Biocompatible microcapsules functionalized with inorganic nanoparticles for enhanced external triggering via light and ultrasound

Designing and fabricating functional composite capsules are of considerable interest to both academic and industrial fields. Inorganic nanoparticles (NPs) have great potential to modify properties of Layer-by-layer (LbL) polyelectrolyte (PE) capsules, but using prefabricated NPs to functionalize capsules still has considerable challenges such as poor distribution in the capsule walls. The present work proposed and validated a novel approach of fabricating functional capsules with in situ formation and incorporation of inorganic carbon dots (CDs), TiO2 and SiO2 NPs in PAH/PSS multilayers.[1,2] CDs were synthesized within capsule shells through autoclaving the PE capsules in dextran solution, while SiO2 and TiO2 NPs functionalized capsules were fabricated by hydrolysis of Titanium butoxide (TIBO), Tetraethyl orthosilicate (TEOS) respectively. The morphology, composition, shell thickness, permeability and stimuli sensitivity, etc. of the formed capsules with different composition were investigated, and characterized by SEM, TEM, EDX, FTIR, and CLSM. The three types of capsules demonstrated prominent properties compared with the traditional capsule without hybrid with inorganic NPs: i) the PE/CDs capsules displayed a rigid bowl-like morphology (Figure 1A), increased shell thickness (178.4nm, Figure 1B) and an excellent fluorescent property originated from the CDs (Figure 1D, E), and it can efficiently prevent the penetration of a small molecule Rhodamine B (Figure 1F); ii) the PE/SiO2 capsules showed a free-standing sphere morphology and a reduced permeability; iii) the capsules in situ composited with TiO2 NPs were found as a sphere shape and susceptible to UV irradiation (320-400nm, ~110 mW cm-2). Ultrasound irradiation tests demonstrated that all these three types of capsules possessed effective ultrasound sensitivity. It was validated by the fragmentation of PE/SiO2 and PE/TiO2 capsules in a few seconds of 50W ultrasound irradiation and the completely break of PE/CDs capsules in a few minutes of the treatment (Figure 1C). Besides, the cell viability data demonstrated that all the three types of composite capsules possessed good biocompatibility. In summary, those innovative composite capsules were demonstrated with great capability of small molecule encapsulation, high mechanical strength, good biocompatibility and high sensitivity to ultrasound and UV, which could be promising for various applications such as cosmetics, environment and biomedicine areas. Please click Additional Files below to see the full abstract

Silver-Coated Colloidosomes as Carriers for an Anticancer Drug.

Small drug molecules are widely developed and used in the pharmaceutical industry. In the past few years, loading and delivering such molecules using polymer-shell colloidosomes has attracted interest. Traditional polymer capsules fail to encapsulate low-molecular-weight materials for long times, since they are inherently porous and permeable for small molecules. In this paper, we report a method for encapsulating an anticancer drug with small molecule weight, for cell viability tests. The silver-coated colloidosomes are prepared by making an aqueous core capsule with a polymer shell and then adding AgNO3, surfactant, and l-ascorbic acid to form a second shell. The capsules are impermeable and can be triggered using ultrasound. We propose to use the capsules as drug carriers. The silver demonstrates a low cytotoxicity for up to 10 capsules per cell. After the silver shells are triggered by ultrasound, the released doxorubicin, the broken silver fragments, and the doxorubicin loading on the capsule surface all kill cells. The results demonstrate a nonpermeable silver-shell microcapsule with ultrasound sensitivity for potential medical applications

Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response

Synthetic microstructures can be engineered to deliver bioactive compounds impacting on their pharmacokinetics and pharmacodynamics. Herein, we applied dextran-based layer-by-layer (LbL) microcapsules to deliver alpha-2-macroglobulin (α2MG), a protein with modulatory properties in inflammation. Extending recent observations made with dextran-microcapsules loaded with α2MG in experimental sepsis, we focused on the physical and chemical characteristics of these microstructures and determined their biology on rodent and human cells. We report an efficient encapsulation of α2MG into microcapsules, which enhanced i) human leukocyte recruitment to inflamed endothelium and ii) human macrophage phagocytosis: in both settings microcapsules were more effective than soluble α2MG or empty microcapsules (devoid of active protein). Translation of these findings revealed that intravenous administration of α2MG-microcapsules (but not empty microcapsules) promoted neutrophil migration into peritoneal exudates and augmented macrophage phagocytic functions, the latter response being associated with alteration of bioactive lipid mediators as assessed by mass spectrometry. The present study indicates that microencapsulation can be an effective strategy to harness the complex biology of α2MG with enhancing outcomes on fundamental processes of the innate immune response paving the way to potential future development in the control of sepsis

Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis

Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil–endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis

Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis

These studies were supported by The Wellcome Trust (program 086867/Z/08) and the William Harvey Research Foundation to MP, the United Kingdom Intensive Care Society to CJH and the National Institutes of Health GM Grant P01GM095967 (awarded to Charles N. Serhan). LVN is supported by an Arthritis Research UK Career Development Fellowship (19909). EPSRC Seed Funding Cross disciplinary Grant (QMUL) awarded to GBS and MP. This work forms part of the research themes contributing to the translational research portfolio of Barts and The London NIHR Cardiovascular BRU

High-efficiency freezing-induced loading of inorganic nanoparticles and proteins into micron- and submicron-sized porous particles

We demonstrate a novel approach to the controlled loading of inorganic nanoparticles and proteins into submicron- and micron-sized porous particles. The approach is based on freezing/thawing cycles, which lead to high loading densities. The process was tested for the inclusion of Au, magnetite nanoparticles, and bovine serum albumin in biocompatible vaterite carriers of micron and submicron sizes. The amounts of loaded nanoparticles or substances were adjusted by the number of freezing/thawing cycles. Our method afforded at least a three times higher loading of magnetite nanoparticles and a four times higher loading of protein for micron vaterite particles, in comparison with conventional methods such as adsorption and coprecipitation. The capsules loaded with magnetite nanoparticles by the freezing-induced loading method moved faster in a magnetic field gradient than did the capsules loaded by adsorption or coprecipitation. Our approach allows the preparation of multicomponent nanocomposite materials with designed properties such as remote control (e.g. via the application of an electromagnetic or acoustic field) and cargo unloading. Such materials could be used as multimodal contrast agents, drug delivery systems, and sensors

Optical coherence microangiography of the mouse kidney for diagnosis of circulatory disorders

Optical coherence tomography (OCT) has become widespread in clinical applications in which precise three-dimensional functional imaging of living organs is required. Nevertheless, the kidney is inaccessible for the high resolution OCT imaging due to a high light attenuation coefficient of skin and soft tissues that significantly limits the penetration depth of the probing laser beam. Here, we introduce a surgical protocol and fixation scheme that enables functional visualization of kidney’s peritubular capillaries via OCT microangiography. The model of reversible/irreversible glomerulus embolization using drug microcarriers confirms the ability of OCT to detect circulatory disorders. This approach can be used for choosing optimal carriers, their dosages and diagnosis of other blood flow pathologies

In vivo optical monitoring of transcutaneous delivery of calcium carbonate microcontainers

We have developed a method for delivery of biocompatible CaCO3 microcontainers (4.0 ± 0.8 µm) containing Fe3O4 nanoparticles (14 ± 5 nm) into skin in vivo using fractional laser microablation (FLMA) provided by a pulsed Er:YAG laser system. Six laboratory rats have been used for the microcontainer delivery and weekly monitoring implemented using an optical coherence tomography and a standard histological analysis. The use of FLMA allowed for delivery of the microcontainers to the depth about 300 μm and creation of a depot in dermis. On the seventh day we have observed the dissolving of the microcontainers and the release of nanoparticles into dermis

Biodegradable Nanocarriers Resembling Extracellular Vesicles Deliver Genetic Material with the Highest Efficiency to Various Cell Types

Efficient delivery of genetic material to primary cells remains challenging. Here, efficient transfer of genetic material is presented using synthetic biodegradable nanocarriers, resembling extracellular vesicles in their biomechanical properties. This is based on two main technological achievements: generation of soft biodegradable polyelectrolyte capsules in nanosize and efficient application of the nanocapsules for co‐transfer of different RNAs to tumor cell lines and primary cells, including hematopoietic progenitor cells and primary T cells. Near to 100% efficiency is reached using only 2.5 × 10−4 pmol of siRNA, and 1 × 10−3 nmol of mRNA per cell, which is several magnitude orders below the amounts reported for any of methods published so far. The data show that biodegradable nanocapsules represent a universal and highly efficient biomimetic platform for the transfer of genetic material with the utmost potential to revolutionize gene transfer technology in vitro and in vivo

Delivery and reveal of localization of upconversion luminescent microparticles and quantum dots in the skin in vivo by fractional laser microablation, multimodal imaging, and optical clearing

Delivery and spatial localization of upconversion luminescent microparticles [Y 2 O 3 ;Yb, Er] (mean size ~1.6 μm) and quantum dots (QDs) (CuInS 2 ZnS nanoparticles coated with polyethylene glycol-based amphiphilic polymer, mean size ~20 nm) inside rat skin was studied in vivo using a multimodal optical imaging approach. The particles were embedded into the skin dermis to the depth from 300 to 500 μm through microchannels performed by fractional laser microablation. Low-frequency ultrasound was applied to enhance penetration of the particles into the skin. Visualization of the particles was revealed using a combination of luminescent spectroscopy, optical coherence tomography, confocal microscopy, and histochemical analysis. Optical clearing was used to enhance the image contrast of the luminescent signal from the particles. It was demonstrated that the penetration depth of particles depends on their size, resulting in a different detection time interval (days) of the luminescent signal from microparticles and QDs inside the rat skin in vivo. We show that luminescent signal from the upconversion microparticles and QDs was detected after the particle delivery into the rat skin in vivo during eighth and fourth days, respectively. We hypothesize that the upconversion microparticles have created a long-time depot localized in the laser-created channels, as the QDs spread over the surrounding tissues