Dissolved Organic Matter Promotes the Aging Process of Polystyrene Microplastics under Dark and Ultraviolet Light Conditions: The Crucial Role of Reactive Oxygen Species.

Microplastics (MPs) interact frequently with dissolved organic matter (DOM) commonly found in the environment, but information on the aging behavior of MPs under the participation of DOM is still lacking. Thus, the polystyrene microplastic (PSMP) aging process with DOM participation was systematically studied by electron paramagnetic resonance spectroscopy, high-performance liquid chromatography, Fourier transform infrared (FTIR) spectroscopy, and two-dimensional correlation spectroscopy analyses under dark and ultraviolet (UV) light conditions. DOM was found to promote electron transfer to generate reactive oxygen species (ROS) under dark conditions and the aging of PSMPs, while the process of DOM generating ROS under UV light was more susceptible to photoelectrons and accelerated the aging process of PSMPs. However, among the four DOM types, fulvic acid (FA) has a more significant promoting effect on the aging process of PSMPs than humic acid, which can be attributed to the stronger conversion ability of FA to semiquinone radicals. Density functional theory calculations are used to describe the difference in the aging process of different structures of plastics with the participation of DOM. This study provides a necessary theoretical basis for the study of the migration of MPs in groundwater and deep surface water.

A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms.

BACKGROUND: Infectious diseases caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative strains, have become a global public health challenge. Multifunctional nanomaterials for controlling MDR bacterial infections via eradication of planktonic bacteria and their biofilms are of great interest. RESULTS: In this study, we developed a multifunctional platform (TG-NO-B) with single NIR laser-triggered PTT and NO release for synergistic therapy against MDR Gram-negative bacteria and their biofilms. When located at the infected sites, TG-NO-B was able to selectively bind to the surfaces of Gram-negative bacterial cells and their biofilm matrix through covalent coupling between the BA groups of TG-NO-B and the bacterial LPS units, which could greatly improve the antibacterial efficiency, and reduce side damages to ambient normal tissues. Upon single NIR laser irradiation, TG-NO-B could generate hyperthermia and simultaneously release NO, which would synergistically disrupt bacterial cell membrane, further cause leakage and damage of intracellular components, and finally induce bacteria death. On one hand, the combination of NO and PTT could largely improve the antibacterial efficiency. On the other hand, the bacterial cell membrane damage could improve the permeability and sensitivity to heat, decrease the photothermal temperature and avoid damages caused by high temperature. Moreover, TG-NO-B could be effectively utilized for synergistic therapy against the in vivo infections of MDR Gram-negative bacteria and their biofilms and accelerate wound healing as well as exhibit excellent biocompatibility both in vitro and in vivo. CONCLUSIONS: Our study demonstrates that TG-NO-B can be considered as a promising alternative for treating infections caused by MDR Gram-negative bacteria and their biofilms.

Self-Assembly of pH-Responsive Microspheres for Intestinal Delivery of Diverse Lipophilic Therapeutics.

Targeted delivery of therapeutics to the intestine is preferred for the management of many diseases due to its diverse advantages. Currently, there are still challenges in creating cost-effective and translational pH-responsive microspheres for intestinal delivery of various hydrophobic drugs. Herein we report a multiple noncovalent interactions-mediated assembly strategy in which carboxyl-bearing compounds (CBCs) are guest molecules, while poly(N-isopropylacrylamide) (PNIPAm) serves as a host polymer. Formation of microparticles and therapeutic packaging can be achieved simultaneously by this assembly approach, leading to well-shaped microspheres with extremely higher drug loading capacity as compared to microspheres based on two FDA-approved materials of poly(d,l-lactide-co-glycolide) (PLGA) and an enteric coating polymer EudragitS 100 (S100). Also, carboxyl-deficient hydrophobic drugs can be effectively entrapped. These assembled microspheres, with excellent reconstitution capability as well as desirable scalability, could selectively release drug molecules under intestinal conditions. By significantly enhancing drug dissolution/release in the intestine, these pH-responsive assemblies may notably improve the oral bioavailability of loaded therapeutics. Moreover, the assembled microspheres possessed superior therapeutic performance in rodent models of inflammation and tumor over the control microspheres derived from PLGA and S100. Therapy with newly developed microspheres did not cause undesirable side effects. Furthermore, in vivo evaluation in mice revealed the carrier material PNIPAm was safe for oral delivery at doses as high as 10 g/kg. Collectively, our findings demonstrated that this type of pH-responsive microsphere may function as superior and translational intestine-directed delivery systems for a diverse array of therapeutics.

Enhanced Intracellular Delivery and Tissue Retention of Nanoparticles by Mussel-Inspired Surface Chemistry.

Nanomaterials have been broadly studied for intracellular delivery of diverse compounds for diagnosis or therapy. Currently it remains challenging for discovering new biomolecules that can prominently enhance cellular internalization and tissue retention of nanoparticles (NPs). Herein we report for the first time that a mussel-inspired engineering approach may notably promote cellular uptake and tissue retention of NPs. In this strategy, the catechol moiety is covalently anchored onto biodegradable NPs. Thus, fabricated NPs can be more effectively internalized by sensitive and multidrug resistant tumor cells, as well as some normal cells, resulting in remarkably potentiated in vitro activity when an antitumor drug is packaged. Moreover, the newly engineered NPs afford increased tissue retention post local or oral delivery. This biomimetic approach is promising for creating functional nanomaterials for drug delivery, vaccination, and cell therapy.

An Osteoimmunomodulatory Biopatch Potentiates Stem Cell Therapies for Bone Regeneration by Simultaneously Regulating IL-17/Ferroptosis Signaling Pathways.

Currently, there are still great challenges in promoting bone defect healing, a common health problem affecting millions of people. Herein an osteoimmunity-regulating biopatch capable of promoting stem cell-based therapies for bone regeneration is developed. A totally biodegradable conjugate is first synthesized, which can self-assemble into bioactive nano micelles (PPT NMs). This nanotherapy effectively improves the osteogenesis of periodontal ligament stem cells (PDLSCs) under pathological conditions, by simultaneously regulating IL-17 signaling and ferroptosis pathways. Incorporation of PPT NMs into biodegradable electrospun nanofibers affords a bioactive patch, which notably improves bone formation in two rat bone defect models. A Janus bio patch is then engineered by integrating the bioactive patch with a stem cell sheet of PDLSCs. The obtained biopatch shows additionally potentiated bone regeneration capacity, by synergistically regulating osteoimmune microenvironment and facilitating stem cell differentiation. Further surface functionalization of the biopatch with tannic acid considerably increases its adhesion to the bone defect, prolongs local retention, and sustains bioactivities, thereby offering much better repair effects in rats with mandibular or cranial bone defects. Moreover, the engineered bioactive patches display good safety. Besides bone defects, this osteoimmunity-regulating biopatch strategy can be applied to promote stem cell therapies for spinal cord injury, wound healing, and skin burns.

Synthesis of ß-cyclodextrin containing copolymer via "click" chemistry and its self-assembly in the presence of guest compounds.

We report the synthesis of a hydrophilic copolymer with one polyethylene glycol (PEG) block and one ß-cyclodextrin (ß-CD) containing block by a "click" reaction between azido-substituted ß-CD and propargyl flanking copolymer. (1)H NMR study suggested a highly efficient conjugation of ß-CD units by this approach. The obtained copolymer was used as a host macromolecule to construct assemblies in the presence of hydrophobic guests. For assemblies containing a hydrophobic polymer, their size can be simply adjusted by simply changing the content of hydrophobic component. By serving as a guest molecule, hydrophobic drugs can also be loaded accompanying the formation of nanoparticles, and the drug payload is releasable. Therefore, the copolymer synthesized herein can be employed as a carrier for drug delivery.

Surface engineering of nanomaterials with phospholipid-polyethylene glycol-derived functional conjugates for molecular imaging and targeted therapy.

In recent years, phospholipid-polyethylene glycol-derived functional conjugates have been widely employed to decorate different nanomaterials, due to their excellent biocompatibility, long blood circulation characteristics, and specific targeting capability. Numerous in vivo studies have demonstrated that nanomedicines peripherally engineered with phospholipid-polyethylene glycol-derived functional conjugates show significantly increased selective and efficient internalization by target cells/tissues. Targeting moieties including small-molecule ligands, peptides, proteins, and antibodies are generally conjugated onto PEGylated phospholipids to decorate liposomes, micelles, hybrid nanoparticles, nanocomplexes, and nanoemulsions for targeted delivery of diagnostic and therapeutic agents to diseased sites. In this review, the synthesis methods of phospholipid-polyethylene glycol-derived functional conjugates, biophysicochemical properties of nanomedicines decorated with these conjugates, factors dominating their targeting efficiency, as well as their applications for in vivo molecular imaging and targeted therapy were summarized and discussed.

Hydrogen Peroxide-Activatable Nanoparticles for Luminescence Imaging and In Situ Triggerable Photodynamic Therapy of Cancer.

Abnormally increased reactive oxygen species (ROS) are intimately related to the development and metastasis of cancer. Since hydrogen peroxide (H2O2) is a major component of ROS, molecular imaging and selective treatment in response to high H2O2 are intriguing for the management of cancers. Herein, we report novel self-assembly luminescent nanoparticles, which can be activated by H2O2, thereby serving as an effective nanotheranostics for luminescence imaging and in situ photodynamic therapy (PDT) of tumors with high H2O2. This functional nanomedicine was assembled from an amphiphilic conjugate (defined as CLP) based on chlorin e6 (Ce6) simultaneously conjugated with luminol and poly(ethylene glycol), exhibiting a well-defined core-shell nanostructure. Upon triggering by pathologically relevant levels of H2O2, CLP nanoparticles produced luminescence due to the luminol unit and simultaneous excitation of Ce6 by chemiluminescence resonance energy transfer, enabling in vitro and in vivo imaging of tumors with highly expressed H2O2. In addition, excited Ce6 can produce singlet oxygen (1O2) for in situ PDT of H2O2-high tumors and inhibiting lung metastasis, which was demonstrated by in vitro and in vivo experiments. Furthermore, preliminary studies revealed the biosafety of CLP nanoparticles. Consequently, the self-illuminating nanoparticles are promising for noninvasive imaging and therapy of tumors with high expression of H2O2.

Multifunctional Supramolecular Hydrogel for Prevention of Epidural Adhesion after Laminectomy.

Postoperative epidural adhesion remains a clinically challenging problem in spine surgery. Currently there are no effective and safe antifibrotic and antiadhesion biomaterials that have been specifically developed for this complication in clinical practice. Herein we designed and engineered an advanced antiadhesion hydrogel with multiple functionalities, including temperature-responsive gelation, self-healing, tissue adhesiveness, antioxidation, anti-inflammation, and antifibrosis. This multifunctional supramolecular hydrogel can be facilely constructed by integrating three functional modules, i.e., a thermosensitive triblock copolymer, poloxamer 407 (PX); a reactive oxygen species-eliminating and anti-inflammatory nanoparticle (TPCD NP); and an adhesion-enhancing compound, tannic acid (TA). The optimal formulation (PXNT) was hierarchically screened based on in vitro properties and in vivo activities. Therapeutically, local treatment with PXNT hydrogel effectively prevented epidural fibrosis and adhesion after laminectomy in both rats and rabbits. Of note, PXNT hydrogel showed more beneficial efficacy than different control thermosensitive hydrogels and a commercially available barrier product, Interceed. Mechanistically, PXNT hydrogel significantly attenuated local oxidative stress, inhibited inflammatory responses, and reduced fibrotic tissue formation. Moreover, treatment with PXNT hydrogel did not cause systemic adverse effects and neurological symptoms. Consequently, PXNT hydrogel is a highly promising biomaterial for preventing postlaminectomy epidural adhesion and adhesions after other surgeries.

A self-illuminating nanoparticle for inflammation imaging and cancer therapy.

Nanoparticles have been extensively used for inflammation imaging and photodynamic therapy of cancer. However, the major translational barriers to most nanoparticle-based imaging and therapy applications are the limited depth of tissue penetration, inevitable requirement of external irradiation, and poor biocompatibility of the nanoparticles. To overcome these critical limitations, we synthesized a sensitive, specific, biodegradable luminescent nanoparticle that is self-assembled from an amphiphilic polymeric conjugate with a luminescent donor (luminol) and a fluorescent acceptor [chlorin e6 (Ce6)] for in vivo luminescence imaging and photodynamic therapy in deep tissues. Mechanistically, reactive oxygen species (ROS) and myeloperoxidase generated in inflammatory sites or the tumor microenvironment trigger bioluminescence resonance energy transfer and the production of singlet oxygen (1O2) from the nanoparticle, enabling in vivo imaging and cancer therapy, respectively. This self-illuminating nanoparticle shows an excellent in vivo imaging capability with suitable tissue penetration and resolution in diverse animal models of inflammation. It is also proven to be a selective, potent, and safe antitumor nanomedicine that specifically kills cancer cells via in situ 1O2 produced in the tumor microenvironment, which contains a high level of ROS.

A systematic evaluation of the biocompatibility of cucurbit[7]uril in mice.

As one of the most water-soluble members in the macrocyclic cucurbit[n]uril (CB[n]) family, CB[7] has attracted increasing attention in pharmaceutical and biomedical fields. Despite extensive studies regarding the potential use of CB[7] for biomedical applications, its full safety and toxicity profile in a clinically relevant model is still lacking. Herein we report the full biocompatibility profile of CB[7], administered orally, peritoneally or intravenously in mice, respectively. Body-weight changes showed no significant differences among various groups of mice after they were administered with CB[7] at a single dose of 5 g/kg orally, 500 mg/kg peritoneally and 150 mg/kg intravenously, respectively. Hematology tests, as well as hepatic and renal function biochemical markers tests, of the blood collected from these mice sacrificed 21 days after CB[7] administration all exhibited normal ranges of values that were comparable with those of the control group. Moreover, histopathological analysis on the sections of major organs (including the heart, liver, spleen, lungs and kidneys) and gastrointestinal tissues revealed no detectable injuries and inflammatory cells infiltration. Taken together, these results suggest an excellent biocompatibility profile of CB[7] in mice, which provide important foundations for further investigations and even clinical applications of CB[7] in biomedical areas.

Self-assembly of affinity-controlled nanoparticles via host-guest interactions for drug delivery.

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or ß-cyclodextrin were synthesized. Using poly(ß-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.

Versatile preparation of fluorescent particles based on polyphosphazenes: from micro- to nanoscale.

A series of intrinsically fluorescent hydrophobic and amphiphilic polyphosphazenes with ethyl tryptophan (EtTrp) and poly(N-isopropylacrylamide) (PNIPAAm) or poly(ethylene glycol) (PEG) as hydrophobic and hydrophilic segments, respectively, are synthesized. Depending on polymer composition and preparation procedure, particles with diameters ranging from micro- to nanoscale can be prepared successfully, which might be used as a visible tracer, both in vitro or in vivo, in drug- or gene-delivery systems, as well as in other biomedical studies such as diagnostic medicine and brain research. Most importantly, in combination with the flexible synthesis and versatile modification of polyphosphazene, this method provides a general protocol to engineer a broad range of fluorescent particles with different properties based on diverse polymers.

Nanomaterial-dependent immunoregulation of dendritic cells and its effects on biological activities of contraceptive nanovaccines.

Nanovehicles are promising delivery systems for various vaccines. Nevertheless, different biophysicochemical properties of nanoparticles (NPs), dominating their in vitro and in vivo performances for vaccination, remain unclear. We attempted to elucidate the effects of NPs and their pH-sensitivity on in vitro and in vivo efficacy of resulting prophylactic nanovaccines containing a contraceptive peptide (FSHR). To this end, pH-responsive and non-responsive nanovaccines were produced using acetalated ß-cyclodextrin (Ac-bCD) and poly(lactic-co-glycolic acid) (PLGA), respectively. Meanwhile, FSHR derived from an epitope of the follicle-stimulating hormone receptor was used as the model antigen. FSHR-containing Ac-bCD and PLGA NPs were successfully prepared by a nanoemulsion technique, leading to well-shaped nanovaccines with high loading efficiency. The pH-sensitivity of Ac-bCD and PLGA nanovaccines was examined by in vitro hydrolysis and antigen release studies. Nanovaccines could be effectively engulfed by dendritic cells (DCs) via endocytosis in both dose and time dependent manners, and their intracellular trafficking was closely related to the pH-sensitivity of the carrier materials. Furthermore, nanovaccines could induce the secretion of inflammatory cytokines by DCs and T cells co-cultured with the stimulated DCs. In vivo evaluations demonstrated that nanovaccines were more potent than that based on the complete Freund's adjuvant, with respect to inducing anti-FSHR antibody, reducing the sperm count, inhibiting the sperm motility, and increasing the teratosperm rate. Immunization of male mice with nanovaccines notably decreased the parturition incidence of the mated females. Consequently, both in vitro and in vivo activities of FSHR could be considerably augmented by NPs. More importantly, our studies indicated that the pH-responsive nanovaccine was not superior over the non-responsive counterpart for the examined peptide antigen.

Facile Assembly of Cost-Effective and Locally Applicable or Injectable Nanohemostats for Hemorrhage Control.

Currently, there is still unmet demand for effective and safe hemostats to control abnormal bleeding in different conditions. With the aim to develop affordable, safe, effective, easily stored, and low-cost hemostats, we developed a series of positively charged nanoparticles by a facile one-pot assembly approach. In this strategy, nanoparticles were formed by cholic-acid-mediated self-assembly of polyethylenimine (PEI). Regardless of different structures of cholic acids and PEIs, well-defined nanoparticles could be successfully formed. The assembly process was dominated by multiple interactions between cholic acid and PEI, including electrostatic, hydrogen bonding, and hydrophobic forces. In vitro studies showed that assembled nanoparticles effectively induced aggregation and activation of platelets. Local application of aqueous solution containing nanoparticles assembled by different cholic acids and PEIs significantly reduced bleeding times in different rodent models including tail transection in mice as well as liver bleeding and femoral artery bleeding in rats or rabbits. Moreover, intravenous (i.v.) injection of this type of positively charged nanoparticles notably prevented bleeding in the femoral artery in rats by targeting the injured site via opsonization of nanoparticles with fibrinogen. By contrast, a control negatively charged nanoparticle showed no hemostatic activity after i.v. delivery. Also, preliminary evaluations in rats revealed a good safety profile after i.v. administration of assembled nanoparticles at a dose 4-fold higher than that used for hemostasis. These results demonstrated that cholic acid/PEI-assembled positive nanoparticles may function as cost-effective and locally applicable or injectable nanohemostats for hemorrhage control in the civilian setting and on the battlefield.

Salicylic acid and PEG-contained polyanhydrides: synthesis, characterization, and in vitro salicylic acid release.

Poly [bi(o-carboxyphenyl)adipate-polyethylene glycol] anhydrides--P(BOCA-PEG)--polymeric drugs were synthesized and characterized by Fourier transformed infrared spectroscopy, NMR, DSC, gel permeation chromatography, etc. Salicylic acid loading efficiency of these polymers ranged from 43.5% to 71.3%, which was much higher than that of other polymeric drugs with salicylic acid. The in vitro release of salicylic acid from the polymers was carried out in buffer conditions with different pH values and and rat gastrointestinal contents. The results showed the release rate of salicylic acid increased with the increase of PEG content in the polymers and the increase of pH value of degradation buffer solution. The rat cecal contents also greatly promoted the release of salicylic acid. In 0.1M phosphate buffer solution at pH8.0, 37 degrees C containing 5% rat cecal contents, P(BOCA-PEG200)(80:20) had 15% salicylic acid released in 21 hr, indicating its potential use in colon-specific salicylic acid delivery.

Engineering of Biocompatible pH-Responsive Nanovehicles from Acetalated Cyclodextrins as Effective Delivery Systems for Tumor Therapy.

There is still an unmet demand for materials with excellent biocompatibility, controlled hydrolytic capability, and elegant responsiveness to chemical or physical stimuli. To engineer biocompatible materials from ß-cyclodextrin (ß-CD), in this study, we synthesized acetalated ß-CDs (Ac-ßCDs) by one-pot acetalation using 2-ethoxypropene as an acetonation reagent, which can be further processed into nanoparticles (NPs) via the emulsion technique. Ac-ßCD NPs showed pH-labile hydrolysis and pH-triggered release of docetaxel (DTX) payload. Both properties were mainly dominated by the molar ratio of linear to cyclic acetal, which can be conveniently modulated by the acetalation time used for materials synthesis. Ac-ßCD NPs were found to be biocompatible in both in vitro cell culture and in vivo acute toxicity evaluations following intravenous injection. In vitro cell culture experiments demonstrated that antitumor activity of DTX against both sensitive and resistant cancer cells was remarkably improved by formulation into Ac-ßCD nanomedicines. In vivo antitumor study also substantiated the dramatically enhanced efficacy of DTX/Ac-ßCD NPs in a melanoma-bearing nude mouse model. These studies demonstrated that NPs derived from Ac-ßCDs may serve as biocompatible and effective carriers for drug delivery.

Biocompatible reactive oxygen species (ROS)-responsive nanoparticles as superior drug delivery vehicles.

A novel reactive oxygen species (ROS)-responsive nanoplatform can be successfully manufactured from a ROS-triggerable ß-cyclodextrin material. Extensive in vitro and in vivo studies validate that this nanoscaled system may serve as a new drug delivery vehicle with well-defined ROS-sensitivity and superior biocompatibility. This nanocarrier can be used for ROS-triggered transport of diverse therapeutics and imaging agents.

Polyelectrolyte multilayer coating with two regulatory molecules on titanium: construction and its biological effects.

AIM: This study aimed at constructing a novel disulfide-crosslinked collagen I/hyaluronic acid polyelectrolyte multilayer (PEM) coating incorporated with bFGF and arginine-glycine-aspartic acid on titanium via the layer-by-layer technique, and evaluating its biological effects. MATERIALS & METHODS: The surface topography and components, thickness, degradation behaviors and bFGF release profiles of the PEM coating were investigated. The effects of the PEM coating on osteoprogenitor cell growth and bone implant interfacial binding strength in the rabbit femur model were evaluated separately. RESULTS: The formation of disulfide bonds improved the stability of the PEM coating, resulting in a coating that can release bFGF in a slow and sustained manner. Biological evaluations revealed that the resultant PEM coating on titanium promoted various cell behaviors and enhanced the binding strength. CONCLUSION: The employed cotreatment regimen enabled bFGF and arginine-glycine-aspartic acid to have a synergistic effect on the cell responses, which, in turn, improved the osseointegration.