription and post‑transcriptional processing. LncRNA H19 was considered as an independent prognostic marker for patients with tumors. The expression of lncRNA H19 was identified to be significantly upregulated in bone marrow samples from patients with AML‑M2. Furthermore, it was demonstrated that the knockdown of lncRNA H19 resulted in increased expression of hsa‑microRNA (miR)‑19a/b and decreased expression of inhibitor of DNA binding 2 (ID2) in AML cells. The knockdown of lncRNA H19 inhibited the proliferation of AML cells in vitro, which could be partially reversed by ID2 overexpression. Furthermore, the results of the bioinformatic analysis revealed potential hsa‑miR‑19a/b‑3p binding sites in lncRNA H19 and ID2. Altogether, the results of the present study suggest that lncRNA H19 regulates the expression of ID2 through competitive binding to hsa‑miR‑19a and hsa‑miR‑19b, which may serve a role in AML cell proliferation.

Drug-loaded injectable hydrogels have been proven to possess huge potential for applications in tissue engineering. However, increasing the drug loading capacity and regulating the release system to adapt to the microenvironment after myocardial infarction face a huge challenge. In this research, an ROS-sensitive injectable hydrogel strengthened by self-nanodrugs was constructed. A hyperbranched ROS-sensitive macromer (HB-PBAE) with multiacrylate end groups was synthesized through dynamic controlled Michael addition. Meanwhile, a simple protocol based on dopamine polymerization was employed to generate a polydopamine (PDA) layer deposited on the tanshinone IIA (TIIA) nanoparticles (NPs) formed from spontaneous hydrophobic self-assembly. The HB-PBAE reacted with thiolate-modified hyaluronic acid (HA-SH) to form an in situ hydrogel, where TIIA@PDA NPs can be conveniently entrapped through the chemical cross-link between thiolate and quinone groups on PDA, which doubles the modulus of hydrogels. The in vivo degradation behavior of the hydrogels was characterized by MRI, exhibiting a much slower degradation behavior that is markedly different from that of in vitro. Importantly, a significant improvement of cardiac functions was achieved after hydrogel injection in terms of increased ejection fraction and decreased infarction size, accompanied by inhibition of the expression of inflammation factors, such as IL-1β, IL-6, and TNF-α.

Stem-cell-based neural regeneration has received significant attention, as it has potential to restore functionality to diseased or damaged neural tissues that have a limited ability to self-repair or regenerate. Culturing neural stem cells (NSCs) on hydrogel substrates has been shown to facilitate differentiation to neural progenitors, but this has only been achieved on very soft hydrogels, greatly increasing the difficulty of manufacture and limiting their wide applications. Here, we realized the differentiation of NSCs to neural and glial progenitors on high-strength hydrogels. Hydrogen-bonding-strengthened conductive hydrogels (PVV-PANI) were synthesized through one-pot copolymerization of 2-vinyl-4,6-diamino-1,3,5-triazine, 1-vinylimidazole and polyethylene glycol diacrylate, followed by post-coating with polyaniline (PANI). Diaminotriazine-diaminotriazine hydrogen bonding dramatically increases their mechanical strength, while copolymerization with VI pronouncedly promotes the adsorption of PANI particles, endowing the hydrogels with electrical conductivity. These hydrogels exhibit tensile strengths up to 1.16 MPa, a 559% breaking strain, a 9.9 MPa compressive strength and up to 16.7 mS/cm conductivity. Importantly, PVV-PANI hydrogels support the attachment, proliferation, and differentiation of NSCs, and allow the efficient induction of neural and glial differentiation via electrical stimulation. This work demonstrates high-strength conductive hydrogels can serve as an electroactive soft-wet platform for modulating the specific differentiation of NSCs, a significant step towards cell-based therapies for neurological diseases.

A polymeric polyethylenimine (PEI)-based prodrug of anticancer doxorubicin (DOX) (PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug co-delivery in response to the intracellular acid microenvironments in the late endosome/lysosome compartments. The cytotoxicity of PEI-hyd-DOX was evaluated by the MTT assay and the cellular uptake was monitored using confocal laser scanning microscopy. The polymeric prodrug can respond with a high sensitivity to the specific acid condition inside cells, thus permitting the precise biocontrol over intracellular drug liberation with high drug efficacy. The chemical attachment of drug molecules also led to the relatively reduced toxicity and the enhanced transfection efficiency compared with parent PEI. The resulting data adumbrated the potential of PEI-hyd-DOX to co-deliver DOX and therapeutic gene for the combination of chemotherapy and gene therapy.

In principle, not only efficient but rapid transfection is required since it can maximize the bioavailability of vector-carried gene prior to the cellular excretion. However, the "rapid" goal has been paid few attentions so far in the research field of vector-aided transfection. As a pioneering attempt, the present study designed a lysosome-targeting acidity-responsive nanoassembly as gene vectors, which proved the amazing potency to mediate the "Superfast" transnuclear gene transport and gene transfection with high efficiency in vitro and in vivo. The nanoassembly was constructed on the pH-reversible covalent boronic acid-diol coupling between 1,3-diol-rich oligoethylenimine (OEI-EHDO) and phenylboronic acid modified cholesterol (Chol-PBA). The rapid and efficient nuclei-tropic delivery and transfection was demonstrated to highly rely on the lysosome-acidity induced assembly destruction followed by the easy liberation of gene payloads inside cells. The nanoassembly-mediated transfection at 8 h can afford the outcome even comparable to that achieved at 48 h by the golden standard of PEI25k, and the transfection efficiency can still remain at a high level during 48 h. In contrast, time-dependent efficiency enhancement was identified for the transfections using PEI25k and OEI-EHDO as delivery vectors. Moreover, owing to the hydroxyl-rich surface, this delivery nanosystem presented strong tolerance to the serum-induced transfection inhibition that frequently occurred for the polycationic gene vectors such as PEI25k. The in vitro and in vivo results manifested the low toxicity of this bio-decomposable nanoassembly.

In this paper, a multifunctional theranostic magnetic mesoporous silica nanoparticle (MMSN) with magnetic core was developed for magnetic-enhanced tumor-targeted MR imaging and precise therapy. The gatekeeper beta-cyclodextrin (beta-CD) was immobilized on the surface of mesoporous silica shell via platinum(IV) prodrug linking for reduction-triggered intracellular drug release. Then Arg-Gly-Asp (RGD) peptide ligand was further introduced onto the gatekeeper beta-CD via host-guest interaction for cancer targeting purpose. After active-targeting endocytosis by cancer cells, platinum(IV) prodrug in MMSNs would be restored to active platinum(II) drug in response to the innative reducing microenvironment in cancer cells, resulting in the detachment of beta-CD gatekeeper and thus simultaneously triggering the in situ release of anticancer drug doxorubicin (DOX) entrapped in the MMSNs to kill cancer cells. It was found that with the aid of an external magnetic field, drug loaded MMSNs showed high contrast in MR imaging in vivo and exhibited magnetically enhanced accumulation in the cancer site, leading to significant inhibition of cancer growth with minimal side effects. This multifunctional MMSN will find great potential as a theranostic nanoplatform for cancer treatment. (c) 2015 Elsevier Ltd. All rights reserved.

A novel self-delivered prodrug system was fabricated for tumor-targeting therapy. In this nanosystem, the Arg-Gly-Asp-Ser (RGDS) tetrapeptide was used to improve the therapeutic index to integrin-overexpressing tumor cells. The antitumorous drug camptothecin was further appended to the e-amino group of lysine by 20-O-succinyl linkage and controllably released via hydrolytic cleavage. Prodrug molecules self-assembled into fibrillar nano-architectures and achieved the capability of self-delivery after being injected subcutaneously into mice. Introduction of hydrophobic myristic acid favored the self-assembly and enhanced the cellular internalization of the prodrugs. In vitro and in vivo studies demonstrated that the self-assembled nanofibers could effectively target integrinoverexpressing tumorous cells and inhibit tumor growth via RGD-mediated specific targeting. Therefore, the traditional idea that fibrillar structures hold low therapeutic efficacy due to poor cell uptake can be challenged.

Inflammation represents a real micromilieu of many diseases as well as the actual application environment of nanocarriers. However, few studies have focused on the influence of the inflammatory environment on the effects of nanoparticle delivery. Herein, a novel inflammation self-adaptive nanocarrier is designed and fabricated by attaching the ascorbyl palmitate (AP) onto the surface of gene-entrapped polymeric nanocomplexes through the formation of phenylboronate bond. In vitro and in vivo studies demonstrate that the introduction of AP enhances considerably the accumulation of entrapped gene in inflammation and facilitates the intracellular uptake of gene-loading nanoparticles. Meanwhile, the gene transfection efficiency of DNA and in vivo gene therapy of nanocomplexes under an inflammation stimulus is significantly enhanced. Hence, our delicate design concept opens up a new pathway to develop an inflammation self-adaptive drug delivery system for precise drug/gene delivery and therapy.

Carrier‐free nanoparticles with high drug loading have attracted increasing attention; however, in situ on‐demand drug release remains a challenge. Here, a novel near‐infrared (NIR) laser‐induced blasting carrier‐free nanodrug delivery system is designed and fabricated by coating doxorubicin (DOX) nanoparticles (DNPs) with a polydopamine film (PDA) that would prolong the blood circulation time of DNPs and avoid the preleakage of the DOX during blood circulation. Meanwhile, the NH4HCO3 is introduced to trigger in situ “bomb‐like” release of DOX for the production of carbon dioxide (CO2) and ammonia (NH3) gases driven by NIR irradiated photothermal effect of PDA. Both in vitro and in vivo studies demonstrate that the carrier‐free nanovectors with high drug loading efficiency (85.8%) prolong tumor accumulation, enhance chemotherapy, achieve the synergistic treatment of chemotherapy and photothermal treatment, and do not induce any foreign‐body reaction over a three‐week implantation. Hence, the delicate design opens a self‐assembly path to develop PDA‐based NIR‐responsive multifunctional carrier‐free nanoparticles for tumor therapy.

Myocardial infarction (MI) leads to the mass death of cardiomyocytes accompanying with the unfavorable alternation of microenvironment, a fibrosis scar deprived of electrical communications, and the lack of blood supply in the infarcted myocardium. The three factors are inextricably intertwined and thus result in a conservative MI therapy efficacy in clinic. A holistic approach pertinently targeted to these three key points would be favorable to rebuild the heart functions. Here, an injectable conductive hydrogel was constructed via in situ Michael addition reaction between multi-armed conductive crosslinker tetraaniline-polyethylene glycol diacrylate (TA-PEG) and thiolated hyaluronic acid (HA-SH). The resultant soft conductive hydrogel with equivalent myocardial conductivity and anti-fatigue performance was loaded with plasmid DNA encoding eNOs (endothelial nitric oxide synthase) nanocomplexes and adipose derived stem cells (ADSCs) for treating MI. The TA-PEG/HA-SH/ADSCs/Gene hydrogel-based holistic system was injected into the infarcted myocardium of SD rats. We demonstrated an increased expression of eNOs in myocardial tissue the heightening of nitrite concentration, accompanied with upregulation of proangiogenic growth factors and myocardium related mRNA. The results of electrocardiography, cardiogram, and histological analysis convincingly revealed a distinct increase of ejection fraction (EF), shortened QRS interval, smaller infarction size, less fibrosis area, and higher vessel density, indicating a significant improvement of heart functions. This conception of combination approach by a conductive injectable hydrogel loaded with stem cells and gene-encoding eNOs nanoparticles will become a robust therapeutic strategy for the treatment of MI.

A dual-Forster resonance energy transfer (FRET)-based versatile prodrug (V-prodrug), in which the fluorescence of both 5(6)-carboxylfluorescein (FAM) and doxorubicin (DOX) can be quenched by 4-(dimethylaminoazo)benzene-4-carboxylic acid (Dabcyl) with high quenching efficiency, is developed in this paper. The V-prodrug can selectively bind to the αvβ3 integrin overexpressed cancer cells through the Arg-Gly-Asp (RGD) targeting moiety. After that, the acid-mediated DOX release of the V-prodrug can be real-time monitored by the increase of the red fluorescence from DOX. Thereafter, DOX-induced cell apoptosis can also be in situ assessed by the fluorescence recovery of the FAM, due to the caspase-3-mediated Asp-Glu-Val-Asp (DEVD) peptide sequence cleavage. This novel prodrug provides a cascaded imaging of real-time drug release and subsequent cell apoptosis, which enables the in situ detection of the cancer response and the therapeutic efficacy evaluation of the prodrug.

This study reports a linear-hyperbranched supramolecular amphiphile and its vesicular nanoassembly with acidity-sensitive susceptibility including volume extension and membrane rupture. Involvement of a host-guest interaction in the amphiphilic construction allows not only facile control of the assembly types (solid and hollow nanoparticles), but also the one-step achievement of both polymersome fabrication and drug encapsulation. The pH-dependency of assembly stability leads to the controlled release of encapsulated hydrophilic agents in an acidity-accelerated manner. By blocking the endosomal acidification progression using NH4 Cl treatment, the lysosomal acid environment is suggested to play an important role in the drug release behavior inside cells and contributes much to nuclei-tropic drug transport.

This study reported a flexible nanoplatform constructed on the pH-dependent self-assembly of two kinds of hyperbranched polymers, and then validated its potency as the controllable siRNA/drug co-delivery vehicle for the combination of chemotherapy with RNA interfering (RNAi) therapy. By virtue of pH-reversible phenylboronate linking, phenylboronic acid-tethered hyperbranched oligoethylenimine (OEI600-PBA) and 1,3-diol-rich hyperbranched polyglycerol (HBPO) can be spontaneously interlinked together into a core-corona nanoconstruction. The special buildup of compactly clustering OEI600-PBA units around hydrophobic HBPO aggregate offered significant advantages over parent OEI600-PBA, including strengthened affinity to siRNA, ability of further loading anticancer drug, easier cellular transport, and acidity-responsive release of payloads. To evaluate the co-delivery capability, Beclin1 siRNA and antitumor DOX were used as the therapeutic models in order to suppress the post-chemotherapy survival of tumor cells caused by drug-induced autophagy. The nanoassembly-mediated single delivery of DOX displayed even better anticancer effects than free DOX, demonstrating the superiority of our pH-responsive nano-design. The nanoassembly-mediated co-delivery of siRNA together with DOX can effectively silence Beclin1 gene, suppress DOX-induced autophagy, and consequently provide strong synergism with a significant enhancement of cell-killing effects in cultured cancerous cells. The in vivo combinational treatment was shown to make the tumor more sensitive to DOX chemotherapy while displaying substantially improved safety as compared with the monochemotherapy.

A versatile gold nanoparticle-based multifunctional nanocomposite AuNP@CD-AD-DOX/RGD was constructed flexibly via host-guest interaction for targeted cancer chemotherapy. The pH-sensitive anticancer prodrug AD-Hyd-DOX and the cancer-targeted peptide AD-PEG8-GRGDS were modified on the surface of AuNP@CD simultaneously, which endowed the resultant nanocomposite with the capability to selectively eliminate cancer cells. In vitro studies indicated that the AuNP@CD-AD-DOX/RGD nanocomposite was preferentially uptaken by cancer cells via receptor-mediated endocytosis. Subsequently, anticancer drug DOX was released rapidly upon the intracellular trigger of the acid microenvirenment of endo/lysosomes, inducing apoptosis in cancer cells. As the ideal drug nanocarrier, the multifunctional gold nanoparticles with the active targeting and controllable intracellular release ability hold the great potential in cancer therapy.

In this study, a pH sensitive chimeric peptide is developed to codeliver a photosensitizer, protoporphyrin IX (PpIX), and plasmid DNA simultaneously. In the presence of matrix metalloproteinase-2 (MMP-2), the chimeric peptide undergoes the process of hydrolysis of PLGVR peptide sequence, exfoliation of PEG, and increase of positive charges. As a result, the chimeric peptide can be preferentially uptaken by MMP-2 rich tumor cells. To realize synergistic effect of drug and gene delivery, a dual-stage light irradiation strategy is developed, i.e., the short time light irradiation can efficiently enhance the endosomal escape of the chimeric peptide/PpIX/DNA complexes by the formation the reactive oxygen species (ROS), resulting in synergistic endosomal escape and improved DNA expression. In addition, due to the screened phototoxicity of PpIX, short time light irradiation does not lead to detectable changes in the cell viability. After the gene transfection, the screened phototoxicity of PpIX is subsequently stimulated by long time irradiation to achieve high synergistic efficacy of photodynamic and gene therapies. Both in vitro and in vivo studies confirm the chimeric peptide-based nanocarrier with a good synergistic effect is a promising nanoplatform for tumor treatments.

In this paper, an intracellular glutathione (GSH) responsive mesoporous silica nanoparticle (MSN-S-S-RGD) was developed as a drug nanocarrier by immobilizing the gatekeeper (RGD containing peptide) onto MSNs using disulfide bonds. The antitumor drug, DOX was loaded onto the porous structure of the MSNs and the DOX@MSN-S-S-RGD system has been proved to be an effective nanocarrier. It was determined that most of the drug could be entrapped with only a slight leakage. After being accumulated in tumor cells via the receptor-mediated endocytosis, the surface peptide layer of DOX@MSN-S-S-RGD was removed to trigger the release of the entrapped drug to kill the tumor cell due to the cleavage of the disulfide bonds by intracellular GSH.

A programmed pre-targeting system for tumor cell imaging and targeting therapy was established based on the "biotin-avidin" interaction. In this programmed functional system, transferrin-biotin can be actively captured by tumor cells with the overexpression of transferrin receptors, thus achieving the pre-targeting modality. Depending upon avidin-biotin recognition, the attachment of multivalent FITC-avidin to biotinylated tumor cells not only offered the rapid fluorescence labelling, but also endowed the pre-targeted cells with targeting sites for the specifically designed biotinylated peptide nano-drug. Owing to the successful pre-targeting, tumorous HepG2 and HeLa cells were effectively distinguished from the normal 3T3 cells via fluorescence imaging. In addition, the self-assembled peptide nano-drug resulted in enhanced cell apoptosis in the observed HepG2 cells. The tumor cell specific pre-targeting strategy is applicable for a variety of different imaging and therapeutic agents for tumor treatments.

Atopic dermatitis (AD) is one of the most prevalent skin diseases around the world. Excessive histamine plays a critical role as an inflammatory factor in the pathogenesis of AD. Deregulated microRNAs (miRNAs) were involved in atopic dermatitis by targeting various genes. MiR-223 had been reported to play a vital role in hematopoiesis. In this study, we identified upregulated miR-223 in the whole blood cells of a large group of AD patients. What's more, we found for the first time that one of the major histamine degradation enzymes, histamine-N-methyltransferase (HNMT), was increased in AD patients and AD model mice. Although there was one miR-223 binding site in the 3'- untranslated region of the HNMT gene, HNMT were not inhibited by miR-223. Taken together, it suggested that miR-223 participates in AD through upregulating HNMT indirectly to degrade the excessive histamine.

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies employing microRNA-seq and genome-wide sequencing have identified some non-coding RNAs that are influentially involved in AD pathogenesis. Non-coding RNAs can compete with other endogenous RNAs by microRNA response elements (MREs) and manipulate biological processes, such as tumorigenesis. However, only a few non-coding RNAs have been reported in the pathogenesis of AD. In this study, we constructed the first competing endogenous RNA (ceRNA) network leveraging whole transcriptome sequencing and a previously studied microRNA-seq of APPswe/PS1ΔE9 transgenic mice. The underlying mechanisms for the involvement of ceRNA in AD were validated using the Dual Luciferase Reporter Assay, detection of transcription levels by quantitative RT-PCR and translation levels by Western blotting, and morphological examination in primary cultured neurons. In the ceRNA network, four lncRNAs (C030034L19Rik, Rpph1, A830012C17Rik, and Gm15477) and five miRNAs (miR-182-5p, miR-330-5p, miR-326-3p, miR-132-3p, and miR-484) are enriched in nine pathways and an AD-related gene pool. Among them, Ribonuclease P RNA component H1 (Rpph1) is upregulated in the cortex of APPswe/PS1ΔE9 mice compared to wild type controls. Rpph1 binds to miR326-3p/miR-330-5p and causes the release of their downstream target Cdc42, which leads to CDC42 upregulation. This effect was disrupted upon mutation of the MRE on Rpph1. Moreover, overexpression of Rpph1 increased dendritic spine density in primary cultured hippocampal pyramidal neurons, whereas knocking down of Rpph1 had the reverse effect. In conclusion, Rpph1 modulates CDC42 expression level in a ceRNA-dependent manner, which may represent a compensatory mechanism in the early stage of the AD pathogenesis.

In this paper, a novel stepwise-acid-active multifunctional mesoporous silica nanoparticle (MSN-(SA)TAT(DMA)K11) was developed as a drug carrier. The MSN-(SA)TAT(DMA)K11 is able to reverse its surface charge from negative to positive in the mildly acidic tumor extracellular environment. Then, the fast endo/lysosomal escape and subsequent nucleus targeting as well as intranuclear drug release can be realized after cellular internalization. Because of the difference in acidity between the tumor extracellular environment and that of endo/lysosomes, this multifunctional MSN-(SA)TAT(DMA)K11 exhibits a stepwise-acid-active drug delivery with a tumor-specific nucleus-targeted property.

Taking advantage of the special fluoride-promoted cleavage reaction of the Si–O bond, new chemical reaction-based probe ( F1 ) towards fluoride anion was designed and synthesized. Upon the addition of fluoride ion (in NaF), the probe displayed apparent fluorescence changes from non-emission to strong green fluorescence. F1 gave response to F − with high sensitivity with the detection limit of 18 μM in HEPES-THF (9/1, v/v, 10 mM HEPES, pH 7.2). Furthermore, F1 was successfully applied to the detection of F − anion in HeLa cells with turn-on fluorescent signals.

Advanced drug delivery systems, which possess post-functionalization feasibility to achieve targetability and traceability, favorable pharmacokinetics with dynamic but controllable stability, and preferable tumor accumulation with prolonged drug residence in disease sites, represent ideal nanomedicine paradigm for tumor therapy. To address this challenge, here we reported a dynamic module-assembly strategy based on reversible boronic acid/1,3-diol bioorthogonality. As a prototype, metastable hybrid nanoself-assembly between hydrophobic hyperbranched diol-enriched polycarbonate (HP-OH) and hydrophilic linear PEG terminated with phenylboronic acid (mPEG-PBA) is demonstrated in vitro and in vivo. The nanoconstruction maintained excellent stability with little leakage of loaded drugs under the simulated physiological conditions. Such a stable nanostructure enabled the effective in vivo tumor accumulation in tumor site as revealed by NIR imaging technique. More importantly, this nanoconstruction presented a pH-labile destruction profile in response to acidic microenvironment and simultaneously the fast liberation of loaded drugs. Accordingly at the cellular level, the intracellular structural dissociation was also proved in terms of the strong acidity in late endosome/lysosome, thus favoring the prolonged retention of remaining drug-loaded HP-OH aggregates within tumor cells. Hence, our delicate design open up a dynamical module-assembly path to develop site and time dual-controlled nanotherapeutics for tumor chemotherapy, allowing enhanced tumor selectivity through prolonged retention of delivery system in tumor cells followed by a timely drug release pattern.

To address the inherent barriers of gene transfection, two reduction-sensitive branched polypeptides (RBPs) are synthesized and explored as novel non-viral gene vectors. The introduced disulfide linkages in RBPs facilitate glutathione-triggered intracellular gene release and reduce polymer degradation-induced cytotoxicity. Furthermore, the highly branched architecture concurrently realizes multivalency for strong DNA binding and elicits conformational flexibility for tight DNA compacting, which are beneficial for cellular entry. To increase the endosomal escape of plasmid DNA, pH-sensitive histidyl residues are incorporated into RBPs to improve buffer capacity in an acidic environment. In vitro study demonstrates that RBPs can efficiently mediate the DNA transfection and avoid apparent cytotoxicity in HeLa and COS7. The present gene delivery system offers a simple and flexible approach to fabricate microenvironment-specific branched gene vectors for gene therapy.

This paper reports a drug nanovehicle self-assembled from an amine-functionalized block copolymer poly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione)-block-poly(1,3-dioxepan-2-one) (PADMC-b-PTeMC), which is prepared by controlable ring-opening block copolymerization attractively in a "one-shot feeding" pathway. The copolymers display high cell-biocompatibility with no apparent cytotoxicities detected in 293T and HeLa cells. Due to their amphiphilic nature, PADMC-b-PTeMC copolymers can self-assemble into nanosized micelles capable of loading anticancer drugs such as camptothecin (CPT) and doxorubicin (DOX). In particular, the outer PADMC shell endows the PADMC-b-PTeMC nanomicelles with pH-dependent control over the micellar morphology, cell uptake efficiency, and the drug release pattern. Confocal inspection reveals the remarkably enhanced cellular internalization of drug loaded micelles by cancerous HeLa cells at relatively lower pH 5.8 simulating the mildly acid microenvironment in tumors. Along with the acidity-triggered volume expansion of micelles, an accelerated CPT release in vitro occurs. The obtained results adumbrate the possibility of completely biodegradable PADMC-b-PTeMC as pH-sensitive drug carriers for tumor chemotherapy.

A novel pH- and redox- dual-responsive tumor-triggered targeting mesoporous silica nanoparticle (TTTMSN) is designed as a drug carrier. The peptide RGDFFFFC is anchored on the surface of mesoporous silica nanoparticles via disulfide bonds, which are redox-responsive, as a gatekeeper as well as a tumor-targeting ligand. PEGylated technology is employed to protect the anchored peptide ligands. The peptide and monomethoxypolyethylene glycol (MPEG) with benzoic-imine bond, which is pH-sensitive, are then connected via "click" chemistry to obtain TTTMSN. In vitro cell research demonstrates that the targeting property of TTTMSN is switched off in normal tissues with neutral pH condition, and switched on in tumor tissues with acidic pH condition after removing the MPEG segment by hydrolysis of benzoic-imine bond under acidic conditions. After deshielding of the MPEG segment, the drug-loaded nanoparticles are easily taken up by tumor cells due to the exposed peptide targeting ligand, and subsequently the redox signal glutathione in tumor cells induces rapid drug release intracellularly after the cleavage of disulfide bond. This novel intelligent TTTMSN drug delivery system has great potential for cancer therapy.

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function.

By exploiting boronic acid coupling and host-guest chemistry, a pH-responsive drug/gene co-delivery nanoplatform is designed for cancer treatments with the excellently serum-tolerant transfection activity and the capability to load and release hydrophobic drugs in an acidity-accelerated manner. Via boronate linkage, γ-CD is allowed to spontaneously attach onto phenylboronic-acid-modified oligoethylenimine (PEI1.8K-PB2.9 ) at neutral condition. The formed vehicle/DNA nanoformulation is thus surrounded densely by γ-CD moieties to biomimic the carbohydrate-rich cell surface, providing a novel approach to overcome serum-susceptible drawbacks frequently associated with synthetic gene carriers. PEI1.8K-PB2.9 -γ-CD conjugates demonstrate significantly improved cell-biocompatibility and transfection activity over PEI1.8K-PB2.9 . Noticeably, serum-associated inhibition effect is negligible for PEI1.8K-PB2.9 -γ-CD-mediated transfection whereas marked transfection reduction occurs for PEI25K and PEI1.8K-PB2.9 upon serum exposure. Consequently, PEI1.8K-PB2.9 -γ-CDs afford much higher transfection efficiency, that is, 25-fold higher luciferase expression over PEI25K in presence of 30% serum. An anticancer drug of doxorubicin (DOX) is shown to be readily accommodated into the nanoformulation via host-guest chemistry and intracellularly co-delivered together with plasmid DNA. Due to the acidity-labile feature of boronate linkage, DOX/γ-CD inclusion complexes would be mostly detached from the nanoformulation triggered by acidity, leading to faster drug release. Furthermore, drug inclusion does not alter the serum-compatible transfection efficiency of PEI1.8K-PB2.9 -γ-CD.

4-(1H-Phenanthro[9,10-d]imidazol-2-yl)benzaldehyde (P-1) was prepared as a new ratiometric optical probe for hydrogen sulfite. Upon the addition of HSO3−, it displayed large emission wavelength shift (Δλ = 120 nm) and the detection limit was determined to be as low as 2 μM. In addition to its high selectivity for hydrogen sulfite rather than other common anions, P-1 was successfully applied to the detection of hydrogen sulfite in HeLa cells with ratiometric fluorescent methods.

In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against He La cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications.

A unique peptide nanofibrous indicator (NFI) is fabricated by mixing a borono-peptide with alizarin red S, followed by subsequent binding and self-assembly. The NFI thus obtained exhibits an intense response to sialyl Lewis X tetrasaccharide, which is overexpressed in human hepatocellular carcinoma cell lines. Importantly, this NFI has the capability of specifically recognizing human hepatocellular liver carcinoma (HepG2) cells through the eye-detectable color change resulting from strong binding-induced displacement. This novel technique for cancer cell identification through direct unaided eye judgment will open up an innovative platform for cancer cell detection.

In this report, an amphiphilic mitochondria-targeted chimeric peptide-based drug delivery system (DDS) was designed to overcome drug resistance. In vitro studies revealed that chimeric peptide could encapsulate doxorubicin (DOX) with high efficacy and target tumor mitochondria, realizing controlled release of DOX and in situ photodynamic therapy (PDT) in mitochondria. Importantly, reactive oxygen species (ROS) during PDT significantly disrupted mitochondria, leading to a dramatic decrease of intracellular adenosine 5'-triphophate (ATP). As a result, ATP-dependent efflux of DOX was remarkably inhibited. Trinitarian therapeutic strategy was developed to ablation of drug-resistant cells, that is, (1) enhanced cellular uptake of hydrophobic DOX via encapsulation in DDS, (2) combined chemo-/photodynamic therapies, and (3) suppressed generation of intracellular ATP as well as drug efflux via in situ PDT in mitochondria. This trinitarian strategy may open a new window in the fabrication of subcellular organelle destructive DDS in overcoming drug resistance.

It is challenging but imperative to merge together specific inorganic nanomaterials with macromolecular and small-molecule therapeutics into one nanoentity for all-in-one theranostic/remedy. We establish a versatile nanotechnology to nanoentrap magnetic nanoparticles, doxorubicin, and DNA, thus allowing the combination of magnetic targeting, magnetic resonance (MR) imaging, gene transport, and bioresponsive chemotherapy. We hope this nanotechnology can prompt the development of complex inorganic/organic nanosystems for various applications.

Introducing drugs into gene delivery systems to fabricate co-delivery systems for synergy therapy has become a promising strategy for tumor therapy. In this study, a dual responsive co-delivery system RHD/p53 was fabricated to enhance the antitumor efficacy with a low dose of doxorubicin (DOX). The reducible branched cationic polypeptide (RBCP), which was cross-linked via the thiol groups of two three-armed cationic peptides (CRR)2KRRC and (CHH)2KHHC, was designated as RH. Then, DOX was immobilized on RH via pH-sensitive hydrazone bonds to obtain RHD. The positively charged RHD could compress p53 plasmid to form RHD/p53 complexes. After RHD/p53 complexes accumulated in tumor sites, the ability of cell penetrating by cationic peptide (CRR)2KRRC would facilitate the cellular internalization of complexes. Then, the complexes would be trapped in endosome, and the cleavage of hydrazone bonds in the intracellular acidic endosome could lead to pH-induced release of DOX. Additionally, the ability of protonation by (CHH)2KHHC could promote the escape of complexes from endosome to cytoplasm. Due to the cleavage of disulfide bonds triggered by the high-content GSH in cytoplasm, the complexes would be degraded and released p53 for co-therapy to improve antitumor efficacy. Both in vitro and in vivo studies indicated that dual responsive co-delivery system RHD/p53 could enhance antitumor efficacy, which provides a useful strategy for co-delivery of different therapeutic agents in tumor treatment.

Supramolecular microcapsules (SMCs) with the drug-loaded wall layers for pH-controlled drug delivery were designed and prepared. By using layer-by-layer (LbL) technique, the SMCs were constructed based on the self-assembly between polyaldenhyde dextran-graft-adamantane (PAD-g-AD) and carboxymethyl dextran-graft-β-CD (CMD-g-β-CD) on CaCO(3) particles via host-guest interaction. Simultaneously, adamantine-modified doxorubicin (AD-Dox) was also loaded on the LbL wall via host-guest interaction. The in vitro drug release study was carried out at different pHs. Because the AD groups were linked with PAD (PAD-g-AD) or Dox (AD-Dox) by pH-cleavable hydrazone bonds, AD moieties can be removed under the weak acidic condition, leading to destruction of SMCs and release of Dox. The pH-controlled drug release can enhance the uptake by tumor cells and thus achieve improved cancer therapy efficiency.

Fluorescent-magnetic-biotargeting multifunctional microcapsules (FMBMMs) are designed and fabricated via layer-by-layer assembly. It is found that the arginine-glycine-aspartate-modified FMBMMs were capable of sensitively detecting and efficiently isolating approximately 80% target cancer cells within 20 min. More importantly, FMBMMs present a general template for identifying and separating multiple types of cancer cells simply by altering the recognition motif.

A new series of intramolecular-charge-transfer (ICT) molecules (compounds 1, 2, and 3) were synthesized by attaching various electron-donating thiophenes groups to a triphenylamine backbone with an aldehyde group as the electron acceptor. Based on the protection reaction between ethanethiol and aldehyde, the corresponding dithioacetals (compounds S1, S2, and S3) were prepared to serve as novel colorimetric and fluorescent chemosensors for Hg(2+) ions. Also, compound S1 was further utilized to construct the chemical-reaction-based conjugated polymer probe (PS1) towards Hg(2+) ions. In the presence of as little as 10 nM Hg(2+), compound PS1 displayed an apparent change in the fluorescent intensity. The sensing processes were revealed to be mediated by ICT, as confirmed by time-dependent DFT calculations. Furthermore, compound S1 was successfully applied to microscopic imaging for the detection of Hg(2+) in HeLa cells with ratiometric fluorescent methods.

A simple, efficient, and convenient method for the photodimerization of 4-aryl-1,4-dihydropyridine in room-temperature ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]) has b...

This study reports a linear-hyperbranched supramolecular amphiphile and its vesicular nanoassembly with acidity-sensitive susceptibility including volume extension and membrane rupture. Involvement of a host-guest interaction in the amphiphilic construction allows not only facile control of the assembly types (solid and hollow nanoparticles), but also the one-step achievement of both polymersome fabrication and drug encapsulation. The pH-dependency of assembly stability leads to the controlled release of encapsulated hydrophilic agents in an acidity-accelerated manner. By blocking the endosomal acidification progression using NH4 Cl treatment, the lysosomal acid environment is suggested to play an important role in the drug release behavior inside cells and contributes much to nuclei-tropic drug transport.

In order to produce a more efficient cancer cell death, a dual-functional polypeptide, xPolyR8–KLA(TPP), was synthesized by disulfide cross-linking CR8C and C-KLA(TPP). The obtained xPolyR8–KLA(TPP) could not only initiate tumor cell apoptosis by C-KLA(TPP) with improved cell penetrating ability, but was also capable of loading and delivering the tumor cell suppressing p53 gene. It was found that, after internalization by cancer cells, the xPolyR8–KLA(TPP)/p53 complex released the C-KLA(TPP) moiety and the p53 gene in the cytoplasm due to its reducible disulfide bonds. By regulating both the intrinsic and extrinsic apoptotic pathways, the xPolyR8–KLA(TPP)/p53 complex performed as a synergetic system and lead to a more efficient cancer cell death.

This study plans to develop a nanoparticle technology that can assemble different polymeric “building blocks” with various desired functionalities into one nanosystem in a pH-dependent manner. For this purpose, polymeric building blocks were specifically designed with hyperbranched architectures, and orthogonal pH-reversible phenylboronic acid-diols were taken as “joints” to integrate them together. To verify the idea, a corona-core dual-polymer nanoassembly was prepared as the vehicle for lysosomotropic gene/drug co-delivery. Phenylboronic acid modified hyperbranched oligoethylenimine (OEI-PBA) was arranged to cluster around the hydrophobic core composed of hyperbranched polyglycerol, just by mixing two polymers in an appropriate ratio at neutral conditions. Compared with the parent OEI-PBA, this nanoassembly demonstrated better capture of plasmid DNA, highly enhanced activity for cellular transport and gene transfection (up to 100 fold), the ability to further load hydrophobic drugs, lysosome acidity-targeting pH-dependent release of both carried cargoes, and improved cell-biocompatibility. To evaluate its potential for combinational gene/drug therapy, in vitro experiments using the therapeutic p53 gene and antitumor doxorubicin as models were carried out. This intracellular co-delivery led to apparently synergetic anti-cancer effects in cultured cancer cells. This dynamic paradigm shows interesting features including easy manipulation, reversible conjugation, lysosome-targeting pH-responsiveness, high co-delivery efficiency, and functional expandability by further accommodating other building blocks.

To improve the tumor therapeutic efficiency and reduce undesirable side effects, ternary FK/p53/PEG-PLL(DA) complexes with a detachable surface shielding layer were designed. The FK/p53/PEG-PLL(DA) complexes were fabricated by coating the folate incorporated positively charged FK/p53 complexes with charge-switchable PEG-shield (PEG-PLL(DA)) through electrostatic interaction. At the physiological pH 7.4 in the bloodstream, PEG-PLL(DA) could extend the circulating time by shielding the positively charged FK/p53 complexes. After the accumulation of the FK/p53/PEG-PLL(DA) complexes in tumor sites, tumor-acidity-triggered charge switch led to the detachment of PEG-PLL(DA) from the FK/p53 complexes, and resulted in efficient tumor cell entry by folate-mediated uptake and electrostatic attraction. Stimulated by the high content glutathione (GSH) in cytoplasm, the cleavage of disulfide bond resulted in the liberation of proapoptosis peptide C-KLA(TPP) and the p53 gene, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. Both in vitro and in vivo studies confirmed that the ternary detachable complexes FK/p53/PEG-PLL(DA) could enhance antitumor efficacy and reduce adverse effects to normal cells. These findings indicate that the tumor-triggered decomplexation of FK/p53/PEG-PLL(DA) supplies a useful strategy for targeting delivery of different therapeutic agents in synergetic anticancer therapy.