Dual-loaded nano pesticide system based on industrial grade scaleable carrier materials with combinatory efficacy and improved safety.

Repeated and widespread use of single chemical pesticides raises concerns about efficiency and safety, developing multi-component synergistic pesticides provides a new route for efficient control of diseases. Most commercial compound formulations are open systems with non-adjustable released rates, resulting in a high frequency of applications. Meanwhile, although nano pesticide delivery systems constructed with different carrier materials have been extensively studied, realizing their actual scale-up production still has important practical significance due to the large-scale field application. In this study, a boscalid and pyraclostrobin dual-loaded nano pesticide system (BPDN) was constructed with industrial-grade carrier materials to facilitate the realization of large-scale production. The optimal industrial-scale preparation mechanism of BPDN was studied with surfactants as key factors. When agricultural emulsifier No.600 and polycarboxylate are used as the ratio of 1:2 in the preparation process, the BPDN has a spherical structure with an average size of 270 nm and exhibits superior physical stability. Compared with commercial formulation, BPDN maintains rate-stabilized release up to 5 times longer, exhibits better dispersion and spreading performance on foliar, has more than 20% higher deposition amounts, and reduces loss. A single application of BPDN could efficiently control tomato gray mold during the growing period of tomatoes due to extended duration and combinatory effectiveness, reducing two application times and labor costs. Toxicology tests on various objects systematically demonstrated that BPDN has improved safety for HepG2 cells, and nontarget organism earthworms. This research provides insight into creating safe, efficient, and environmentally friendly pesticide production to reduce manual operation times and labor costs. Accompanied by production strategies that can be easily scaled up industrially, this contributes to the efficient use of resources for sustainable agriculture.

Liquid Oil Marbles: Increasing the Bioavailability of Poorly Water-Soluble Drugs.

Many new therapeutic candidates and active pharmaceutical ingredients (APIs) are poorly soluble in an aqueous environment, resulting in their reduced bioavailability. A promising way of enhancing the release of an API and, thus, its bioavailability seems to be the use of liquid oil marbles (LOMs). An LOM system behaves as a solid form but consists of an oil droplet in which an already dissolved API is encapsulated by a powder. This study aims to optimize the oil/powder combination for the development of such systems. LOMs were successfully prepared for 15 oil/powder combinations, and the following properties were investigated: particle mass fraction, dissolution time, and mechanical stability. Furthermore, the release of API from both LOMs and LOMs encapsulated into gelatine capsules was studied.

X-ray-Mediated Release of Molecules and Engineered Proteins from Nanostructure Surfaces.

Many applications call for initiation of chemical reactions with highly penetrating X-rays with nanometer precision and little damage to the surroundings, which is difficult to realize because of low interaction cross-sections between hard X-rays and organic matters. Here, we demonstrate that a combination of computational protein design of single conjugation site green fluorescent proteins and nanomaterial engineering of silica-covered gold nanoparticles can enhance the release efficiencies of proteins from the surface of nanoparticles. The nanoparticles, to which the proteins are attached through DNA linkers, provide increased X-ray absorption without scavenging radicals, and single conjugation sites allow efficient release of proteins.

Remote Trice Light, Temperature, and pH-actuation of Switchable Magneto-Plasmonic Nanocarriers for Combinational Photothermal and Controlled/Targeted Chemotherapies.

Three magneto-plasmonic nanohybrids were synthesized using Au- and Ag-coated Fe3O4 nanoparticles (NPs)-modified dual pH- and temperature-responsive triblock copolymer of poly (butyl methacrylate-co-acrylamide-co-methacrylic acid) to serve as drug carriers with potential of using in both photothermal and controlled/targeted chemotherapies. The internal superparamagnetic core gives the carriers targeted-delivery characteristics, and surface plasmon resonance-based noble metallic Au/Ag shells give them on-demand photothermal and photo-triggering release properties. To investigate the effect of coating method on the targeting property of synthesized carriers, Au NPs were attached to the magnetic core by 2 different direct/indirect procedures and the properties of the synthesized carriers including swelling ratio and thermal and optical sensitivity and switching were comprehensively investigated in 2 different buffer solutions with pH 5.5 and 7.4 at 37°C. Letrozole was used as a model anticancer drug and its loading and release properties were evaluated for the four nanocarriers. The cytotoxicity of drug-free and letrozole-loaded nanocarriers on normal L929 fibroblast and MDAMB 231 breast cancer cell lines was evaluated in absence/presence of laser radiation. The results revealed that the carriers have the potential of serving as switchable trimodal light/temperature/pH-triggered and targeted/controlled drug delivery platforms for chemophotothermal therapy.

Tunable Surface Plasmon Resonance-Based Remote Actuation of Bimetallic Core-Shell Nanoparticle-Coated Stimuli Responsive Polymer for Switchable Chemo-Photothermal Synergistic Cancer Therapy.

New dual light/temperature-responsive nanocarriers were synthesized using bimetallic plasmonic Au-Ag and Ag-Au nanoparticles (NPs) as cores of vehicles which subsequently functionalized with an upper critical solubility temperature-based poly acrylamide-co-acrylonitrile using reversible addition-fragmentation chain transfer for spatiotemporally controlled chemo-photothermal synergistic cancer therapy. The bimetallic cores were assigned to sense wavelengths close to the localized surface plasmon resonance of monometallic NP shell to produce heat which not only can increase the surrounding temperature over the upper critical solubility temperature of polymer to open its valves and promote drug diffusion but also can kill cancerous cells through photothermal effects with increase in environment temperature by nearly 18°C after about 5 min radiation. The bimetallic NPs were shown good reusability even after 5 heating/cooling cycles, and the efficiency of both photothermal/chemotherapic procedures can be modulated by manipulating carrier's concentration and radiation time. In addition, the cytotoxicity of drug-free nanocarriers on normal L929 fibroblast and letrozole-loaded nanocarriers on MDAMB 231 breast-cancer cell lines were investigated in the absence/presence of laser radiation. Finally, the prepared nanocomposites were exhibited switchable on/off drug release in 2 buffered solutions (pH 5.5 and 7.4) with light actuation. The results revealed that the prepared nanocarriers can be served as efficient delivery platforms for remote-control chemophotothermal synergistic cancer therapy.

Switchable on/off drug release from gold nanoparticles-grafted dual light- and temperature-responsive hydrogel for controlled drug delivery.

A switchable dual light- and temperature-responsive drug carrier using gold nanoparticles (Au NPs)-grafted poly(dimethylacrylamide-co-acrylamide)/poly acrylic acid [P(DMA-co-AAm)/PAAc] hydrogel was prepared by free radical polymerization procedure using N,N-methylenebisacrylamide as cross-linker and ammonium persulfate as initiator. Initial P(DMA-co-AAm) hydrogel and uniformly-distributed stable Au NPs, prepared by reduction of hydrogen tetrachloroaureate (III) hydrate in the presence of trisodium citrate, were synthesized separately. Then, the prepared P(DMA-co-AAm) and Au NPs were added to an acrylic acid solution along with the cross-linker and initiator to prepare PAAc hydrogel within the mixture. This improves the swelling ratio and stabilizes Au NPs in networks. Furthermore, a cross-linked P(DMA-co-AAm-co-AAc) random hydrogel was also prepared with the same monomer compositions as the above hydrogel for comparison of their properties. Then, swelling, thermal sensitivity and thermal and optical switching properties of the prepared hydrogels were investigated in two acidic (pH=1.2) and neutral (pH=7.4) buffered solutions to simulate stomach and intestine body conditions. Finally, loading and cumulative release (%) of ofloxacin antibiotic as model drug were considered in both thermal and optical switching conditions. Based on these results, pulsatile release vehicle was obtained which have the "on" state at higher temperatures and the "off" state at lower temperatures.

Laser-assisted triggered-drug release from silver nanoparticles-grafted dual-responsive polymer.

Laser assisted drug release from a synthesized plain polymer composed of poly (butyl methacrylate-co-acrylamide-co-methacrylic acid) [P(BMA-co-AAm-co-MAA)] and a metallo-polymer composed of silver nanoparticles (Ag NPs) grafted plain polymer (the nanocomposite) were studied to investigate their capability to serve as drug carriers. Positive temperature dependent swelling changes were observed for both carriers and their thermal sensitivity and thermal and optical switching properties were investigated in two buffered solutions. An acidic solution with pH=1.2 to simulate stomach body condition and a neutral solution with pH=7.4 to simulate intestine condition. Reversible phase transition (collapsing/swelling) with fast response time in the order of few seconds were observed by applying heat or by applying light radiation at the surface plasmon resonance wavelength of the attached NPs. Finally, cumulative release (%) of ofloxacin antibiotic as a model drug was investigated for both thermal and optical switching conditions. Based on these results, pulsatile release was observed which have the "on" and "off" states at higher and lower temperatures with respect to their volume-phase transition temperatures respectively.

Intracellular Delivery of Colloidally Stable Core-Cross-Linked Triblock Copolymer Micelles with Glutathione-Responsive Enhanced Drug Release for Cancer Therapy.

Design and development of amphiphilic block copolymer-based nanocarriers exhibiting enhanced colloidal stability upon dilution in the blood and cellular glutathione-responsive rapid drug release is highly desired for tumor-targeting chemotherapy. Herein, we report a novel ABA-type triblock copolymer consisting of a hydrophilic central poly(ethylene glycol) block and two terminal hydrophobic blocks of a polymethacrylate having pendant disulfides (PHMssEt), thus PHMssEt-b-PEG-b-PHMssEt (ssTP). Aqueous self-assembly and the following disulfide-exchange reaction of the resulting ssTP allow for formation of core-cross-linked micelles (CCMs) through the formation of new disulfide linkages, retaining enhanced colloidal stability in physiological conditions and in the presence of proteins. Further, they exhibit reduction-responsive enhanced release of encapsulated drugs in response to cellular concentrations of glutathione in cancer cells, confirmed by dynamic light scattering and spectroscopic analysis. Combined with these results, in vitro (cells) and in vivo (mouse model) biological results suggest that ssTP-based CCMs are effective candidates as intracellular nanocarriers targeting tumors for cancer therapy.

Dual Location Dual Reduction/Photoresponsive Block Copolymer Micelles: Disassembly and Synergistic Release.

Self-assembled micellar systems designed with multiple stimuli-responsive degradation have been considered as effective candidates for polymer-based delivery systems exhibiting enhanced/controlled release. However, most conventional approaches involve the incorporation of single, dual, or multiple cleavable linkages positioned at single locations, as in hydrophobic cores or at core/corona interfaces. Herein, a novel dual location dual reduction and photoresponsive block copolymer containing a disulfide linkage at the block junction and pendant o-nitrobenzyl thioether (NBS) groups in the hydrophobic methacrylate block (PEG-ss-PhvM) are reported, which are synthesized by a combination of controlled radical polymerization and facile coupling reaction. The amphiphilic design of the PEG-ss-PhvM enables the formation of self-assembled micellar aggregates with disulfides at the core/corona interfaces and pendant photocleavable NBS groups in the hydrophobic cores. The dual cleavable linkages respond to each stimulus (GSH or light), exhibiting enhanced release; further to a combination of dual locational stimuli, promoting synergistic release at dual locations.

Intracellular delivery cellulose-based bionanogels with dual temperature/pH-response for cancer therapy.

Polysaccharide-based crosslinked nanogles (bionanogels) exhibiting multiple stimuli-responsive release of encapsulated therapeutics hold a great potential as tumor-targeting intracelluar durg delivery nanocarriers. Herein, we report the synthesis of monodisperse dual temperature/acidic pH-responsive bionanogels (DuR-BNGs) by aqueous crosslinking polymerization through temperature-induced self-association method. The DuR-BNGs have prolonged colloidal stability and negligible non-specific interactions with proteins. In response to acidic pH at higher temperature (above lower critical solution temperature), they exhibit synergistic release of anticancer drugs as a consequence of both acidic pH-sensitivity of carboxymethyl cellulose and temperature-induced volume change of grafted thermoresponsive copolymers. In vitro cell culture results suggest that new colloidally-stable DuR-BNG is a promising candidate promoting dual stimuli-responsive drug release for cancer therapy.

Reductively-sheddable cationic nanocarriers for dual chemotherapy and gene therapy with enhanced release.

The development of a versatile strategy to synthesize cationic nanocarriers capable of co-delivery and enhanced release of drugs and oligonucleotides is promising for synergic dual chemotherapy and gene therapy. Herein, we report a novel cationic amphiphilic diblock copolymer having a single reduction-responsive disulfide linkage at a junction between a FDA-approved polylactide (PLA) block and a cationic methacrylate block (C-ssABP). The amphiphilic design of the C-ssABP enables the formation of cationic micellar aggregates possessing hydrophobic PLA cores, encapsulating anticancer drugs; cationic coronas, ensuring complementary complexation with negatively-charged oligonucleotides through electrostatic interactions; and disulfides at interfaces, leading to enhanced release of both encapsulated drugs and complexed oligonucleotides. The reduction-responsive intracellular trafficking results from flow cytometry, confocal laser scanning microscopy, and cell viability, as well as in vitro gene transfection assay suggest that C-ssABP offers versatility as an effective nanocarrier platform for dual chemotherapy and gene therapy.

Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation.

A selection of porous silicas were combined with a model drug using a recently developed, controlled microwave heating process to determine if the application of microwave irradiation could enhance subsequent drug release. Five mesoporous silica types were investigated (core shell, core shell rehydrox, SBA-15, silica gel, SYLOID®) and, for comparison, one non-porous silica (stober). These were formulated using a tailored microwave heating method at drug/excipient ratios of 1:1, 1:3 and 1:5. In addition, all experiments were performed both in the presence and absence of water, used as a fluidising media to aid interaction between drug and support, and compared with results obtained using more traditional heating methods. All formulations were then characterised using differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FT-IR). Pharmaceutical performance was investigated using in vitro drug release studies. A significant enhancement in the release profile of fenofibrate was observed for formulations prepared using microwave heating in the absence of water for five of the six silica based formulations. Of all the formulations analysed, the greatest extent of drug release within the experimental 30 min was the 1:5 core shell rehydrox achieving a total of 86.6 ± 2.8%. The non-porous (stober) particles did not exhibit an increased release of the drug under any experimental conditions studied. This anomaly is thought to be a result of the comparatively small surface area of the silica particles, thus preventing the adsorption of drug molecules.