Small-Angle X-ray Scattering for PEGylated Liposomal Doxorubicin Drugs: An Analytical Model Comparison Study.

Liposomal delivery systems are recognized as efficient and safe platforms for chemotherapeutic agents, with doxorubicin-loaded liposomes being the most representative nanopharmaceuticals. Characterizing the structure of liposomal nanomedicines in high spatial and temporal resolution is critical to analyze and evaluate their stability and efficacy. Small-angle X-ray scattering (SAXS) is a powerful tool increasingly used to investigate liposomal delivery systems. In this study, we chose a Doxil-like PEGylated liposomal doxorubicin (PLD) as an example and characterized the liposomal drug structure using synchrotron SAXS. Classical analytical models, including the spherical-shell or flat-slab geometries with Gaussian or uniform electron density profiles, were used to model the internal structure of the liposomal membrane. A cylinder model was applied to fit the scattering from the drug crystal loaded in the liposomes. The high-resolution structures of the original drug, Caelyx, and a similar research drug prepared in our laboratory were characterized using these analytical models. The structural parameters of PLDs, including the thickness of the liposomal membrane and morphology of the drug crystal, were further compared. The results demonstrated that both spherical-shell and flat-slab geometries with Gaussian electron density distribution were suitable to elucidate the structural features of the liposomal membrane under a certain range of scattering vectors, while models with uniform electron density distribution exhibited poor fitting performance. This study highlights the technical features of SAXS, which provides structural information at the nanoscale for liposomal drugs. The demonstrated methods are reliable and easy-to-use for the structural analysis of liposomal drugs, which are helpful for a broader application of SAXS in the production and regulation of nanopharmaceuticals.

Robust Natural Polyphenolic Adhesives against Various Harsh Environments.

Although adhesive hydrogels have been extensively explored, the development of adhesives with long-term strong adhesion capacity under various harsh environments is still met with profound challenges such as sophisticated preparation, long-term curing, and low bonding strength. Herein, a series of robust adhesive hydrogels have been developed via the polyphenol-epoxy-cross-linking (PEC) reactions between natural polyphenols (extracts) and epoxy glycidyl ethers. The as-prepared natural polyphenolic adhesive hydrogels could induce strong adhesion onto several kinds of typical substrates (i.e., wood, glass, paper, PET, PMMA, and Fe) under both dry and wet conditions based on multi-interactions. Moreover, those natural polyphenolic adhesives exhibited good low-temperature and solvent resistance performances, which could be widely used in different kinds of device repairment (i.e., chemical, petroleum, wood, metal, glass, plastic, rubber, and other industries) under different conditions. This work could provide new opportunities toward natural-inspired robust adhesives in various fields ranging from chemical transportation, industrial manufacturing, architectural design, and marine engineering to daily life.

Bifunctional and Bioreducible Dendrimer Bearing a Fluoroalkyl Tail for Efficient Protein Delivery Both In Vitro and In Vivo.

Rational design of stimuli-responsive polymers for cytosolic protein delivery with robust efficiency is of great importance but remains a challenging task. Here, we reported a bioreducible and amphiphilic dendrimer bearing a fluoroalkyl tail for this purpose. The fluorolipid was conjugated to the focal point of a cysteamine-cored polyamidoamine dendrimer via disulfide bond, while phenylboronic acid moieties were decorated on dendrimer surface for efficient protein binding. The yielding polymer showed high protein binding capability and complex stability and could efficiently release the cargo proteins in a glutathione-responsive manner. The designed polymer was effective in the delivery of various membrane-impermeable proteins into living cells with reserved bioactivities. In addition, the polymer efficiently delivered a toxin protein saporin into 4T1 breast cancer cells and inhibited the tumor growth in vivo after intravenous injection. The developed polymer in this study is a promising vector for the delivery of membrane-impermeable proteins to treat various diseases.

Natural polyphenol assisted delivery of single-strand oligonucleotides by cationic polymers.

Single-strand oligonucleotides provide promising potential as new therapeutics towards various diseases. However, the efficient delivery of oligonucleotide therapeutics is still challenging due to their susceptibility to nuclease degradation and the lack of effective carriers for condensation. In this study, we reported the use of natural polyphenol to facilitate the condensation of single-strand oligonucleotides by cationic polymers. Green tea catechin complexed with single-strand oligonucleotides to form anionic nanoparticles, which were further coated by low molecular weight cationic polymers to increase their cell internalization. The resulting core-shell structured nanoparticles, so-called green nanoparticles (GNPs), showed improved cargo stability, and achieved high efficiency in the delivery of several types of single-strand oligonucleotides including antisense oligonucleotides, anti-miRNA, and DNAzyme. This study provides a facile strategy for the efficient delivery of single-strand oligonucleotides.

Design and Synthesis of Polymer Prodrugs for Improving Water-Solubility, Pharmacokinetic Behavior and Antitumor Efficacy of TXA9.

PURPOSE: TXA9, a novel cardiac glycoside, has a potent anti-proliferative effect against A549 human lung cancer cells, however, possesses a poor water-solubility and a rapid metabolic rate in vivo which limited the further development of TXA9. To overcome the shortcomings of TXA9, four polymer prodrugs of TXA9 were designed and synthesized. METHODS: Poly (ethylene glycol) monomethyl ether (mPEG) and α-tocopherol polyethylene glycol succinate (TPGS) were applied to modify TXA9 via carbonate ester and glycine linkers respectively to obtain four polymer prodrugs. The water-solubility and stability of prodrugs were studied in vitro while their pharmacokinetic behaviors and antitumor activity were investigated in vivo. RESULTS: The water-solubility of TXA9 was obviously increased and prodrugs with glycine linkers showed a better stability in rat plasma. Their pharmacokinetic investigation found that the t1/2 and AUC0-∞ of TPGS-Gly-TXA9 was increased by 80- and 9.6-fold compared with that of TXA9, which was more superior than the other three prodrugs. More importantly, the tumor inhibition rate of TPGS-Gly-TXA9 (43.81%) on A549 xenograft nude mice was significantly increased compared with that of TXA9 (25.26%). CONCLUSION: The above results suggested that TPGS-Gly-TXA9 possessed better antitumor efficiency than TXA9 and could be further investigated as an anti-cancer agent.

Cooperation of Amphiphilicity and Smectic Order in Regulating the Self-Assembly of Cholesterol-Functionalized Brush-Like Block Copolymers.

Nanoparticle morphology significantly affects the application of nanometer-scale materials. Understanding nanoparticle formation mechanisms and directing morphological control in nanoparticle self-assembly processes have received wide attention. Herein, a series of brush-like amphiphilic liquid crystalline block copolymers, PChEMA m- b-POEGMA n, containing cholesteryl mesogens with different hydrophobic/hydrophilic block ratios were designed and synthesized. The self-assembly behaviors of the resulting PChEMA m- b-POEGMA n block copolymers in different solvents (tetrahydrofuran/H2O, 1,4-dioxane/H2O, and N, N-dimethylformamide) were investigated in detail. Desirable micellar aggregates with well-organized architectures, including short cylindrical micelles, nanofibers, fringed platelets, and ellipsoidal vesicles with smectic micellar cores, were observed in 1,4-dioxane/H2O with an increasing hydrophobic block ratio. Although both amphiphilicity and smectic order governed the self-assembly, these two factors were differently balanced in the different solvents. This unique supramolecular system provides a new strategy for the design of advanced functional nanomaterials with tunable morphologies.

Polycatechol Nanoparticle MRI Contrast Agents.

Amphiphilic triblock copolymers containing Fe(III) -catecholate complexes formulated as spherical- or cylindrical-shaped micellar nanoparticles (SMN and CMN, respectively) are described as new T1-weighted agents with high relaxivity, low cytotoxicity, and long-term stability in biological fluids. Relaxivities of both SMN and CMN exceed those of established gadolinium chelates across a wide range of magnetic field strengths. Interestingly, shape-dependent behavior is observed in terms of the particles' interactions with HeLa cells, with CMN exhibiting enhanced uptake and contrast via magnetic resonance imaging (MRI) compared with SMN. These results suggest that control over soft nanoparticle shape will provide an avenue for optimization of particle-based contrast agents as biodiagnostics. The polycatechol nanoparticles are proposed as suitable for preclinical investigations into their viability as gadolinium-free, safe, and effective imaging agents for MRI contrast enhancement.

Pathway toward large two-dimensional hexagonally patterned colloidal nanosheets in solution.

We report the solution self-assembly of an ABC block terpolymer consisting of a polystyrene-block-poly(ethylene oxide) (PS-b-PEO) diblock copolymer tail tethered to a fluorinated polyhedral oligomeric silsesquioxane (FPOSS) cage in 1,4-dioxane/water. With increasing water content, abundant unconventional morphologies, including circular cylinders, two-dimensional hexagonally patterned colloidal nanosheets, and laterally patterned vesicles, are sequentially observed. The formation of toroids is dominated by two competing free energies: the end-cap energy of cylinders and the bending energy to form the circular structures. Incorporating the superhydrophobic FPOSS cages enhances the end-cap energy and promotes toroid formation. Lateral aggregation and fusion of the cylinders results in primitive nanosheets that are stabilized by the thicker rims to partially release the rim-cap energy. Rearrangement of the parallel-aligned FPOSS cylindrical cores generates hexagonally patterned nanosheets. Further increasing the water content induces the formation of vesicles with nanopatterned walls.

Photoresponsive Amphiphilic Macrocycles Containing Main-Chain Azobenzene Polymers.

Herein, the first example of photosensitive cyclic amphiphilic homopolymers consisting of multiple biphenyl azobenzene chromophores in the cyclic main chain tethered with hydrophilic tetraethylene glycol monomethyl ether units is presented. The synthetic approach involves sequentially performed thermal catalyzed "click" step-growth polymerization in bulk, and Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) intramolecular cyclization from α-alkyne/ω-azide linear precursors. It is observed that such amphiphilic macrocycles exhibit increased glass transition temperatures (Tg ), slightly faster trans-cis-trans photoisomerization, and enhanced fluorescence emission intensity compared with the corresponding linear polymers. In addition, the cyclic amphiphilic homopolymers self-assemble into spherical nanoparticles with smaller sizes which possess slower photoresponsive behaviors in a tetrahydrofuran/water mixture compared with those of the linear ones. All these interesting observations suggest that the cyclic topology has a great influence on the physical properties and self-assembly behavior of these photoresponsive amphiphilic macrocycles in general.

Quaternary Ammonium Assisted Synthesis of Melanin-like Poly(l-DOPA) Nanoparticles with a Boosted Photothermal Effect.

Poly(levodopa) nanoparticles (P(l-DOPA) NPs) are another kind of melanin mimetic besides well-established polydopamine nanoparticles (PDA NPs). Due to the presence of carboxyl groups, the oxidative polymerization of l-DOPA to obtain particles was not as efficient as that of dopamine. Several established methods toward P(l-DOPA) NP fabrication do not combine convenience, morphological regularity, size controllability, low cost, and adaptability to metal-free application scenarios. In this work, P(l-DOPA) NPs were successfully prepared in hot water with the assistant of organic quaternary ammonium, due to the extra physical cross-linking mediated by cations. The employed physical interactions could also be affected by quaternary ammonium structure (i.e., number of cation heads, length of alkyl chain) to achieve different polymerization acceleration effects. The obtained P(l-DOPA) NPs retained superior photothermal properties and outperformed PDA-based melanin materials. Furthermore, P(l-DOPA) NPs were used in photothermal tumor therapy and showed better efficacy. This study offers new insights into the synthesis of melanin-like materials, as well as new understanding of the interaction between quaternary ammonium and bioinspired polyphenolic materials.

Efficient intracellular and in vivo delivery of toxin proteins by a ROS-responsive polymer for cancer therapy.

Rational design of efficient cytosolic protein delivery carriers holds enormous promise for biotherapeutics development. Several delivery systems have been developed during the past decades, while tailoring the balance between extracellular protein binding and intracellular cargo release is still challenging. In this study, we synthesized a series of oxygen-sensitive reactive polymers, rich in boron, by radical polymerization and post-modification for cytosolic protein delivery in vitro and in vivo. The introduction of boronate building blocks into the polymer scaffold significantly enhanced its protein binding affinity, and the polymer/protein complexes with high stability were obtained by tailoring the molecular ratios between the boronate ligands and the amine groups. The lead material screened from the polymer library exhibited efficient protein delivery efficacy that can release cargo proteins in cytosol in a reactive oxygen species responsive manner, which enables intracellular delivery of proteins with maintained bioactivity. In addition, the polymer-based nanoformulations efficiently delivered saporin, a toxin protein, into osteosarcoma cells and tumor tissues, and exhibited high therapeutic efficacy in an osteosarcoma mouse model. The synthesized polymer in this study can be developed as a promising nanocarrier for cytosolic delivery of protein therapeutics to treat a variety of diseases.

Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives.

In the past decade, nanomedicine with its promise of improved therapy and diagnostics has revolutionized conventional health care and medical technology. Dendrimers and dendrimer-based therapeutics are outstanding candidates in this exciting field as more and more biological systems have benefited from these starburst molecules. Anticancer agents can be either encapsulated in or conjugated to dendrimer and be delivered to the tumour via enhanced permeability and retention (EPR) effect of the nanoparticle and/or with the help of a targeting moiety such as antibody, peptides, vitamins, and hormones. Imaging agents including MRI contrast agents, radionuclide probes, computed tomography contrast agents, and fluorescent dyes are combined with the multifunctional nanomedicine for targeted therapy with simultaneous cancer diagnosis. However, an important question reported with dendrimer-based therapeutics as well as other nanomedicines to date is the long-term viability and biocompatibility of the nanotherapeutics. This critical review focuses on the design of biocompatible dendrimers for cancer diagnosis and therapy. The biocompatibility aspects of dendrimers such as nanotoxicity, long-term circulation, and degradation are discussed. The construction of novel dendrimers with biocompatible components, and the surface modification of commercially available dendrimers by PEGylation, acetylation, glycosylation, and amino acid functionalization have been proposed as available strategies to solve the safety problem of dendrimer-based nanotherapeutics. Also, exciting opportunities and challenges on the development of dendrimer-based nanoplatforms for targeted cancer diagnosis and therapy are reviewed (404 references).

Layer-by-Layer Assembled Smart Antibacterial Coatings via Mussel-Inspired Polymerization and Dynamic Covalent Chemistry.

Bacterial colonization on the surface of medical implanted devices and bacterial infection-induced biofilm have been a lethal risk for patients of clinical treatment. While antibacterial coatings fabricated by layer-by-layer (LBL) assembly techniques have been well explored, the facile preparation of substrate-independent smart antibacterial coatings with on-demand antibiotics release profile and excellent antibacterial performance is still urgently needed. In this work, this goal is addressed by LBL assembly fabrication of robust antibacterial coatings using naturally occurring and commercially available building blocks (i.e., aminoglycosides, 5,6-dihydroxyindole, and formylphenylboronic acid) via the subsequentially performed mussel-inspired polymerization and dynamic covalent chemistries. The resulting antibacterial coatings on different substates all presente a dynamic feature (i.e., pH-responsive), on-demand antibiotics release properties, and highly effective antibacterial performance both in vitro and in vivo. It is envisioned that this work can expand the scope of LBL assembly technique toward the next generation of robust and universal antibacterial coating materials by using natural building blocks and readily available chemistries.

The oral microbiota and cardiometabolic health: A comprehensive review and emerging insights.

There is mounting evidence demonstrating that oral dysbiosis causes periodontal disease and promotes the development of cardiovascular disease. The advancement of omics techniques has driven the optimization of oral microbiota species analysis and has provided a deeper understanding of oral pathogenic bacteria. A bi-directional relationship exists between the oral microbiota and the host, and oral-gut microbiota transfer is known to alter the composition of the gut microbiota and may cause local metabolic disorders. Furthermore, cardiovascular health can also be highly affected by oral microbiota functions and metabolites, including short-chain fatty acids (SCFAs), nitric oxide (NO), hydrogen sulfide (H2S), and some lipid metabolites. Studies have found that trimethylamine oxide (TMAO) may have adverse effects on cardiovascular health, whereas SCFAs, NO, and H2S have cardioprotective effects. SCFAs and H2S exert varying oral and cardiovascular effects, however reports on this specific topic remain controversial. Previous evidences are accustomed to summarizing the functions of oral microbiota in the context of periodontitis. The direct relationship between oral microbiota and cardiovascular diseases is insufficient. By systematically summarizing the methods associated with oral microbiota transplantation (OMT), this review facilitates an investigation into the causal links between oral microbiota and cardiovascular disease. The concomitant development of omics, bioinformatics, bacterial culture techniques, and microbiota transplantation techniques is required to gain a deeper understanding of the relationship between oral microbiota and cardiovascular disease occurrence.

Dynamic Polymer Amphiphiles for Efficient Intracellular and In Vivo Protein Delivery.

Intracellular delivery of proteins is receiving considerable attention in biotherapeutics for various diseases by replacing dysfunctional proteins. Successful intracellular protein delivery highly relies on the development of efficient and safe polymeric carriers, which remains a grand challenge due to the lack of strong binding sites on proteins and their distinct molecular sizes and polarities. In this work, a strategy is proposed for efficient intracellular protein delivery by using dynamic polymer supra-amphiphiles, which are prepared by grafting boronated polylysine with a series of lipidated catechols via dynamic covalent catechol-boronate ester bonds. The prepared supra-amphiphiles can coassemble with proteins to form stable nanoparticles in water and also enable the release of bound proteins in cells due to their dynamic features, thereby strongly promoting the intracellular delivery process. The lead supra-amphiphiles screened in the library demonstrate high efficiency in the delivery of various proteins including bovine serum albumin, ß-galactosidase, α-chymotrypsin, saporin, R-phycoerythrin, ovalbumin, catalase, and superoxide dismutase, and show great potency in delivering superoxide dismutase to treat ulcerative colitis in vivo. This work provides new opportunities for rational design and facile construction of robust intracellular protein delivery materials by the integration of polymer chemistry and supramolecular engineering strategies.

Metal-phenolic network coated cellulose foams for solar-driven clean water production.

Solar-driven water steam generation is a promising strategy for seawater desalination and wastewater purification. However, oil contaminants commonly exist in real water resources, which drives us to design and fabricate photothermal materials with high efficient water steam generation and outstanding anti-oil-fouling ability. Herein, we developed a metal-phenolic network-coated cellulose foam (Fe3+/TA@CF), which exhibits not only superb hydrophilicity and underwater lipophobicity, but also achieves high water evaporation rate of ∼1.3 kg m-2 h-1 even in oil-polluted seawater under one sun illumination. In addition, Fe3+/TA@CF is demonstrated to be both anti-oil-fouling and anti-salt-fouling, which benefits to long-term evaporation in practical utilizations. Metal ions and oil contaminants in the condensed water vapor are almost eliminated after purification. We believe that this low-cost, biodegradable Fe3+/TA@CF paves a way for rationally designing and fabricating high-performance evaporator for oil contaminated water purification.

Reduced polydopamine nanoparticles incorporated oxidized dextran/chitosan hybrid hydrogels with enhanced antioxidative and antibacterial properties for accelerated wound healing.

Hydrogels with antioxidative and antibacterial properties have emerged as potential dressings for accelerated wound healing. Herein, a series of reduced polydopamine nanoparticles (rPDA NPs) incorporated oxidized dextran/chitosan hybrid hydrogels have been designed for wound healing due to their excellent antioxidative property and antibacterial activity. The physicochemical properties as well as the antioxidative activities of the hydrogels were carefully characterized. The results demonstrated rPDA NPs have better antioxidative activity than the untreated PDA NPs. And the rPDA NPs incorporated oxidized dextran/chitosan hybrid hydrogels had excellent antioxidative properties to protect cells against external oxidative stress. Besides, the hydrogels also showed antibacterial ability to protect the wound against infections. In vitro and in vivo investigations concluded that rPDA NPs incorporated oxidized dextran/chitosan hybrid hydrogels could be served as an effective dressing for accelerated wound healing.

Polydopamine antibacterial materials.

Recently, the development of polydopamine (PDA) has demonstrated numerous excellent performances in free radical scavenging, UV shielding, photothermal conversion, and biocompatibility. These unique properties enable PDA to be widely used as efficient antibacterial materials for various applications. Accordingly, PDA antibacterial materials mainly include free-standing PDA materials and PDA-based composite materials. In this review, an overview of PDA antibacterial materials is provided to summarize these two types of antibacterial materials in detail, including the fabrication strategies and antibacterial mechanisms. The future development and challenges of PDA in this field are also presented. It is hoped that this review will provide an insight into the future development of antibacterial functional materials based on PDA.

Efficient Iron and ROS Nanoscavengers for Brain Protection after Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) will be accompanied by the overload of iron and reactive oxygen species (ROS) following hematoma clearance. Although deferoxamine (DFO) has been widely utilized as a clinical first-line siderophore to remove the iron overload, the ROS-inducing damage still greatly limits the therapeutic effect of DFO. To address this issue, we designed and fabricated a series of dual-functional macromolecular nanoscavengers featuring high-density DFO units and catechol moieties. Note that the former units could effectively remove the iron overload, while the latter ones could efficiently deplete the ROS. The resulting nanoscavengers efficiently down-regulate the iron and ROS levels as well as significantly reduce the cell death in both iron-overloaded RAW 264.7 cells and the ICH mice model. This work suggests a novel clue for the ICH-ameliorated iron-depleting interventional therapeutic regimen.

In vitro saliva-gastrointestinal digestion and fecal fermentation of Oudemansiella radicata polysaccharides reveal its digestion profile and effect on the modulation of the gut microbiota.

Oudemansiella radicata is a commercialized and nutrient-rich mushroom farmed in China. Polysaccharides (ORP) found in this mushroom possess strong biological properties. In this study, the digestibility and fermentation of ORP and its effects on gut microbiota composition were examined in a simulated digestion and fermentation system in vitro. Results showed that the molecular weight of ORP decreased after simulated digestion. However, no free monosaccharide was detected, indicating that ORP was indigestible. Besides, the overall structure of ORP was not damaged after digestion. When ORP was degraded and utilized by gut microbiota during the fermentation process, several short-chain fatty acids were formed, acetic acid, propionic acid and n-butyric acid were the main products. Notably, ORP could significantly modulate the composition, via increasing the relative abundances of Bacteroides and Parabacteroides. These results suggest that ORP can be used as a functional food to improve health and prevent diseases by promoting gut health.