Fabrication of a dual pH-responsive and photothermal microcapsule pesticide delivery system for controlled release of pesticides.

BACKGROUND: The development of stimulus-responsive and photothermally controlled-release microcapsule pesticide delivery systems is a promising solution to enhance the effective utilization and minimize the excessive use of pesticides in agriculture. RESULTS: In this study, an AVM@CS@TA-Fe microcapsule pesticide delivery system was developed using avermectin as the model drug, chitosan and tannic acid as the wall materials, and tannic acid-Fe complex layer as the photothermal agent. The optical microscope, scanning electron microscope, transmission electron microscope, and Fourier-transform infrared spectroscope were used to characterize the prepared microcapsule. The slow-release, UV-shielding, photothermal performance, and nematicidal activity of the microcapsule were systematically investigated. The results showed that the system exhibited excellent pH-responsive and photothermal-sensitive performances. In addition, the UV-shielding performance of the delivery system was improved. The photothermal conversion efficiency (η) of the system under the irradiation of near-infrared (NIR) light was determined to be 14.18%. Moreover, the nematicidal activities of the system against pine wood nematode and Aphelenchoides besseyi were greatly increased under the irradiation of light-emitting diode (LED) simulated sunlight. CONCLUSION: The release of the pesticide-active substances in such a pesticide delivery system could be effectively regulated with the irradiation of NIR light or LED-simulated sunlight. Thus, the developed pesticide delivery system may have broad application prospects in modern agriculture fields. © 2022 Society of Chemical Industry.

Ceria-Containing Hybrid Multilayered Microcapsules for Enhanced Cellular Internalisation with High Radioprotection Efficiency.

Cerium oxide nanoparticles (nanoceria) are believed to be the most versatile nanozyme, showing great promise for biomedical applications. At the same time, the controlled intracellular delivery of nanoceria remains an unresolved problem. Here, we have demonstrated the radioprotective effect of polyelectrolyte microcapsules modified with cerium oxide nanoparticles, which provide controlled loading and intracellular release. The optimal (both safe and uptake efficient) concentrations of ceria-containing microcapsules for human mesenchymal stem cells range from 1:10 to 1:20 cell-to-capsules ratio. We have revealed the molecular mechanisms of nanoceria radioprotective action on mesenchymal stem cells by assessing the level of intracellular reactive oxygen species (ROS), as well as by a detailed 96-genes expression analysis, featuring genes responsible for oxidative stress, mitochondrial metabolism, apoptosis, inflammation etc. Hybrid ceria-containing microcapsules have been shown to provide an indirect genoprotective effect, reducing the number of cytogenetic damages in irradiated cells. These findings give new insight into cerium oxide nanoparticles' protective action for living beings against ionising radiation.

Application of Gamma Radiation on Hard Gelatin Capsules as Sterilization Technique and Its Consequences on the Chemical Structure of the Material.

Hard capsules are made from gelatin, an organic polymer obtained through the hydrolysis of collagen present in animal tissues. Gelatin can be degraded by microorganisms and some strategies can be used to control contaminating micro-organisms. Gamma irradiation is considered as an effective sterilization method; however, its application can alter the chemical structure of the irradiated product. Samples of hard gelatin capsules were irradiated at doses of 5, 15, and 25 kGy at room temperature. The characterizations of the physical and chemical effects were evaluated by scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry techniques. Furthermore, hard gelatin capsule samples were dissolved and inoculated with Bacillus subtilis, a Gram-positive spore-forming bacterium, to evaluate the effect of gamma ray radiation on bacterial counts. The results showed that gamma radiation did not interfere on physical parameters of the capsule, such as moisture content, mass, body and cap length, and disintegration time. Nevertheless, differential scanning calorimetry results demonstrated changes in the glass transition temperature, indicating the formation of crosslinking in irradiated capsules. It was observed that there were significant reductions on the inoculated bacterial population starting from the lowest irradiation dose and there was no detection of bacterial growth from the 15 kGy dose, while in the non-irradiated samples were found with 104 CFU mL-1 of bacteria. Therefore, this work concludes that the gamma radiation is effective on the reduction of the microbial population, cause discrete physical-chemical alterations, and could be used as a hard capsule sterilization technique.

Orthogonal near-infrared upconversion co-regulated site-specific O2 delivery and photodynamic therapy for hypoxia tumor by using red blood cell microcarriers.

Pre-existing hypoxia in tumors can result in an inadequate oxygen supply during photodynamic therapy (PDT), which in turn hampers photodynamic efficacy. To overcome this problem, we developed an orthogonal near-infrared upconversion controlled red blood cell (RBC) microcarriers to selectively deliver O2 in hypoxia area. Moreover, this RBC microcarriers are able to overcome a series of complex biological barriers which include transporting across the inflamed endothelium, evading mononuclear phagocyte system, reducing reticuloendothelial system uptake. Based on these abilities, RBC microcarriers have efficient tumors accumulation and are capable of delivery a large amount of O2 for PDT under near-infrared (NIR) irradiation to realize effective solid tumor eradication.

Conducting polymers with defined micro- or nanostructures for drug delivery.

Conducting polymers (CPs) are redox active materials with tunable electronic and physical properties. The charge of the CP backbone can be manipulated through redox processes, with accompanied movement of ions into and out of the polymer to maintain electrostatic neutrality. CPs with defined micro- or nanostructures have greatly enhanced surface areas, compared to conventionally prepared CPs. The resulting high surface area interface between polymer and liquid media facilities ion exchange and can lead to larger and more rapid responses to redox cycling. CP systems are maturing as platforms for electrically tunable drug delivery. CPs with defined micro- or nanostructures offer the ability to increase the amount of drug that can be delivered whilst enabling systems to be finely tuned to control the extent and rate of drug release. In this review, fabrication approaches to achieve CPs with micro- or nanostructure are outlined followed by a detailed review and discussion of recent advances in the application of the materials for drug delivery.

Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier opening and local gene delivery.

Previous studies have demonstrated that circulating DNA-encapsulated microbubbles (MBs) combined with focused ultrasound (FUS) can be used for local blood-brain barrier (BBB) opening and gene delivery. However, few studies focused on how to increase the efficiency of gene delivery to brain tumors after the released gene penetrating the BBB. Here, we proposed the use of folate-conjugated DNA-loaded cationic MBs (FCMBs). When combined with FUS as a trigger for BBB opening, FCMBs were converted into nanometer-sized vesicles that were transported to the brain parenchyma. The FCMBs can selectively aggregate around tumor cells that overexpressed the folate receptor, thus enhancing gene delivery via folate-stimulated endocytosis. Our results confirmed that FCMBs can carry DNA on the surface of the MB shell and have good targeting ability on C6 glioma cells. In addition, the optimized FUS parameters for FCMBs-enhanced gene delivery were confirmed by cell experiments (center frequency = 1 MHz; acoustic pressure = 700 kPa; pulse repetition frequency = 5 Hz; cycle number = 10000; exposure time = 1 min; FCMBs concentration = 4 × 10(7) MB/mL). In vivo data also indicated that FCMBs show better gene transfection efficiency than MBs without folate conjugation and the traditional approach of directly injecting the gene. This study described our novel development of multifunctional MBs for FUS-triggered gene delivery/therapy.

Ultrasonically Assisted Polysaccharide Microcontainers for Delivery of Lipophilic Antitumor Drugs: Preparation and in Vitro Evaluation.

High toxicity, poor selectivity, and severe side effects are major drawbacks of anticancer drugs. Various drug delivery systems could be proposed to overcome these limitations. The aim of this study was to fabricate polysaccharide microcontainers (MCs) loaded with thymoquinone (TQ) by a one-step ultrasonication technique and to study their cellular uptake and cytotoxicity in vitro. Two MC fractions with a mean size of 500 nm (MC-0.5) and 2 µM (MC-2) were prepared and characterized. Uptake of the MCs by mouse melanoma M-3 cells was evaluated in both 2D (monolayer culture) and 3D (multicellular tumor spheroids) models by confocal microscopy, flow cytometry, and fluorimetry. The higher cytotoxicity of the TQ-MC-0.5 sample than the TQ-MC-2 fraction was in good correlation with higher MC-0.5 accumulation in the cells. The MC-0.5 beads were more promising than the MC-2 particles because of a higher cellular uptake in both 2D and 3D models, an enhanced antitumor effect, and a lower nonspecific toxicity.

Evaluation of the potential of doxorubicin loaded microbubbles as a theranostic modality using a murine tumor model.

In this study, a novel phospholipid-based microbubble formulation containing doxorubicin and perfluoropropane gas (DLMB) was developed. The DLMBs were prepared by mechanical agitation of a phospholipid dispersion in the presence of perfluoropropane (PFP) gas. An anionic phospholipid, distearoyl phosphatidylglycerol (DSPG) was selected to load doxorubicin in the microbubbles by means of electrostatic interaction. The particle size, zeta potential, echogenicity and stability of the DLMBs were measured. Drug loading was ⩾ 92%. The potential of the DLMBs for use as a theranostic modality was evaluated in tumor bearing mice. Gas chromatography analysis of PFP showed significant enhancement of PFP retention when doxorubicin was used at concentrations of 10-82% equivalent to DSPG. The inhibitory effects on the proliferation of B16BL6 melanoma murine cells in vitro were enhanced using a combination of ultrasound (US) irradiation and DLMBs. Moreover, in vivo DLMBs in combination with (US) irradiation significantly inhibited the growth of B16BL6 melanoma tumor in mice. Additionally, US echo imaging showed high contrast enhancement of the DLMBs in the tumor vasculature. These results suggest that DLMBs could serve as US triggered carriers of doxorubicin as well as tumor imaging agents in cancer therapy.

Targeted concurrent chemoradiotherapy, by using improved microcapsules that release carboplatin in response to radiation, improves detectability by computed tomography as well as antitumor activity while reducing adverse effect in vivo.

PURPOSE: The effect of alginate-hyaluronate microcapsules that release carboplatin in response to radiation was improved by adding ascorbic acid (AA). MATERIALS AND METHODS: Four measures of the effectiveness of the microcapsules were evaluated: 1) release of carboplatin in response to radiation in vitro and in vivo; 2) detectability of their accumulation by computed tomography (CT) in vivo; 3) enhancement of antitumor effects in vivo; and 4) reduction of adverse effects in vivo. RESULTS: There were significant increases in the rupture of microcapsules by adding AA in vitro. Subcutaneously injected microcapsules around the tumor could be detected by using CT and the alteration of CT-values correlated with the accumulation of the microcapsules. Those microcapsules released carboplatin and resulted in synergistic antitumor effect with concomitant radiation. With the encapsulation of carboplatin, chemotherapeutic effects were still observed two weeks after treatment. However, addition of AA did not result in increased antitumor effect in vivo. A reduction in adverse effects was observed with the encapsulation of carboplatin, through localization of carboplatin around the tumor. CONCLUSION: Addition of AA to the materials of microcapsules did not result in increasing antitumor effect. However encapsulation of carboplatin will be useful as a clinical cancer-therapy option.

Delivery of molecules to the lymph node via lymphatic vessels using ultrasound and nano/microbubbles.

Lymph node (LN) dissection is the primary option for head and neck cancer when imaging modalities and biopsy confirm metastasis to the sentinel LN. However, there are no effective alternative treatments to dissection for LN metastasis. Here, we describe a novel drug delivery system combining nano/microbubbles (NMBs) with ultrasound (US) that exhibits considerable potential for the delivery of exogenous molecules into LNs through the lymphatic vessels. A solution containing fluorophores (as a model of a therapeutic molecule) and NMBs was injected into the subiliac LNs of MXH10/Mo-lpr/lpr mice, which develop systemic swelling of LNs (up to 13 mm in diameter, similar to human LNs). It was found that the NMBs were delivered to the entire area of the proper axillary LN (proper-ALN) via the lymphatic channels and that these were retained there for more than 8 min. Furthermore, exposure to US in the presence of NMBs enhanced the delivery of fluorophores into the lymphocytes near the lymphatic channels, compared with exposure to US in the absence of NMBs. It is proposed that a system using US and NMBs to deliver therapeutic drugs via lymphatic vessels can serve as a new treatment method for LN metastasis.

Sonochemical fabrication of dual-targeted redox-responsive smart microcarriers.

In the present study, the molecular and magnetic dual-targeted redox-responsive folic acid-cysteine-Fe3O4 microcapsules (FA-Cys-Fe3O4 MCs) have been synthesized via the sonochemical technique, and targeting molecule (folic acid) and Fe3O4 magnetic nanoparticles are introduced into the microcapsule shells successfully. The obtained FA-Cys-Fe3O4 MCs show excellent magnetic responsive ability by the oriented motion under an external magnetic field. The hydrophobic fluorescent dye (Coumarin 6) is successfully loaded into the FA-Cys-Fe3O4 MCs, demonstrating that it could be also easily realized to encapsulate hydrophobic drugs into the FA-Cys-Fe3O4 MCs when the drugs are dispersed into the oil phase before sonication. Cellular uptake demonstrates that FA-Cys-Fe3O4 MCs could target selectively the cells via folate-receptor-mediated endocytosis. Moreover, the FA-Cys-Fe3O4 MCs show their potential ability to be an attractive carrier for drug controlled release owing to the redox responsiveness of the disulfide in the microcapsule shells.

Albumin acts like transforming growth factor ß1 in microbubble-based drug delivery.

Unlike lipid-shelled microbubbles (MBs), albumin-shelled microbubbles (MBs) have not been reported to be actively targeted to cells without the assistance of antibodies. Recent studies indicate that the albumin molecule is similar to transforming growth factor ß (TGF-ß) both structurally and functionally. The TGF-ß superfamily is important during early tumor outgrowth, with an elevated TGF-ß being tumor suppressive; at later stages, this switches to malignant conversion and progression, including breast cancer. TGF-ß receptors I and II play crucial roles in both the binding and endocytosis of albumin. However, until now, no specific albumin receptor has been found. On the basis of the above-mentioned information, we hypothesized that non-antibody-conjugated albumin-shelled MBs can be used to deliver drugs to breast cancer cells. We also studied the possible roles of TGF-ß1 and radiation force in the behavior of cells and albumin-shelled MBs. The results indicate that albumin-shelled MBs loaded with paclitaxel (PTX) induce breast cancer cell apoptosis without the specific targeting produced by an antibody. Applying either an acoustic radiation force or cavitation alone to cells with PTX-loaded albumin MBs increased the apoptosis rate to 23.2% and 26.3% (p < 0.05), respectively. We also found that albumin-shelled MBs can enter MDA-MB-231 breast cancer cells and remain there for at least 24 h, even in the presence of PTX loading. Confocal micrographs revealed that 70.5% of the breast cancer cells took up albumin-shelled MBs spontaneously after 1 d of incubation. Applying an acoustic radiation force further increased the percentage to 91.9% in our experiments. However, this process could be blocked by TGF-ß1, even with subsequent exposure to the radiation force. From these results, we conclude that TGF-ß1 receptors are involved in the endocytotic process by which albumin-shelled MBs enter breast cancer cells. The acoustic radiation force increases the contact rate between albumin-shelled MBs and tumor cells. Combining a radiation force and cavitation yields an apoptosis rate of 31.3%. This in vitro study found that non-antibody-conjugated albumin-shelled MBs provide a useful method of drug delivery. Further in vivo studies of the roles of albumin MBs and TGF-ß in different stages of cancer are necessary.

In vitro gene delivery with ultrasound-triggered polymer microbubbles.

In the work described here, gene delivery using polymer microbubbles triggered by ultrasound in vitro was investigated. The effects of pressure amplitude (0-2 MPa), center frequency (1-5 MHz), pulse length (3-12,000 µs), pulse repetition frequency (5-20,000 Hz) and exposure time (0-30 s) on transfection efficiency and cell viability were examined. The effects of radiation force, calcium ion concentration and timing of treatments were also examined. Cells were successfully transfected with pressure amplitudes as low as 250 kPa. Transfection was most efficient at lower frequencies and longer pulse lengths, with a transfection efficiency of 24.2 ± 2.0% achieved using a center frequency of 1 MHz, pressure amplitude of 1 MPa, pulse length of 12,000 µs and pulse repetition frequency of 5 Hz. Gene delivery was also affected by the extracellular calcium ion concentration and the timing of treatments.

Towards theranostic multicompartment microcapsules: in-situ diagnostics and laser-induced treatment.

Paving the way towards the application of polyelectrolyte multilayer capsules in theranostics, we describe diagnostic multi-functionality and drug delivery using multicompartment polymeric capsules which represent the next generation of drug delivery carriers. Their versatility is particularly important for potential applications in the area of theranostics wherein the carriers are endowed with the functionality for both diagnostics and therapy. Responsiveness towards external stimuli is attractive for providing controlled and on-demand release of encapsulated materials. An overview of external stimuli is presented with an emphasis on light as a physical stimulus which has been widely used for activation of microcapsules and release of their contents. In this article we also describe existing and new approaches to build multicompartment microcapsules as well as means available to achieve controlled and triggered release from their subcompartments, with a focus on applications in theranostics. Outlook for future directions in the area are highlighted.

Near-infrared light-responsive graphene oxide composite multilayer capsules: a novel route for remote controlled drug delivery.

A novel and simple route for near-infrared (NIR)-light controlled release of drugs has been demonstrated using graphene oxide (GO) composite microcapsules based on the unique optical properties of GO. Upon NIR-laser irradiation, the microcapsules were ruptured in a point-wise fashion due to local heating which in turn triggers the light-controlled release of the encapsulated anticancer drug doxorubicin (Dox) from these capsules.

Irradiation depolymerized guar gum as partial replacement of gum Arabic for microencapsulation of mint oil.

Spray dried microcapsules of mint oil were prepared using gum Arabic alone and its blends with radiation or enzymatically depolymerized guar gum as wall materials. Microcapsules were evaluated for retention of mint oil during 8-week storage during which qualitative changes in encapsulated mint oil was monitored using principal component analysis. The microcapsules with radiation depolymerized guar gum as wall material component could better retain major mint oil compounds such as menthol and isomenthol. The t(1/2) calculated for mint oil in microcapsules of gum Arabic, gum Arabic:radiation depolymerized guar gum (90:10), gum Arabic:enzyme depolymerized guar gum (90:10) was 25.66, 38.50, and 17.11 weeks, respectively. The results suggested a combination of radiation depolymerized guar gum and gum Arabic to show better retention of encapsulated flavour than gum Arabic alone as wall material.

Neuron cells uptake of polymeric microcapsules and subsequent intracellular release.

Neuron cells uptake of biodegradable and synthetic polymeric microcapsules functionalized with aggregates of gold nanoparticles incorporated into their shells is demonstrated in situ. In addition to traditionally used optical microscopy, electron microscopy is used both for higher-resolution imaging and for confirming the uptake by focused ion beam cross-sectioning of specific cells in situ. Subsequently, physical methods of release are compared to chemical methods wherein laser-induced intracellular release of dextran molecules into the cytosol of hippocampal neuron cells is studied in comparison to biodegradation. Implications of this work for neuroscience, bio-medicine and single cell studies are discussed.

Active control of microcapsules in artificial blood vessel by producing local acoustic radiation force.

Micrometer-sized microcapsules collapse upon exposure to ultrasound. Use of this phenomenon for a drug delivery system (DDS), not only for local delivery of medication but also for gene therapy, should be possible. However, enhancing the efficiency of medication is limited because capsules in suspension diffuse in the human body after injection, since the motion of capsules in blood flow cannot be controlled. To control the behavior of microcapsules, acoustic radiation force was introduced. We detected local changes in microcapsule density by producing acoustic radiation force in an artificial blood vessel. Furthermore, we theoretically estimated the conditions required for active path selection of capsules at a bifurcation point in the artificial blood vessel. We observed the difference in capsule density at both in the bifurcation point and in alternative paths downstream of the bifurcation point for different the acoustic radiation forces. Also we confirmed the microcapsules are trapped against flow with the condition when the acoustic radiation force is more than fluid resistance of the capsules. The possibility of controlling capsule flow towards a specific point in a blood vessel was demonstrated.

Targeted delivery of chemotherapeutic agents using improved radiosensitive liquid core microcapsules and assessment of their antitumor effect.

PURPOSE: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. METHODS AND MATERIALS: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 microg) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl(2) solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy (60)Co gamma-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. RESULTS: Microcapsules that had been polymerized using a 4.34% CaCl(2) solution supplemented with 5.0 x 10(-3)% (10(-3)% meant or 10%(-3)) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. CONCLUSION: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

Biological properties of photocrosslinked alginate microcapsules.

An alternative form of gene therapy using recombinant cell lines delivering therapeutic products encapsulated in alginate hydrogel has proven effective in treating many murine models. The lack of long-term capsule stability has led to a new strategy to reinforce the microcapsules with a photopolymerized interpenetrating covalent network of N-vinylpyrrolidone (NVP) and sodium acrylate. Here the properties for potential application in gene therapy are reported. In assessing potential toxicity of the unpolymerized residues, HPLC showed that even after 1 week of washing, no toxic monomers could be detected. Their ability to sustain cell growth was monitored with growth of the encapsulated cells in vitro and in vivo. Although the initial photopolymerization caused significant cell damage, the cells were able to recover normal growth rates thereafter. After implanting into mice, the NVP-modified capsules showed a high level of biocompatibility as measured by hematological and biochemical functional tests. There was also no difference in the amount and type of plasma proteins adsorbing to the NVP-modified and the classical alginate capsules, thus indicating their similar biological compatibility. Both in vitro and in vivo tests confirmed that the NVP-modified capsules were more resistant to osmotic stress than the alginate microcapsules. Furthermore, when applied to the treatment of a murine model of human cancer by delivering encapsulated cells secreting angiostatin, the NVP-modified microcapsules suppressed tumor growth as successfully as the regular alginate microcapsules. In conclusion, the covalently modified microcapsules have shown a high level of biocompatibility, safety, increase in stability, and clinical efficacy for use as immunoisolation devices in gene therapy.