Synthesis of manganese-oxide and palladium nanoparticles co-decorated polypyrrole/graphene oxide (MnO2@Pd@PPy/GO) nanocomposites for anti-cancer treatment.

Design and fabrication of novel multifunctional nanomaterials as novel "theranostic nanoagents"with high efficiency and low side effects is important for cancer treatment. Herein, we synthesized manganese-oxide and palladium nanoparticle-co-decorated polypyrrole/graphene oxide (MnO2@Pd@PPy/GO) nanocomposites, which could be used as a novel "theranostic nanoagent" for cancer treatment. Various spectroscopic and microscopic characterizations of the synthesized MnO2@Pd@PPy/GO nanocomposites suggest that the nanocomposites are assembled sequentially by graphene oxide, polypyrrole, palladium nanoparticles and manganese-oxide nanoplates. Further research revealed that the nanocomposites had excellent photothermal conversion performance (reached near 50 °C after 10 min of irradiation), pH responsive enzymatic-like catalytic activity and enhanced magnetic resonance imaging (MRI) performance (r 1 = 7.74 mM-1 s-1 at pH 5.0 and glutathione (GSH)). Cell experiments also testified that combined cancer treatment (the viability of cancer cells is 30%) with photothermal therapy (PTT, the viability of cancer cells is 91% only with irradiation) and chemodynamic therapy (CDT, the viability of cancer cells is 74.7% only with nanocomposites) guided by MRI was achieved when the as-prepared nanocomposites were employed as theranostic nanoagents. This work could provide some new ideas for the controllable synthesis and application of multicomponent nanomaterials.

Tumor microenvironment-responsive versatile "Trojan horse" theranostic nanoplatform for magnetic resonance imaging-guided multimodal synergistic antitumor treatment.

A natural killer (NK)-92 cell membrane-camouflaged mesoporous MnO2-enveloped Au@Pd (Au@Pd@MnO2) nanoparticles (denoted as APMN NPs)-based versatile biomimetic theranostic nanoplatform was developed for magnetic resonance (MR) imaging-guided multimodal synergistic antitumor treatments. In this core-shell nanostructure, an Au@Pd core induced near-infrared (NIR)-activatable hyperthermal effects and nanozyme catalytic activity, while a mesoporous MnO2 shell not only afforded a high drug-loading capability, tumor microenvironment (TME)-triggered MR imaging and drug release, but also endowed catalase-, glutathione peroxidase-, and Fenton-like activities. Furthermore, the NK-92 cell membrane camouflaging endowed the NPs with enhanced tumor-targeting capability, immune escape function, and membrane protein-mediated tumoral uptake property. The doxorubicin-loaded APMN (D-APMN) NPs exhibited TME-responsive drug release properties. Furthermore, the cellular uptake, in vivo MR imaging, and NIR thermal imaging confirmed the active tumor-targeting capability and TME-responsive MR imaging property of these biomimetic NPs. An antitumor efficacy test, histological analyses, and blood biochemical profiles suggested that the developed D-APMN NPs possessed a high antitumor activity and biosafety in tumor-bearing nude mice. Therefore, the developed APMN NPs held great potential as an intelligent and comprehensive theranostic nanoplatform for tumor-specific bioimaging and TME-responsive multimodality treatment based on photothermal therapy, chemodynamic therapy, and chemotherapy. STATEMENT OF SIGNIFICANCE: Exploring intelligent and comprehensive theranostic nanoplatforms to integrate tumor-specific bioimaging and TME-responsive multimodal therapy effectively is a challenge. Herein, we successfully developed a new kind of NK-92 cell membrane-camouflaged mesoporous MnO2-enveloped Au@Pd nanoparticles (APMN NPs)-based versatile biomimetic theranostic nanoplatform for the potential MR imaging-guided multimodal synergistic antitumor treatments. These NPs could integrate unique structural, optical, multiple-catalytic, paramagnetic, and biological merits of NK-92 cell membrane, Au@Pd cores and mesoporous MnO2 shell in a single nanoplatform. The NK-92 cell membrane camouflaging endowed the NPs with enhanced tumor-targeting capability, immune escape function, and membrane protein-mediated tumoral uptake property. The new information obtained from this study may be beneficial to promote the development of novel TME-responsive versatile "Trojan horse" theranostic nanoplatforms for efficient MR imaging-guided multimodal synergistic treatment.

Biomimetic ZIF8 Nanosystem With Tumor Hypoxia Relief Ability to Enhance Chemo-Photothermal Synergistic Therapy.

Tumor hypoxic microenvironment can reduce the therapeutic effects of chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, etc. It is also a potential source of tumor recurrence and metastasis. A biomimetic nanosystem based on zeolitic imidazolate framework 8 (ZIF8), which had multifunctions of hypoxia relief, chemotherapy, and photothermal therapy, was established to improve tumor hypoxic microenvironment and overcome the corresponding therapeutic resistance. ZIF8 enveloped with DOX and CuS nanoparticles (DC@ZIF8) was synthesized by a sedimentation method. Red blood cell membrane and catalase (CAT) were coated onto DC@ZIF8 and biomimetic nanosystem (DC@ZIF8-MEMC) was formed. The designed DC@ZIF8-MEMC had a shape of polyhedron with an average particle size around 254 nm. The loading content of DOX, CAT, and CuS was 4.9%, 6.2%, and 2.5%, separately. The release of DOX from DC@ZIF8-MEMC was pH dependent and significantly faster at pH 5 due to the degradation of ZIF8. DC@ZIF8-MEMC exhibited outstanding photothermal conversion properties and excellent antitumor effect in vitro and in vivo. Moreover, the hypoxia relief by CAT was proved to have good sensitization effect on chemo-photothermal combined therapy. DC@ZIF8-MEMC is a prospective nanosystem, which can realize great chemo-photothermal synergistic antitumor effect under the sensitization of CAT. The biomimetic multifunctional nanoplatform provides a potential strategy of chemo-photothermal synergistic antitumor effect under the sensitization of CAT.

Hyaluronic acid-modified manganese dioxide-enveloped hollow copper sulfide nanoparticles as a multifunctional system for the co-delivery of chemotherapeutic drugs and photosensitizers for efficient synergistic antitumor treatments.

This paper presents the design of a new type of intelligent and versatile all-in-one therapeutic nanoplatform for the co-delivery of chemotherapeutic drugs and photosensitizers to facilitate multimodal antitumor treatment; the system is based on hyaluronic acid (HA)-modified manganese dioxide (MnO2)-enveloped hollow porous copper sulfide (CuS) nanoparticles (CuS@MnO2/HA NPs). In this system, a CuS inner shell allows for the co-loading of doxorubicin (DOX) and indocyanine green (ICG) and induces photothermal effects, and a biodegradable MnO2 external shell affords on-demand tumor microenvironment (TME)-triggered release and catalase- andFenton-like activities. Moreover, the HA modification endows the system with a CD44 receptor-mediated tumor-targeting property. The formulated DOX and ICG co-loaded CuS@MnO2/HA (DOX/ICG-CuS@MnO2/HA) NPs were found to exhibit excellent photothermal performance both in vitro and in vivo. In addition, DOX/ICG-CuS@MnO2/HA NPs were found to display both TME and near-infrared (NIR)-responsive controlled release properties. The NPs also have a superior reactive oxygen species (ROS) generation capacity due to the combination of enhanced ICG-induced singlet oxygen and CuS@MnO2-mediated hydroxyl radicals. The cellular uptake, fluorescence imaging property, cytotoxicity, and thermal imaging of these NPs were also evaluated. In tumor-bearing mice, the DOX/ICG-CuS@MnO2/HA NPs displayeda superior antitumor efficacy (2.57-fold) as compared with free DOX. Therefore, the developed DOX/ICG-CuS@MnO2/HA NPs have a great potential for use as an all-in-one nanotherapeutic agent for the efficient and precise induction of chemo/photothermal/photodynamic/chemodynamic therapy with superior antitumor efficacy and fewer side effects.

Compound Stability in Nanoparticles: The Effect of Solid Phase Fraction on Diffusion of Degradation Agents into Nanostructured Lipid Carriers.

The stability of active compounds encapsulated in nanoparticles depends on the resistance of the particles to diffusion of environmental degradation agents. In this paper, off-lattice Monte Carlo simulations are used to investigate a suspension of nanostructured lipid carriers (NLC) composed of interspaced liquid and solid lipid domains, immersed in a solution containing molecules representing oxidative or other degradation agents. The simulations examine the diffusion of the degradation agents into the nanoparticles as a function of nanoparticle size, solid domain fraction, and domain size. Two types of suspensions are studied: one (representing an infinitely dilute nanoparticle suspension) where the concentration of oxidative agents is constant in the solution around the particle and the other, finite system where diffusion into the nanoparticle causes depletion in the concentration of degradation agents in the surrounding solution. The total number of degradation agent molecules in the NLCs is found to decrease with the solid domain fraction, as may be expected. However, their concentration in the liquid domains is found to increase with the solid domain fraction. Since the degradation reaction depends on the concentration of the degradation agents, this suggests that compounds encapsulated in nanoparticles with high liquid content (such as emulsions) will degrade less and be more stable than those encapsulated in NLCs with high solid domain fraction, in agreement with previous experimental results.

Distribution of a model bioactive within solid lipid nanoparticles and nanostructured lipid carriers influences its loading efficiency and oxidative stability.

The overall goal of this study was to characterize the distribution of a model bioactive encapsulant in the lipid domain of SLNs and NLCs and its relationship with loading efficiency and reactivity of the model encapsulant with oxidative stress agents. Distribution of a model bioactive (beta-carotene) was compared to that of a fluorescent dye (Nile red) in SLNs, 10% NLC, 30% NLC, 50% NLC, 70% NLC (the number represents the percentage of liquid lipid within the total lipid amount) and emulsions. Fluorescence imaging shows that the distribution of Nile red in the lipid domain of colloidal carriers was similar to that of beta-carotene in all formulations. Based on the combination of imaging observations and loading efficiency measurements, the results demonstrate that beta-carotene was excluded from the lipid domain in both SLNs and NLCs. The extent of exclusion decreased, while uniformity in the distribution of encapsulant in the lipid domain of colloidal carrier increased with an increase in percentage of liquid lipid content of NLCs. Oxidative stability of the encapsulated beta-carotene in SLN and NLCs (at least until 30% liquid lipid composition) was significantly lower compared to that in emulsion. Only for the NLCs with 50 and 70% liquid lipid content, oxidative stability of the encapsulated compound was significantly higher than that in emulsions. Overall, the results demonstrate that differences in loading efficiency and oxidative stability of beta-carotene in SLNs and NLCs may be explained by the differences in the distribution of beta-carotene.

Real-time measurements to characterize dynamics of emulsion interface during simulated intestinal digestion.

Efficient delivery of bioactives remains a critical challenge due to their limited bioavailability and solubility. While many encapsulation systems are designed to modulate the digestion and release of bioactives within the human gastrointestinal tract, there is limited understanding of how engineered structures influence the delivery of bioactives. The objective of this study was to develop a real-time quantitative method to measure structural changes in emulsion interface during simulated intestinal digestion and to correlate these changes with the release of free fatty acids (FFAs). Fluorescence resonant energy transfer (FRET) was used for rapid in-situ measurement of the structural changes in emulsion interface during simulated intestinal digestion. By using FRET, changes in the intermolecular spacing between the two different fluorescent probes labeled emulsifier were characterized. Changes in FRET measurements were compared with the release of FFAs. The results showed that bile salts and pancreatic lipase interacted immediately with the emulsion droplets and disrupted the emulsion interface as evidenced by reduction in FRET efficacy compared to the control. Similarly, a significant amount of FFAs was released during digestion. Moreover, addition of a second layer of polymers at emulsion interface decreased the extent of interface disruption by bile salts and pancreatic lipase and impacted the amount or rate of FFA release during digestion. These results were consistent with the lower donor/acceptor ratio of the labeled probes from the FRET result. Overall, this study provides a novel approach to analyze the dynamics of emulsion interface during digestion and their relationship with the release of FFAs.

Effect of layer-by-layer coatings and localization of antioxidant on oxidative stability of a model encapsulated bioactive compound in oil-in-water emulsions.

Oxidation of encapsulated bioactives in emulsions is one of the key challenges that limit shelf-life of many emulsion containing products. This study seeks to quantify the role of layer-by-layer coatings and localization of antioxidant molecules at the emulsion interface in influencing oxidation of the encapsulated bioactives. Oxidative barrier properties of the emulsions were simulated by measuring the rate of reaction of peroxyl radicals generated in the aqueous phase with the encapsulated radical sensitive dye in the lipid core of the emulsions. The results of peroxyl radical permeation were compared to the stability of encapsulated retinol (model bioactive) in emulsions. To evaluate the role of layer-by-layer coatings in influencing oxidative barrier properties, radical permeation rates and retinol stability were evaluated in emulsion formulations of SDS emulsion and SDS emulsion with one or two layers of polymers (ϵ-polylysine and dextran sulfate) coated at the interface. To localize antioxidant molecules to the interface, gallic acid (GA) was chemically conjugated with ϵ-polylysine and subsequently deposited on SDS emulsion based on electrostatic interactions. Emulsion formulations with localized GA molecules at the interface were compared with SDS emulsion with GA molecules in the bulk aqueous phase. The results of this study demonstrate the advantage of localization of antioxidant at the interface and the limited impact of short chain polymer coatings at the interface of emulsions in reducing permeation of radicals and oxidation of a model encapsulated bioactive in oil-in-water emulsions.

Improved oxidative barrier properties of emulsions stabilized by silica-polymer microparticles for enhanced stability of encapsulants.

The materials encapsulated within oil-in-water emulsions are prone to oxidation due to the permeation of oxidative species across the oil-water interface and into the lipid phase. Thus, the oxidative barrier properties of the interfacial layer are pivotal in reducing oxidation within emulsified oils. To enhance these barrier properties, we explored an approach of stabilizing emulsions using 'silica-polymer microparticles'. We hypothesize that these microparticles will enhance the barrier properties of emulsion interfaces by mechanisms such as higher interfacial thickness and quenching of oxidative species before they permeate into the emulsions. Silica-ε-polylysine (Si-EPL) microparticles were synthesized by electrostatic aggregation of anionic silica nanoparticles and cationic ε-polylysine in the aqueous phase. Formation of Si-EPL microparticles was validated using particle size, ζ-potential and scanning electron microscopy measurements. These microparticles were subsequently used for emulsion stabilization. Emulsions stabilized by silica nanoparticles alone were used as control. Oxidative barrier properties were determined by measuring the rate of permeation of peroxyl radicals from the aqueous to the oil phase of the emulsion using fluorescence based methods. The rate of permeation of peroxyl radicals was significantly lower in emulsions stabilized by Si-EPL microparticles compared to that stabilized by silica nanoparticles. One of the mechanisms responsible for the observed effect was enhanced quenching of peroxyl radical by Si-EPL microparticles before they can permeate inside the oil phase. To further validate the results, stability of a model bioactive compound, retinol, encapsulated in these emulsions was compared. Consistent with peroxyl radical permeation measurements, emulsion stabilized by Si-EPL microparticles significantly improved the oxidative stability of retinol compared to that stabilized by silica nanoparticles alone. Thus, by engineering the physical properties of the interfacial layers, the oxidation of the encapsulants in emulsions can be controlled.

Effect of antioxidant properties of lecithin emulsifier on oxidative stability of encapsulated bioactive compounds.

Oxidation of encapsulated bioactive compounds in emulsions is one of the key challenges that limit shelf life of emulsion containing products. Oxidation in these emulsions is triggered by permeation of free radicals generated at the emulsion interface. The objective of this study was to evaluate the role of antioxidant properties of common emulsifiers (lecithin and Tween 20) in reducing permeation of free radicals across the emulsion interface. Radical permeation rates were correlated with oxidative stability of a model bioactive compound (curcumin) encapsulated in these emulsions. Rate of permeation of peroxyl radicals from the aqueous phase to the oil phase of emulsion was inversely proportional to the antioxidant properties of emulsifiers. The rate of radical permeation was significantly higher (p<0.05) for emulsions stabilized using Tween 20 and oxidized lecithin compared to native lecithin that showed higher antioxidant activity. Free radical permeation rate correlated with stability of curcumin in emulsions and was significantly higher (p<0.05) in lecithin stabilized emulsions as compared to Tween 20 emulsions. Overall, this study demonstrates that antioxidant activity of emulsifiers significantly influences permeation of free radicals across the emulsion interface and the rate of oxidation of bioactive encapsulant.