Poly-l-lysine modified MOF nanoparticles with pH/ROS sensitive CIP release and CUR triggered photodynamic therapy against drug-resistant bacterial infection.

The challenge of drug resistance in bacteria caused by the over use of biotics is increasing during the therapy process, which has attracted great attentions of the clinicians and scientists around the world. Recently, photodynamic therapy (PDT) triggered by photosensitizer (PS) has become a promising treatment method because of its high efficacy, easy operation, and low side effect. Herein, the poly-l-lysine (PLL) modified metal-organic framework (MOF) nanoparticles, ZIF/PLL-CIP/CUR, were synthesized to allow both reactive oxygen species (ROS) responsive drug release and photodynamic effect for synergistic therapy against drug resistant bacterial infections. The PLL was modified on the shell of the zeolite imidazole framework (ZIF) by the ROS-responsive thioketal linker for controllable CIP release. CUR were encapsulated in ZIF as the photosensitizer for blue light mediated photodynamic effect to produce singlet oxygen (1O2) and superoxide anion radical (O2-) for efficient inhibition towards methicillin-resistant Staphylococcus aureus (MRSA). The charge conversion from negative charge (-4.6 mV) to positive charge (2.6 mV) was observed at pH 7.4 and pH 5.5, and 70.9 % CIP was found released at pH 5.5 in the presence of H2O2, which suggests the good biosafety at physiological pH and ROS-responsive drug release of the as-prepared nanoparticle in the bacterial microenvironment. The as-prepared nanoparticles could effectively kill MRSA and disrupt bacterial biofilm by combination of chemo- and photodynamic therapy. In mice model, the as-prepared nanoparticles exhibited excellent biosafety and synergistic effect with 98.81 % healing rate in treatment of MRSA infection, which is considered as a promising candidate in combating drug resistant bacterial infection.

Magnetic ion-imprinted polyacrylonitrile-chitosan electro-spun nanofibrous membrane as recyclable adsorbent with selective heavy metal removal and antibacterial fouling in water treatment.

Water pollution has become one of the most concerned environmental issues on the worldwide scale. Due to the harmfulness of the heavy metal ions and microorganisms in wastewater, novel filtration membranes for water treatment are expected to simultaneously clear these pollutants. Herein, the electro-spun polyacrylonitrile (PAN) based magnetic ion-imprinted membrane (MIIM) were fabricated to achieve both selective removal of Pb(II) ions and excellent antibacterial efficiency. The competitive removal experiments showed that the MIIM displayed efficiently selective removal of Pb(II) (45.4 mg·g-1). Pseudo-second-order mode and Langmuir isotherm equation is well matched with the equilibrium adsorption. The MIIM showed sustained removal performance (~79.0 %) against Pb(II) ions after 7 adsorption-desorption cycles with negligible Fe ions loss of 7.3 %. Moreover, the MIIM exhibited excellent antibacterial properties that >90 % of E. coli and S. aureus were killed by the MIIM. In conclusion, the MIIM provides a novel technological platform for integration of multi-function with selective metal ions removal, excellent cycling reusability, and enhanced antibacterial fouling property, which can be potentially utilized as a promising adsorbent in actual treatment of polluted water.

Zwitterionic meso-silica/polypeptide hybrid nanoparticles for efficient azithromycin delivery and photodynamic therapy for synergistic treatment of drug-resistant bacterial infection.

The treatment of drug-resistant bacterial infections attributed to the overuse of antibiotics still remains a serious challenge globally. Herein, zwitterionic charge switchable meso-silica/polypeptide hybrid nanoparticles (MSPNs) were prepared for the synergistic chemo-photodynamic therapy in the treatment of drug-resistant bacterial infections. Subsequently, azithromycin (AZT) and methylene blue (MB) were loaded in the MSPNs to form the combined chemo-photodynamic therapeutic nanoparticles (MSPNs-AZT/MB) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Remarkably, the as-prepared MSPNs-AZT/MB exhibited a negative surface charge of -5.2 mV at physiological pH while switching into positive surface charge of 24.7 mv in an acidic environment, leading to enhanced binding with bacterial surface. The lipase-triggered AZT release up to 77.9 % was achieved, and the loaded MB demonstrated efficient singlet oxygen (1O2) generation for photodynamic therapy. The in vitro experimental results displayed an excellent antibacterial effect against MRSA in both planktonic and biofilm phenotypes. Additionally, the as-prepared MSPNs-AZT/MB exhibited synergistic and enhanced antibacterial infection effect up to 94 % comparing to monotherapy in a mice model. Considering the above advantages, the as-prepared combined chemo-photodynamic therapeutic nanoparticles showed promising biocompatibility and clinical potential for the efficient therapy of drug-resistant bacteria.

Surface charge switchable nano-micelle for pH/redox-triggered and endosomal escape mediated co-delivery of doxorubicin and paclitaxel in treatment of lung adenocarcinoma.

Recently, the stimulus-sensitive drug co-delivery system has gained increasing attentions in the clinic and exhibits improved efficiency rather than the mono-chemotherapy in anti-tumor therapy. Herein, the smart charge switchable nano-micelles (NMs) were fabricated for the endosomal escape mediated co-delivery of doxorubicin (DOX) and paclitaxel (PTX) in treatment of lung adenocarcinoma. The disulfide bonds were facilitated as the linker of the polymer backbone to achieve the redox-sensitive degradation by high intracellular GSH, and acid-liable DMMA was grafted onto DOX molecules for pH-triggered drug release under acidic tumoral microenvironment. Folic acid (FA) was utilized as targeting molecule for facilitating entry of the as prepared NMs into cancer cells. Remarkably, the as fabricated NMs exhibited surface charge-switch from negative to positive during transmitting from physiological pH to the tumor extracellular pH, which can improve the cellular internalization towards cancer cell. Subsequently, the "proton-sponge" effect mediated endosome escape of the NMs was facilitated in the acidic endo/lysosome environment. By the cell assay, the NMs possessed good biocompatibility, excellent cellular uptake, and improved inhibition rate against cancer cell. Moreover, the co-delivery of DOX/PTX exhibited synergistic and enhanced solid tumor inhibition efficiency comparing to mono-chemotherapy in A-549 tumor bearing mice model. Based on above experimental results, the as prepared drug co-delivery system showed promising biosafety and potentials for efficient lung adenocarcinoma treatment in clinic.

Gold nanorods conjugated with biocompatible zwitterionic polypeptide for combined chemo-photothermal therapy of cervical cancer.

Combined chemo-photothermal therapy of gold nanorods (GNRs) for cancer treatment shows better therapeutic efficiency than mono-chemotherapy, which has gained worldwide interests of scientists and clinician in both laboratory and clinic application. However, high cytotoxicity, declined delivery efficiency, and unsatisfactory therapy effect of the GNRs are still challenging in anti-cancer treatment. Herein, a series of pH-sensitively zwitterionic polypeptide conjugated GNRs were synthesized via a gold-thiol interaction for combination of chemo-photothermal therapy in cervical cancer treatment. The acid-labile hydrazone bond was utilized to incorporate the doxorubicin (DOX) for pH-sensitive drug release under tumoral environment. The as prepared GNRs conjugates demonstrated pH-triggered surface charge conversion from negative to positive when transporting from blood circulation to tumor extracellular environment, which can facilitate the cellular uptake via electrostatic interaction. After cellular internalization, the drug release was promoted by cleavage of the hydrazone in GNRs conjugates under cancer intracellular acid environment. As the effective near-infrared (NIR) photothermal materials, the as prepared GNRs conjugates can absorb NIR photo energy and convert it into heat under irradiation, which can efficiently kill the tumor cells. In cell assay, the GNRs conjugates displayed excellent biocompatibility against normal cell, enhanced cancer cell uptake, and remarkable cancer cell killing effects. In HeLa tumor-bearing mice, the GNRs conjugates demonstrated enhanced tumor inhibition efficacy by combination of chemo-photothermal therapy.

Disulfide Cross-Linked Poly(Methacrylic Acid) Iron Oxide Nanoparticles for Efficiently Selective Adsorption of Pb(II) from Aqueous Solutions.

The efficient selectivity of heavy metal ions from wastewater is still challenging but gains great public attention in water treatment on a world scale. In this study, the novel disulfide cross-linked poly(methacrylic acid) iron oxide (Fe3O4@S-S/PMAA) nanoparticles with selective adsorption, improved adsorption capability, and economic reusability were designed and prepared for selective adsorption of Pb(II) ions in aqueous solution. In this study, nuclear magnetic resonance, dynamic light scattering, scanning electron microscopy, X-ray diffraction, vibrating sample magnetometry, and thermogravimetric analysis were utilized to study the chemophysical properties of Fe3O4@S-S/PMAA. The effect of different factors on adsorption properties of the Fe3O4@S-S/PMAA nanoparticles for Co(II) and Pb(II) ions in aqueous solution was explored by batch adsorption experiments. For adsorption mechanism investigation, the adsorption of Fe3O4@S-S/PMAA for Co(II) and Pb(II) ions can be better fitted by a pseudo-second-order model, and the adsorption process of Fe3O4@S-S/PMAA for Co(II) and Pb(II) matches well with the Freundlich isotherm equation. Notably, in the adsorption experiments, the Fe3O4@S-S/PMAA nanoparticles were demonstrated to have a maximum adsorption capacity of 48.7 mg·g-1 on Pb(II) ions with a selective adsorption order of Pb2+ > Co2+ > Cd2+ > Ni2+ > Cu2+ > Zn2+ > K+ > Na+ > Mg2+ > Ca2+ in the selective experiments. In the regeneration experiments, the Fe3O4@S-S/PMAA nanoparticles could be easily recovered by desorbing heavy metal ions from the adsorbents with eluents and showed good adsorption capacity for Co(II) and Pb(II) after eight recycles. In brief, compared to other traditional nanoadsorbents, the as-prepared Fe3O4@S-S/PMAA with improved adsorption capability and high regeneration efficiency demonstrated remarkable affinity for adsorption of Pb(II) ions, which will provide a novel technical platform for selective removal of heavy metal ions from actual polluted water.

Stepwise dual pH and redox-responsive cross-linked polypeptide nanoparticles for enhanced cellular uptake and effective cancer therapy.

The systemic toxicity, reduced cellular internalization, and uncontrollable intracellular drug release of smart nanoparticles (NPs) still need to be overcome for effective cancer therapy. Herein, a series of stepwise dual pH and redox responsive cross-linked polypeptides based on poly(l-lysine-co-N,N-bis(acryloyl)cystamine-co-γ-glutamic acid) (PLBG), were prepared for enhanced cellular uptake and effective cancer therapy. The prepared cross-linked PLBG nanoparticles (PLBG-NPs) exhibit negatively charged surfaces under physiological conditions, and the surface charge of the PLBG-NPs was observed to switch from negative to positive in a slightly acidic tumor extracellular environment at a pH level of ∼6.5. Finally, the endosome escape of the PLBG-NPs was facilitated via a "proton-sponge" effect via protonation of the polymer chain in the endo/lysosome environment of the tumor cell at a pH level of ∼5.0. Moreover, rapid drug release was triggered by a high concentration of reducing glutathione (GSH) in tumor cells via destruction of the disulfide linkages in the PLBG-NPs. Cytotoxicity assays demonstrated that no noticeable cytotoxicity was observed for the PLBG-NPs. However, DOX-loaded PLBG-NPs (PLBG-NPs-DOX) demonstrated remarkable tumor cell killing effects. In HeLa tumor-bearing mice, PLBG-NPs-DOX showed sustained tumor accumulation and enhanced inhibitory effects on tumor growth and angiogenesis. In conclusion, it is suggested that the as-designed novel charge-conversion PLBG-NPs with stepwise pH-responsivity and biodegradability could be used as a potential drug carrier for effective cancer therapy with less systemic toxicity.

Stepwise pH-sensitive and biodegradable polypeptide hybrid micelles for enhanced cellular internalization and efficient nuclear drug delivery.

The short blood circulation time, reduced cellular uptake, and uncontrollable drug release still hinder the polymer micelle as an efficient drug delivery vehicle in clinical applications. In this study, a series of stepwise pH-sensitive and biodegradable polypeptide hybrid terpolymers, poly (lysine-co-N,N-bis(acryloyl) cystamine-co-dimethylmaleic anhydride) (PLB-DMMA), were designed and synthesized to achieve prolonged circulation time, enhanced cellular uptake and controllable anti-cancer drug release. The synthesized terpolymers can self-assemble into spherical nano-micelles (NMs) with narrow distributions and exhibited stepwise responses to extracellular and intracellular pH condition of the tumor cell. The as prepared NMs showed a negative surface charge under normal physiological conditions exhibiting advantageous stability during blood circulation. By the first-step pH response, the surface charge of the NMs switched from negative to positive to enhance cellular uptake under the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response resulted in an endosome escape of the NMs via the "proton-sponge" effect in the acidic endo/lysosome environment. Additionally, a rapid drug release was triggered in response to the intracellular reductive environment of tumor cells via the destruction of disulfide-linked polymer chains to enhance the nucleus delivery of DOX. in vitro cell assays showed that the blank NMs showed negligible systemic toxicity against normal cells while the DOX-loaded NMs significantly inhibited growth of the tumor cells. In general, it was suggested that the as developed stepwise pH-sensitive and biodegradable PLB-DMMA based NMs would be a smart and promising drug delivery candidate for anti-cancer chemotherapy.

Reduction/temperature/pH multi-stimuli responsive core cross-linked polypeptide hybrid micelles for triggered and intracellular drug release.

The high toxicity, poor stability, premature drug release, and lack of intracellular stimuli responsibility of current polymeric micelles still hinder them for potential clinical applications. To address these challenges, a novel type of multi-stimuli responsive, core cross-linked polypeptide hybrid micelles (CCMs) was developed for triggered anticancer drug delivery in tumor microenvironment. The CCMs was prepared via free radical copolymerization by using N,N'-methylene-bis-acylamide (BACy) as the cross-linking agent, 2,2-azobisisobutyronitrile (AIBN) as the initiator, where poly (γ-benzyl-L-glutamate) (PBLG) and N-isopropylacrylamide (NIPPAM) as comonomers. The doxorubicin (DOX) was then introduced into the CCMs by hydrazone bond to prepare the drug-incorporated core cross-linked micelles (CCMs-DOX). By the experimental results, the CCMs showed reduction responsibility due to the degradable disulfide bond in the polymer network. The hydrazone bond can be broken under acidic condition causing a controllable drug release for CCMs-DOX. Compared to only 7.7% DOX release under pH 7.4 at 37°C, a much higher DOX release rate up to 85.3% was observed under 10 mM GSH (pH 5.0, 42°C). In vitro cell assays showed that the blank CCMs showed almost no toxicity against HUVEC cells while the CCMS-DOX exhibited significant cancer cell killing effect. These experimental results suggested that the prepared multi-stimuli responsive polymeric micelles could serve as a smart and promising drug delivery candidate for anti-cancer therapy.

Surface design and preparation of multi-functional magnetic nanoparticles for cancer cell targeting, therapy, and imaging.

Recently, theranostic candidates based on superparamagnetic iron oxide nanoparticles (SPIONs) providing the combination of therapy and diagnosis have become one of the most promising system in cancer research. However, poor stability, premature drug release, lack of specific tumor cell targeting, and complicated multi-step synthesis processes still hinder them for potential clinical applications. In this research, the multi-functional magnetic nanoparticles (MNPs-DOX) were prepared via a simple assembly process for targeted delivery of doxorubicin (DOX) and enhanced magnetic resonance (MR) imaging detection. Firstly, the multi-functional copolymer coating, polyamidoamine (PAMAM), was designed and synthesized by Michael addition reaction, where N,N-bis(acryloyl)cystamine served as backbone linker, and DOX, dopamine (DA), and polyethylene glycol (PEG) acted as comonomers. The PAMAM was then directly assembled to the surface of SPIONs by the ligand exchange reaction with SPIONs forming the MNPs-DOX. The hydrophilic PEG moieties provide the nanoparticles with colloidal stability and good-dispersity in aqueous solution. Comparing with the quick release of free DOX, the drug release behavior of MNPs-DOX exhibited a sustained drug release. Because the chemical cleavage of disulfide in the polymer backbone, a high cumulative drug release up to 60% in GSH within 48 h was observed, rather than only 26% in PBS (pH 7.4) without GSH. The MR imaging detection experiment showed that the MNPs-DOX had an enhanced T 2 relaxivity of 126 mM-1 S-1 for MR imaging. The results of the cytotoxicity assays showed a remarkable killing effect of cancer cells by MNPs-DOX due to the FA tumor-targeting ligand, comparing with non-targeted drug molecules. All the results showed that the as prepared multi-functional magnetic nanoparticles may serve as a promising theranostic candidate for targeted anticancer drug delivery and efficient detection through MR imaging in medical application.

[Study on the designed self-assembling peptide as potential drug carrier by fluorescence spectra].

Amphiphilic peptide is becoming attractive as a potential drug carrier to improve the dissolvability of hydrophobic drugs in aqueous system thus facilitating the drug undertaken by target cells. Here, we reported the ability of a novel designed self-assembling peptide RGA16 (Ac-RADAGAGARADAGAGS-NH2) in drug encapsulation and transfer into lipid vesicles. Pyrene was used as a model hydrophobic drug, and egg phosphatidylcholine (EPC) vesicles were used as plasma membranes mimic. It was found that the pyrene and peptide formed complex in water with mechanical stirring, and the time duration over which the complex formed was about 5 days. Initial evidence of the association between RGA16 and pyrene was the observation of a clouding phenomenon. Further investigation on the interaction between RGA16 and pyrene was carried out using fluorescence spectra and scanning electron microscopy (SEM). SEM micrographs showed that pyrene crystals and peptide were absorbed by each other and the size of the pyrene-peptide complexes was larger than 10 microm, which provided an evidence for the encapsulation of pyrene molecule by the amphiphilic peptide. The steady-fluorescence excitation profiles showed that the pyrene was presented in the crystalline form when stabilized by RGA16 and molecularly migrated from its peptide coating into the membrane bilayers of EPC vesicles when the suspension was mixed with EPC vesicles. The release behavior of pyrene into EPC vesicles was investigated by steady-fluorescence emission spectra, and a calibration curve for the amount of pyrene released into the EPC vesicles at a given time was used to determine the final concentration of pyrene released into lipid vesicles from peptide-pyrene complex. It was found that the pyrene concentration in EPC vesicles was displayed as a function of time. The data presented in the present work suggested that the novel designed amphiphilic peptide could stabilize the hydropholic drug in aqueous solution and deliver it into the membrane bilayers of EPC vesicles.