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Photodynamic therapy (PDT) is an interesting and promising approach to tackle a broad spectrum of cancer types. With the combination of a photosensitizer, light and oxygen, PDT achieves a unique selectivity by the production of localized reactive oxygen species (ROS) inside cells, which leads to their destruction. In addition, the luminescence properties of photosensitizers can be exploited to develop imaging tools. Unfortunately, the cancer selectivity and homogeneity of most photosensitizers are frequently limiting the performances of PDT and cancer detection/characterization by luminescence imaging. Consequently, our study aims to use cellulose nanocrystals to transport and deliver radiolabeled photo-responsive metalla-assemblies to create a new generation of theranostic agents for PDT and imaging applications. The synthesis, structural characterization, cytotoxicity evaluation, and in vivo biodistribution imaging of the compounds are presented. The best candidates show excellent biological activity and selectivity towards ovarian carcinoma cell line (A2780), cisplatin resistant ovarian carcinoma cell line (A2780cis) versus normal human embryonic kidney cells (HEK293T), as well as efficient imaging properties, suggesting a potential use as multimodal theranostic agents.

Hypothesis: Recently, the anomalous shrinkage of surface-supported hyaluronate/poly-L-lysine (HA/PLL) microgels (mu-gels), which exceeds that reported for any other multilayer-based systems, has been reported [1]. The current study investigates the capability of these unique mu-gels for the encapsulation and retention of macromolecules, and proposes the shrinkage-driven assembly of biopolymer-based mu- gels as a novel tool for one-step surface biofunctionalization.Experiments: A set of dextrans (DEX) and their charged derivatives -carboxymethyl (CM)-DEX and diethylaminoethyl (DEAE)-DEX -has been utilized to evaluate the effects of macromolecular mass and net charge on mu-gel shrinkage and macromolecule entrapment. mu-gels formation on the surface of silicone catheters exemplifies their potential to tailor biointerfaces.Findings: Shrinkage-driven mu-gel formation strongly depends on the net charge and mass content of encapsulated macromolecules. Inclusion of neutral DEX decreases the degree of shrinkage several times, whilst charged DEXs adopt to the backbone of oppositely charged polyelectrolytes, resulting in shrinkage comparable to that of non-loaded mu-gels. Retention of CM-DEX in mu-gels is significantly higher compared to DEAE-DEX. These insights into the mechanisms of macromolecular entrapment into biopolymer-based mu-gels promotes fundamental understanding of molecular dynamics within the multilayer assemblies. Organization of biodegradable mu-gels at biomaterial surfaces opens avenues for their further exploitation in a diverse array of bioapplications.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funding Information: V. Känkänen and H.A. Santos acknowledge Bayer Oy (Finland) for financial support. H.A. Santos acknowledges also the Sigrid Jusélius Foundation and the UMCG Research Fund for financial support. Publisher Copyright: © 2022 The Authors The use of amphiphilic block copolymers to generate colloidal delivery systems for hydrophobic drugs has been the subject of extensive research, with several formulations reaching the clinical development stages. However, to generate particles of uniform size and morphology, with high encapsulation efficiency, yield and batch-to-batch reproducibility remains a challenge, and various microfluidic technologies have been explored to tackle these issues. Herein, we report the development and optimization of poly(ethylene glycol)-block-(ε-caprolactone) (PEG-b-PCL) nanoparticles for intravenous delivery of a model drug, sorafenib. We developed and optimized a glass capillary microfluidic nanoprecipitation process and studied systematically the effects of formulation and process parameters, including different purification techniques, on product quality and batch-to-batch variation. The optimized formulation delivered particles with a spherical morphology, small particle size (dH < 80 nm), uniform size distribution (PDI < 0.2), and high drug loading degree (16 %) at 54 % encapsulation efficiency. Furthermore, the stability and in vitro drug release were evaluated, showing that sorafenib was released from the NPs in a sustained manner over several days. Overall, the study demonstrates a microfluidic approach to produce sorafenib-loaded PEG-b-PCL NPs and provides important insight into the effects of nanoprecipitation parameters and downstream processing on product quality.

Skin is a protective barrier that can protect against environmental influences and renew itself. However, in some cases, this regenerative property is lost, and this causes delays in wound healing. Wound healing is a complex and long-lasting phase. Any bacterial infection during the wound healing process delays wound healing. The therapeutic efficacy can be increased by using nanocarrier drug delivery systems to the target tissue with modern wound dressings. Controlled nano drug delivery systems increase the therapeutic efficacy in the treatment of diseases and provide a faster recovery process. In this study, amoxicillin (AMX) and rifampicin (RIF) were loaded into the bismuth ferrite (BFO) particles which were synthesized with the co-precipitation method. Then, these drug-loaded BFO particles (0.075 %) were added separately to 13 % polyvinyl alcohol (PVA) solution and the solutions were printed three-dimensionally to obtain three dimensional scaffolds. With these designed scaffolds, it is aimed to reduce the risk of inflammation in wound tissues and increase therapeutic efficacy with controlled release. The SEM images proved that homogeneous pore distributions could be achieved with these combinations. The tensile test results showed that drug-loaded BFO addition increased the mechanical strength of the 13 % PVA scaffold. The biocompatibility test results demonstrated that the highest viability values of the human adipose tissue-derived mesenchymal stem cells were obtained for AMX-added 13 % PVA scaffolds.

There are many different inhaler devices and medications on the market for the treatment of asthma and chronic obstructive pulmonary disease, with over 230 drug-delivery system combinations available. However, despite the abundance of effective treatment options, the achieved disease control in clinical practice often remains unsatisfactory. In this context, a key determining factor is the match or mismatch of an inhalation device with the characteristics or needs of an individual patient. Indeed, to date, no ideal device exists that fits all patients, and a personalized approach needs to be considered. Several useful choice-guiding algorithms have been developed in the recent years to improve inhaler–patient matching, but a comprehensive tool that translates the multifactorial complexity of inhalation therapy into a user-friendly algorithm is still lacking. To address this, a multidisciplinary expert panel has developed an evidence-based practical treatment tool that allows a straightforward way of choosing the right inhaler for each patient. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-02034-9.

Membrane fusion is a ubiquitous phenomenon linked to many biological processes, and represents a crucial step in liposome-based drug delivery strategies. The ability to control, ever more precisely, membrane fusion pathways would thus be highly valuable for next generation nano-medical solutions and, more generally, the design of advanced biomimetic systems such as synthetic cells. In this article, we present fusogenic nanostructures constructed from synthetic DNA which, different from previous solutions, unlock routes for modulating the rate of fusion and making it conditional to the presence of soluble DNA molecules, thus demonstrating how membrane fusion can be controlled through simple DNA-based molecular circuits. We then systematically explore the relationship between lipid-membrane composition, its biophysical properties, and measured fusion efficiency, linking our observations to the stability of transition states in the fusion pathway. Finally, we observe that specific lipid compositions lead to the emergence of complex bilayer architectures in the fusion products, such as nested morphologies, which are accompanied by alterations in biophysical behaviour. Our findings provide multiple, orthogonal strategies to program lipid-membrane fusion, which leverage the design of either the fusogenic DNA constructs or the physico/chemical properties of the membranes, and could thus be valuable in applications where some design parameters are constrained by other factors such as material cost and biocompatibility, as it is often the case in biotechnological applications.

Low intracellular delivery efficiency and multidrug resistance are among major barriers to effective cancer therapy. Herein, we report a novel, virus-mimicking, endosomolytic liposomal drug-delivery platform to address these two key challenges. The pH-responsive, comb-like pseudopeptides were prepared by grafting relatively long alkyl side chains onto a polyamide, poly(L-lysine isophthalamide), to mimic fusogenic peptides in viral spikes. The cholesterol-containing liposome, which mimics the viral envelope, was readily coated with these pseudopeptides due to their hydrophobic side chains acting as membrane anchors. These endosomolytic pseudopeptides displayed high adsorption onto the liposomal membrane and enabled the significantly higher cellular uptake. The virus-mimicking system showed a pH-triggered content-release profile which could be manipulated by varying the structure and concentration of the adsorbed polymers. The endosomolytic ability of the multifunctional liposome and its use for efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) were demonstrated. The virus-mimicking liposomal system with DOX encapsulation exhibited considerably higher potency against HeLa cervical cancer cells, A549 lung cancer cells, MES-SA uterus cancer cells, and MES-SA/DX5 multidrug-resistant cancer cells than DOX-loaded bare liposomes and free DOX. These results suggest its potential applications for enhanced cytoplasmic delivery and cancer treatment.

There is an increased need and focus to understand how local brain microstructure affects the transport of drug molecules directly administered to the brain tissue, for example in convection-enhanced delivery procedures. This study reports a systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fibres, namely the corpus callosum, the fornix and the corona radiata, with the specific aim to map different regions of the tissue and provide essential information for the development of accurate models of brain biomechanics. Ovine samples are imaged using scanning electron microscopy combined with focused ion beam milling to generate 3D volume reconstructions of the tissue at subcellular spatial resolution. Focus is placed on the characteristic cytological feature of the white matter: the axons and their alignment in the tissue. For each tract, a 3D reconstruction of relatively large volumes, including a significant number of axons, is performed and outer axonal ellipticity, outer axonal cross-sectional area and their relative perimeter are measured. The study of well-resolved microstructural features provides useful insight into the fibrous organization of the tissue, whose micromechanical behaviour is that of a composite material presenting elliptical tortuous tubular axonal structures embedded in the extra-cellular matrix. Drug flow can be captured through microstructurally-based models using 3D volumes, either reconstructed directly from images or generated in silico using parameters extracted from the database of images, leading to a workflow to enable physically-accurate simulations of drug delivery to the targeted tissue.

Nano/micromotors are self-propelled particles that use external stimuli to gain locomotion outperforming Brownian motion. Here, three different polymers are employed that are conjugated to silica particles through a pH-labile linker. At slightly acidic pH, the linkers hydrolyze and release the polymeric chains, resulting in enhanced locomotion. The motors show a maximum velocity of approximate to 3 mu m s(-1) in cell media when poly(ethylene glycol) methyl ether methacrylate is asymmetrically distributed on the surface of the particles. Further, the motor internalization by RAW 264.7 macrophages was compared between motors, which have the polymer conjugated via a pH-labile linker, and the irresponsive particles. Preliminary data indicate enhanced uptake, but further efforts are required to use responsive polymers to propel motors inside mammalian cells.

Current therapeutic treatments for the repair and/or replacement of damaged skin following disease or traumatic injury is severely limited. The chicken eggshell membrane (ESM) is a unique material: its innate physical and mechanical characteristics offer optimal barrier properties and, as a naturally derived extract, it demonstrates inherent biocompatibility/biodegradability. To further enhance its therapeutic and clinical potential, the ESM can be modified with the thermo-responsive polymer, poly(N-isopropylacrylAmide) (PNIPAAm) as well as the incorporation of (drug-loaded) silver nanoparticles (AgNP); essentially, by a simple change in temperature, the release and delivery of the NP can be targeted and controlled. In this study, ESM samples were isolated using a decellularization protocol, and the physical and mechanical characteristics were profiled using SEM, FT-IR, DSC and DMA. PNIPAAm was successfully grafted to the ESM via amidation reactions and confirmed using FT-IR, which demonstrated the distinctive peaks associated with Amide A (3275 cm−1), Amide B (2970 cm−1), Amide I (1630 cm−1), Amide II (1535 cm−1), CH2, CH3 groups, and Amide III (1250 cm−1) peaks. Confirmation of the incorporation of AgNP onto the stratified membrane was confirmed visually with SEM, qualitatively using FT-IR and also via changes in absorbance at 380 nm using UV-Vis spectrophotometry during a controlled release study for 72 h. The biocompatibility and cytotoxicity of the novel constructs were assessed using human dermal fibroblast (HDFa) and mouse dermal fibroblast (L929) cells and standard cell culture assays. Metabolic activity assessment (i.e., MTS assay), LDH-release profiles and Live/Dead staining demonstrated good attachment and spreading to the samples, and high cell viability following 3 days of culture. Interestingly, longer-term viability (>5 days), the ESM-PNIPAAm and ESM-PNIPAAm (AgNP) samples showed a greater and sustained cell viability profile. In summary, the modified and enhanced ESM constructs were successfully prepared and characterized in terms of their physical and mechanical profiles. AgNP were successfully loaded into the construct and demonstrated a desirable release profile dependent on temperature modulation. Fibroblasts cultured on the extracted ESM samples and ESM-PNIPAAm demonstrated high biocompatibility in terms of high cell attachment, spreading, viability and proliferation rates. As such, this work summarizes the development of an enhanced ESM-based construct which may be exploited as a clinical/therapeutic wound dressing as well as a possible application as a novel biomaterial scaffold for drug development.

The necessity of new drugs for lung cancer therapy and imaging is increasing each day. The development of new drugs that are capable of reaching the tumor with specificity and selectivity is required. In this direction, the design of nanoparticles for tumor therapy represents an important alternative. The aim of this study was to develop, characterize, and evaluate target-specific atezolizumab-conjugated poly(lactic acid)/poly(vinyl alcohol) (PLA/PVA) nanoparticles as pharmaceutical fragment candidates for new radiopharmaceuticals. For this purpose, PLA/PVA nanoparticle formulations were prepared by the double emulsifi-cation/solvent evaporation method with a high-speed homoge-nizer. A special focus was oriented to the selection of a suitable method for modification of the nanoparticle surface with a monoclonal antibody. For this purpose, atezolizumab was bound to the nanoparticles during the preparation by solvent evaporation or either by adsorption or covalent binding. PLA/PVA/atezolizumab nanoparticles are characterized by dynamic light scattering, Raman spectroscopy, scanning electron microscopy, and atomic force microscopy. An in vitro assay was performed to evaluate the antibody binding efficiency, stability, and cytotoxicity [A549 (lung cancer cell) and L929 (healthy fibroblast cell)]. The results showed that a spherical nanoparticle with a size of 230.6 +/- 1.768 nm and a zeta potential of-2.23 +/- 0.55 mV was produced. Raman spectroscopy demonstrated that the monoclonal antibody was entrapped in the nanoparticle. The high antibody binding efficiency (80.58%) demonstrated the efficacy of the nanosystem. The cytotoxic assay demonstrated the safety of the nanoparticle in L929 and the effect on A549. In conclusion, PLA/PVA/atezolizumab nanoparticles can be used as drug delivery systems for lung cancer diagnosis and therapy., Scientific and Technological Research Council of Turkey; [TUBITAK-220/S/361], Funding This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK-220/S/361) within the scope of PhD thesis of Meliha Ekinci.

One of the components of bee venom is melittin (M), which has strong lysing properties on membranes. M has high toxicity to cancer cells, but it also affects healthy cells, making it necessary to use methods for targeted delivery to ensure treatment. This research is a continuation of previous studies using graphene nanomaterials as M carriers to breast cancer cells. The studies described below are conducted on a more organized biological structure than what is found in vitro cells, namely, cancerous tumors grown on a chicken embryo chorioallantoic membrane. Caspase 3 and 8 levels are analyzed, and the level of oxidative stress markers and changes in protein expression for cytokines are examined. The results show that M complexes with nanomaterials reduce the level of oxidative stress more than M alone does, but the use of graphene (GN) as a carrier increases the level of DNA damage to a greater extent than the increase caused by M alone. An analysis of cytokine levels shows that the use of the M and GN complex increases the level of proteins responsible for inhibiting tumor progression to a greater extent than the increase occasioned by a complex with graphene oxide (GO). The results suggest that the use of GN as an M carrier may increase the toxic effect of M on structures located inside a cell.

A series of bioactive molecules were synthesized from the condensation of aspirin or chlorambucil with terminal alkynes bearing alcohol or amine substituents. Insertion of the resulting alkynes into the iron-carbyne bond of readily accessible diiron bis(cyclopentadienyl) mu-aminocarbyne complexes, [1a,b]CF3SO3, afforded novel diiron complexes with a bridging vinyliminium ligand, [2-10]CF3SO3, functionalized with a bioactive moiety. All compounds were characterized by elemental analysis and IR and multinuclear NMR spectroscopy and in three cases by single-crystal X-ray diffraction. Moreover, the D2O solubility, stability in D2O and cell culture media, and octanol-water partition coefficients of diiron complexes were determined spectroscopically. The cytotoxicity of the complexes was assessed in the tumorigenic A2780 and A2780cisR and the nontumorigenic HEK 293T cell lines. Some complexes exhibit high potency and the ability to overcome resistance in A2780cisR cells (aspirin complexes) or high selectivity relative to HEK 293T cells (chlorambucil complexes). Further studies indicate that the complexes significantly trigger intracellular ROS production, irrespective of the nature of the bioactive fragment. DNA alkylation and protein binding studies were also undertaken.

Objectives: Gene therapy approaches have become increasingly attractive in the medical, pharmaceutical, and biotechnological industries due to their applicability in the treatment of diseases with no effective conventional therapy. Non-viral delivery using cationic solid lipid nanoparticles (cSLNs) can be useful to introduce large nucleic acids to target cells. A careful selection of components and their amounts is critical to obtain a successful delivery system. In this study, solid Witepsol nanoparticles were formulated, characterized, and evaluated in vitro for gene delivery purposes. Materials and Methods: Solid Witepsol nanoparticles were formulated through the microemulsion dilution technique using two grades of Witepsol and three surfactants, namely Cremephor RH40, Kolliphor HS15, and Peceol. Dimethyldioctadecylammonium bromide was incorporated into the system as a cationic lipid. Twelve combinations of these ingredients were formulated. The obtained nanoparticles were then evaluated for particle size, zeta potential, DNA binding and protection ability, cytotoxicity, and transfection ability. Results: Particle sizes of the prepared cationic cSLNs were between 13.43 +/- 0.06 and 68.80 +/- 0.78 nm. Their zeta potential, which is important for DNA binding efficiency, was determined at >+40 mV. Gel retardation assays revealed that the obtained cSLNs can form a compact complex with plasmid DNA (pDNA) encoding green fluorescent protein and that this complex can protect pDNA from DNase I-mediated degradation. Cytotoxicity evaluation of nanoparticles was performed on the L929 cell line. In vitro transfection data revealed that solid Witepsol nanoparticles could effectively transfect fibroblasts. Conclusion: Our findings indicate that solid Witepsol nanoparticles prepared using the microemulsion dilution technique are promising non-viral delivery systems for gene therapy., Scientific and Technological Research Council of Turkey (TUBITAK) [218S840]; Izmir Katip Celebi University Research Fund [2020-ODL-ECZF-0001], This study has been financially supported by the Scientific and Technological Research Council of Turkey (TUBITAK) under grant code 218S840 and Izmir Katip Celebi University Research Fund under grant code 2020-ODL-ECZF-0001. This paper is dedicated to the memory of our co-author dear Selen Isar, who sadly passed away on Wednesday, December 9th, 2020.

Hereby, fabrication of hyaluronic acid/gelatin/sodium alginate (HA/Gel/SA) polymeric films, which contain electroconductive poly(3,4ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS) particles, is studied for drug release applications. The characterization of synthesized PEDOT:PSS and HA/Gel/SA-(PEDOT:PSS) films is verified by using FT-IR and RAMAN spectroscopy. Conductivity values of the films containing 0, 4, and 6% v/v PEDOT:PSS are found via a four-point probe technique to determine the optimum composition of the films for the targeted field. Additionally, swelling, mechanical, and cytotoxicity tests are carried out according to the related methods. Ciprofloxacin (CIP), which is a commonly used antibiotic, is loaded into the polymeric matrix and its release behavior is investigated. All results indicate that the incorporation of PEDOT:PSS increases the mechanical performance and decreases the burst release of drug resulted in more sustained release profile. The HA/Gel/SA-(PEDOT: PSS) formulation is clearly a promising drug carrier that also supports cell viability due to its high cytocompatibility.

Mucus is a complex barrier for pharmacological treatments and overcoming it is one of the major challenges faced during transmucosal drug delivery. To tackle this issue, a novel class of glycosylated nanoparticles, named "mucosomes," which are based on the most important protein constituting mucus, the mucin, is introduced. Mucosomes are designed to improve drug absorption and residence time on the mucosal tissues. Mucosomes are produced (150-300 nm), functionalized with glycans, and loaded with the desired drug in a single one-pot synthetic process and, with this method, a wide range of small and macro molecules can be loaded with different physicochemical properties. Various in vitro models are used to test the mucoadhesive properties of mucosomes. The presence of functional glycans is indicated by the interaction with lectins. Mucosomes are proven to be storable at 4 °C after lyophilization, and administration through a nasal spray does not modify the morphology of the mucosomes. In vitro and in vivo tests indicate mucosomes do not induce adverse effects under the investigated conditions. This study proposes mucosomes as a ground-breaking nanosystem that can be applied in several pathological contexts, especially in mucus-related disorders.

In the past decade, magnetic nanoparticles (MNPs) have been among the most attractive nanomaterials used in different fields, such as environmental and biomedical applications. The possibility of designing nanoparticles with different functionalities allows for advancing the biomedical applications of these materials. Additionally, the magnetic characteristics of the nanoparticles enable the use of magnetic fields to drive the nanoparticles to the desired sites of delivery. In this context, the development of new MNPs in new approaches for drug delivery systems (DDSs) for cancer treatment has increased. However, the synthesis of nanoparticles with high colloidal stability triggered drug delivery, and good biocompatibility remains a challenge. Herein, multi-core shell MNPs functionalized with Pluronic ® F-127 were prepared and thoroughly characterized as drug carriers for doxorubicin delivery. The functionalized nanoparticles have an average size of 17.71 ± 4.2 nm, high water colloidal stability, and superparamagnetic behavior. In addition, the nanoparticles were able to load 936 μg of DOX per mg of functionalized nanomaterial. Drug release studies at different pH values evidenced a pH-triggered DOX release effect. An increase of 62% in cumulative drug release was observed at pH simulating tumor endosome/lysosome microenvironments (pH 4.5) compared to physiological conditions (pH 7.4). In addition, an innovative dynamic drug delivery study was performed as a function of pH. The results from this test confirmed the pH-induced doxorubicin release capability of carbon multi-core shell MNPs. The validity of traditional kinetic models to fit dynamic pH-dependent drug release was also studied for predictive purposes. The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) and to the ERDF for financial support by funds FCT/MCTES to CIMO (UIBD/00690/2020) and RTChip4Theranostics (NORTE-01-0145-FEDER-029394). This work is a result of these projects. This research was funded by RTChip4Theranostics – Real time Liver-on-a-chip platform with integrated micro(bio)sensors for preclinical validation of graphene-based magnetic nanocarriers towards cancer theranostics, with the reference NORTE-01-0145-FEDER-029394, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); and CIMO (UIDB/00690/2020) through ERDF under the Program PT2020. Adriano S. Silva thanks his doctoral Grant with reference SFRH/BD/151346/2021 financed by the Portuguese Foundation for Science and Technology (FCT), with funds from NORTE2020, under the MIT Portugal Program. info:eu-repo/semantics/publishedVersion

Cells are promising as carriers that can enhance the delivery of nanomedicines. Cells that carry nanomedicinal cargo, either immobilized on the cell surface or internalized, can allow for highly specific delivery and can enable the transport of nanomedicines across challenging physiological barriers. The effective use of cells as carriers for the transport and delivery of nanomedines requires a careful selection of the chemical strategies that are used to load the cell-based carriers with their cargo. To this end, an in-depth understanding of the impact of various cell-surface modification chemistries on the viability and functional properties of the cells is essential, and techniques are needed that allow characterization of nanoparticle-modified living cells. This article touches upon both of these aspects. The first part of this review will present an overview of contemporary strategies that are available for the cell surface immobilization of nanoparticle cargo. After that, the various techniques that are most frequently used for the characterization of nanoparticle-modified cells will be discussed.

Long-term topical application of antibiotics on wounds has led to the emergence of drug-resistant bacterial infections. Antibiotic incorporation into the wound dressing requires enormous advancement of the field to ensure that the needed dose is released when the infection arises. This study synthesized a series of antimicrobial alpha-aminophosphonate derivatives, and the most effective compound was incorporated into thermoresponsive wound dressing patches. Wound dressing mats were fabricated by needleless electrospinning, and the resultant nanofiber mats were coated with a thermoresponsive eicosane/cellulose nanocrystals o/w system loaded with active alpha-aminophosphonate derivatives. Chemical, physical, thermal, and antimicrobial properties of the wound dressings were characterized wound dressings. Using SEM analysis, Nanofibers spun with 20 % w/v solutions were selected for drug-emulsion loading since they showed lower diameters with higher surface area. Furthermore, the drug-emulsion coating on the electrospun dressings improved the hydrophilicity of the wound dressings, and the thermoresponsive behavior of the mats was proved using differential scanning calorimetry data. Finally, the drug-loaded electrospun meshes were found active against tested microorganisms, and clear inhibition zones were observed. In conclusion, this novel approach of synthesizing a new family of antimicrobial molecules and their incorporation into nanofibers from renewable sources exhibits great potential for smart and innovative dressings.

Porous silicon (PSi) is a biocompatible and biodegradable material, which can be utilized in biomedical applications. It has several favorable properties, which makes it an excellent material for building engineered nanosystems for drug delivery and diagnostic purposes. One significant hurdle for commercial applications of PSi is the lack of industrial scale production of nanosized PSi particles. Here, we report a novel two-step production method for PSi nanoparticles. The method is based on centrifuge chemical vapor deposition (cCVD) of elemental silicon in an industrial scale reactor followed by electrochemical post-processing to porous particles. Physical properties, biocompatibility and in vivo biodistribution of the cCVD produced nanoparticles were investigated and compared to PSi nanoparticles conventionally produced from silicon wafers by pulse electrochemical etching. Our results demonstrate that the cCVD production provides PSi nanoparticles with comparable physical and biological quality to the conventional method. This method may circumvent several limitations of the conventional method such as the requirements for high purity monocrystalline silicon substrates as starting material and the material losses during the top-down milling process of the pulse-etched films to porous nanoparticles. However, the electroless etching required for the porosification of cCVD-produced nanoparticles limited control over the pore size, but is amenable for scaling of the production to industrial requirements.

The increasing cases of bacterial infections originating from resistant bacteria are a serious problem globally and many approaches have been developed for different purposes to treat bacterial infections. Aerogels are a novel class of smart porous materials composed of three-dimensional networks. Recently, aerogels with the advantages of ultra-low density, high porosity, tunable particle and pore sizes, and biocompatibility have been regarded as promising carriers for the design of delivery systems. Recently, aerogels have also been provided with antibacterial activity through loading of antibacterial agents, incorporation of metal/metal oxides and via surface functionalization and coating with various functional groups. In this mini-review, the synthesis of aerogels from both conventional and low-cost precursors is reported and examples of aerogels displaying antibacterial properties are summarized. As a result, it is clear that the encouraging antibacterial performance of aerogels promotes their use in many antibacterial applications, especially in the food industry, pharmaceutics and medicine.

Cells are attractive carriers for the transport and delivery of nanoparticulate cargo. The use of cell-based carriers allows one to enhance control over the biodistribution of drug-loaded polymers and polymer nanoparticles. One key element in the development of cell-based delivery systems is the loading of the cell-based carrier with the nanoparticle cargo, which can be achieved either by internalization of the payload or by immobilization on the cell surface. The surface modification of cells with nanoparticles or the internalization of nanoparticles by cells is usually monitored with fluorescence-based techniques, such as flow cytometry and confocal microscopy. In spite of the widespread use of these techniques, the use of fluorescent labels also poses some risks and has several drawbacks. Fluorescent dyes may bleach, or leach from, the nanoparticles or alter the physicochemical properties of nanoparticles and their interactions with and uptake by cells. Using poly(d,l-lactic acid) nanoparticles that are loaded with Coumarin 6, BODIPY 493/503, or DiO dyes as a model system, this paper demonstrates that the use of physically entrapped fluorescent labels can lead to false negative or erroneous results. The use of nanoparticles that contain covalently tethered fluorescent dyes instead was found to provide a robust approach to monitor cell surface conjugation reactions and to quantitatively analyze nanoparticle-decorated cells. Finally, it is shown that optical diffraction tomography is an attractive, alternative technique for the characterization of nanoparticle-decorated cells, which obviates the need for fluorescent labels.

In biomedicine, polymer blends are frequently applied in wound dressing design or drug delivery. Within these applications, poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are emerging as a popular matrix d...

Colorectal cancer (CRC) is the third most common and the second deadliest type of cancer worldwide, urging the development of more comprehensive models and of more efficient treatments. Although the combination of nanotechnology with chemo- and immuno-therapy has represented a promising treatment approach, its translation to the clinic has been hampered by the absence of cellular models that can provide reliable and predictive knowledge about the in vivo efficiency of the formulation. Herein, a 3D model based on CRC multicellular tumor spheroids (MCTS) model was developed by combining epithelial colon cancer cells (HCT116), human intestinal fibroblasts and monocytes. The developed MCTS 3D model mimicked several tumor features with cells undergoing spatial organization and producing extracellular matrix, forming a mass of tissue with a necrotic core. Furthermore, monocytes were differentiated into macrophages with an anti-inflammatory, pro-tumor M2-like phenotype. For a combined chemoimmunotherapy effect, spermine-modified acetalated dextran nanoparticles (NPs) loaded with the chemotherapeutic Nutlin-3a (Nut3a) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were produced and tested in 2D cultures and in the MCTS 3D model. NPs were successfully taken-up by the cells in 2D, but in a significant less extent in the 3D model. However, these NPs were able to induce an anti-proliferative effect both in the 2D and in the 3D models. Moreover, Nut3a was able to partially shift the polarization of the macrophages present in the MCTS 3D model towards an anti-tumor M1-like phenotype. Overall, the developed MCTS 3D model showed to recapitulate key features of tumors, while representing a valuable model to assess the effect of combinatorial nano-therapeutic strategies in CRC. In addition, the developed NPs could represent a promising approach for CRC treatment.

Significance Synthetic nanomaterials are being sought to shuttle therapeutic payloads directly into the cell nucleus as a major target for chemo- and gene-based therapies. However, it remains uncertain whether and how synthetic entities are able to bypass the nuclear pore complexes (NPCs) that regulate transport into and out of the nucleus. We have constructed biocompatible polymer vesicles that infiltrate NPCs and resolved their nuclear uptake mechanism in vitro and in vivo. Their ability to deliver payloads directly into cell nuclei is further validated by transmission electron microscopy., Organelle-specific nanocarriers (NCs) are highly sought after for delivering therapeutic agents into the cell nucleus. This necessitates nucleocytoplasmic transport (NCT) to bypass nuclear pore complexes (NPCs). However, little is known as to how comparably large NCs infiltrate this vital intracellular barrier to enter the nuclear interior. Here, we developed nuclear localization signal (NLS)-conjugated polymersome nanocarriers (NLS-NCs) and studied the NCT mechanism underlying their selective nuclear uptake. Detailed chemical, biophysical, and cellular analyses show that karyopherin receptors are required to authenticate, bind, and escort NLS-NCs through NPCs while Ran guanosine triphosphate (RanGTP) promotes their release from NPCs into the nuclear interior. Ultrastructural analysis by regressive staining transmission electron microscopy further resolves the NLS-NCs on transit in NPCs and inside the nucleus. By elucidating their ability to utilize NCT, these findings demonstrate the efficacy of polymersomes to deliver encapsulated payloads directly into cell nuclei.

The sol-gel derived porous bioactive glasses have drawn worldwide attention by virtue of the convenience and flexibility of this versatile synthesis method. In this review, the recent advances in sol-gel processed porous bioactive glasses in biomedical fields, especially for bone tissue regeneration applications have been comprehensively reviewed. Generally, it is envisaged that the morphology and chemical compositions of sol-gel derived porous bioactive glasses significantly affect their biological properties. Therefore, the controlled synthesis of these porous glasses is critical to their effective use in the biomedical fields. With this context, the first part of the review briefly describes the fundamentals of the sol-gel technique. In the subsequent section, different approaches frequently used for the sol-gel synthesis of porous glasses such as microemulsion and acid-catalyzed based synthesis have been reviewed. In the later part of the review, different types of sol-gel derived bioactive glasses namely silica, phosphate and silica-titania based glasses along with organic-inorganic hybrids materials have been discussed. The review also discusses the chemical, surface, mechanical and biological properties and further highlights the strategies to control the pore structure, shape, size and compositions of sol-gel derived bioactive glasses. Finally, the review provides a detailed discussion about the bone tissue regeneration application of different types of sol-gel derived bioactive glasses and presents future research perspectives.

Erythrocyte-based drug delivery systems have been investigated for their biocompatibility, long circulation time, and capability to transport cargo all around the body, thus presenting enormous potential in medical applications. In this study, we investigated hybrid nanoparticles consisting of nano-sized autologous or allogeneic red blood cell (RBC) membranes encapsulating porous silicon nanoparticles (PSi NPs). These NPs were functionalized with a model cancer antigen TRP2, which was either expressed on the surface of the RBCs by a cell membrane-mimickingblockcopolymer polydimethylsiloxane-b-poly-2-methyl-2-oxazoline, or attached on the PSi NPs, thus hidden within the encapsulation. When in the presence of peripheral blood immune cells, these NPs resulted in apoptotic cell death of T cells, where the NPs having TRP2 within the encapsulation led to a stronger T cell deletion. The deletion of the T cells did not change the relative proportion of CD4+and cytotoxic CD8+T cells. Overall, this work shows the combination of nano-sized RBCs, PSi, and antigenic peptides may have use in the treatment of autoimmune diseases. A. R. acknowledges financial support from the Finnish Cultural Foundation. H. A. S. acknowledges financial support from the University of Helsinki Research Funds, the Sigrid Juselius Foundation, the HiLIFE Research Funds, the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013; Grant No. 310892) and European Research Council Proof-of-Concept Grant (Decision No. 825020). The authors acknowledge the following core facilities funded by Biocenter Finland: Electron Microscopy Unit of the University of Helsinki for providing the facilities for TEM imaging and the Flow Cytometry Unit for providing the facilities for FACS experiments, and Nanomicroscopy Center of Aalto University for providing the facilities for the cryo-TEM imaging. A. R. acknowledges ¿nancial support from the Finnish Cultural Foundation. H. A. S. acknowledges ¿nancial support from the University of Helsinki Research Funds, the Sigrid Juselius Foundation, the HiLIFE Research Funds, the European Research Council under the European Union's Seventh Frame-work Programme (FP/2007–2013; Grant No. 310892) and European Research Council Proof-of-Concept Grant (Decision No. 825020). The authors acknowledge the following core facilities funded by Biocenter Finland: Electron Microscopy Unit of the University of Helsinki for providing the facilities for TEM imaging and the Flow Cytometry Unit for providing the facilities for FACS experiments, and Nanomicroscopy Center of Aalto University for providing the facilities for the cryo-TEM imaging.

Cells can take up nanoscale materials, which has important implications for understanding cellular functions, biocompatibility as well as biomedical applications. Controlled uptake, transport and triggered release of nanoscale cargo is one of the great challenges in biomedical applications of nanomaterials. Here, we study how human immune cells (neutrophilic granulocytes, neutrophils) take up nanomaterials and program them to release this cargo after a certain time period. For this purpose, we let neutrophils phagocytose DNA-functionalized single-walled carbon nanotubes (SWCNTs) in vitro that fluoresce in the near infrared (980 nm) and serve as sensors for small molecules. Cells still migrate, follow chemical gradients and respond to inflammatory signals after uptake of the cargo. To program release, we make use of neutrophil extracellular trap formation (NETosis), a novel cell death mechanism that leads to chromatin swelling, subsequent rupture of the cellular membrane and release of the cell's whole content. By using the process of NETosis, we can program the time point of cargo release via the initial concentration of stimuli such as phorbol 12-myristate-13-acetate (PMA) or lipopolysaccharide (LPS). At intermediate stimulation, cells continue to migrate, follow gradients and surface cues for around 30 minutes and up to several hundred micrometers until they stop and release the SWCNTs. The transported and released SWCNT sensors are still functional as shown by subsequent detection of the neurotransmitter dopamine and reactive oxygen species (H2O2). In summary, we hijack a biological process (NETosis) and demonstrate how neutrophils transport and release functional nanomaterials.

openaire: EC/H2020/788489/EU//BioELCell There is an increased interest in renewable carbon as a source of materials, where lignin is expected to play a prominent role. This stems, partially, from new regulations aiming to achieve a cleaner and safer environment. Lignin, as a polyaromatic plant-derived biomolecule, is not only abundant but widely accessible in industrial streams. Due to recent developments in production scalability as well as promising application prospects, nanoscaled lignin particles have recently generated interest in the research and industrial communities. This review describes the main routes to prepare spherical lignin particles, highlighting aspects associated to their shape and topology as well as performance. We discuss the use of spherical lignin particles as dispersants and in the formulation of coatings, adhesives and composites, focusing on the advantages of the spherical shape and nanoscaled size. The state of the particles is furthermore compared in terms of their applicability in dry and wet forms. Finally, we discuss the sustainability, stability and degradation of lignin particles, which are issues that are critically important for any prospective use.

This review paper provides a recent overview of current international research that is being conducted into the functional properties of cellulose as a nanomaterial. A particular emphasis is placed on fundamental and applied research that is being undertaken to generate applications, which are now becoming a real prospect given the developments in the field over the last 20 years. A short introduction covers the context of the work, and definitions of the different forms of cellulose nanomaterials (CNMs) that are most widely studied. We also address the terminology used for CNMs, suggesting a standard way to classify these materials. The reviews are separated out into theme areas, namely healthcare, water purification, biocomposites, and energy. Each section contains a short review of the field within the theme and summarizes recent work being undertaken by the groups represented. Topics that are covered include cellulose nanocrystals for directed growth of tissues, bacterial cellulose in healthcare, nanocellulose for drug delivery, nanocellulose for water purification, nanocellulose for thermoplastic composites, nanocellulose for structurally colored materials, transparent wood biocomposites, supercapacitors and batteries.

Chitosan is an interesting polymer to produce hydrogels suitable for the 3D printing of customized drug delivery systems. This study aimed at the achievement of chitosan-based scaffolds suitable for the incorporation of active components in the matrix or loaded into the pores. Several scaffolds were printed using different chitosan-based hydrogels. To understand which parameters would have a greater impact on printability, an optimization study was conducted. The scaffolds with the highest printability were obtained with a chitosan hydrogel at 2.5 wt%, a flow speed of 0.15 mm/s and a layer height of 0.41 mm. To improve the chitosan hydrogel printability, starch was added, and a design of experiments with three factors and two responses was carried out to find out the optimal starch supplementation. It was possible to conclude that the addition of starch (13 wt%) to the chitosan hydrogel improved the structural characteristics of the chitosan-based scaffolds. These scaffolds showed potential to be tested in the future as drug-delivery systems.

Natural biopolymer nanoparticles (NPs), including nanocrystalline cellulose (CNC) and lignin, have shown potential as scaffolds for targeted drug delivery systems due to their wide availability, cost‐efficient preparation, and anticipated biocompatibility. Since both CNC and lignin can potentially cause complications in cell viability assays due to their ability to scatter the emitted light and absorb the assay reagents, we investigated the response of bioluminescent (CellTiter‐Glo®), colorimetric (MTT® and AlamarBlue®) and fluorometric (LIVE/DEAD®) assays for the determination of the biocompatibility of the multimodal CNC and lignin constructs in murine RAW 264.7 macrophages and 4T1 breast adenocarcinoma cell lines. Here, we have developed multimodal CNC and lignin NPs harboring the radiometal chelator DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) and the fluorescent dye Cyanine 5 for the investigation of nanomaterial biodistribution in vivo with nuclear and optical imaging, which were then used as the model CNC and lignin nanosystems in the cell viability assay comparison. CellTiter‐Glo® based on the detection of ATP‐dependent luminescence in viable cells revealed to be the best assay for both nanoconstructs for its robust linear response to increasing NP concentration and lack of interference from either of the NP types. Both multimodal CNC and lignin NPs displayed low cytotoxicity and favorable interactions with the cell lines, suggesting that they are good candidates for nanosystem development for targeted drug delivery in breast cancer and for theranostic applications. Our results provide useful guidance for cell viability assay compatibility for CNC and lignin NPs and facilitate the future translation of the materials for in vivo applications.

Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture ispartof: International Journal Of Molecular Sciences vol:23 issue:3 ispartof: location:Switzerland status: published

Up-Conversion materials have received great attention in drug delivery applications in recent years. A specifically emerging field includes the development of strategies focusing on photon processes that promote the development of novel platforms for the efficient transport and the controlled release of drug molecules in the harsh microenvironment. Here, modified reaction time, thermal treatment, and pH conditions were controlled in the synthesis of NaYF4:Yb,Tm up-converted (UC) material to improve its photoluminescence properties. The best blue-emission performance was achieved for the UC3 sample prepared through 24 h-synthesis without thermal treatment at a pH of 5, which promotes the presence of the β-phase and smaller particle size. NaYF4:Yb,Tm has resulted in a highly efficient blue emitter material for light-driven drug release under near-IR wavelength. Thus, NaYF4:Yb,Tm up-converted material promotes the N-O bond cleavage of the oxime ester of Ciprofloxacin (prodrug) as a highly efficient photosensitized drug delivery process. HPLC chromatography and transient absorption spectroscopy measurements were performed to evaluate the drug release conversion rate. UC3 has resulted in a very stable and easily recovered material that can be used in several reaction cycles. This straightforward methodology can be extended to other drugs containing photoactive chromophores and is present as an alternative for drug release systems.

Miniaturization is a key aspect of materials science. Owing to the increase in quality experimental and computational tools available to researchers, it has become clear that the crystal size and morphology of porous framework materials, including metal-organic frameworks and covalent organic frameworks, play a vital role in defining the physicochemical behaviour of these materials. However, given the multiscale and multidisciplinary challenges associated with establishing how crystal size and morphology affect the structure and behaviour of a material–from local to global structural modifications and from static to dynamic effects–a comprehensive mechanistic understanding of size and morphology effects is missing. Herein, we provide our perspective on the current state-of-the-art of this topic, drawn from various complementary disciplines. From a fundamental point of view, we discuss how controlling the crystal size and morphology can alter the mechanical and adsorption properties of porous framework materials and how this can impact phase stability. Special attention is also given to the quest to develop new computational tools capable of modelling these multiscale effects. From a more applied point of view, given the recent progress in this research field, we highlight the importance of crystal size and morphology control in drug delivery. Moreover, we provide an outlook on how to advance each discussed field by size and morphology control, which would open new design opportunities for functional porous framework materials.

Pectin has found extensive interest in biomedical applications, including wound dressing, drug delivery, and cancer targeting. However, the low viscosity of pectin solutions hinders their applications in 3D bioprinting. Here, we developed multicomponent bioinks prepared by combining pectin with TEMPO-oxidized cellulose nanofibers (TOCNFs) to optimize the inks’ printability while ensuring stability of the printed hydrogels and simultaneously print viable cell-laden inks. First, we screened several combinations of pectin (1%, 1.5%, 2%, and 2.5% w/v) and TOCNFs (0%, 0.5%, 1%, and 1.5% w/v) by testing their rheological properties and printability. Addition of TOCNFs allowed increasing the inks’ viscosity while maintaining shear thinning rheological response, and it allowed us to identify the optimal pectin concentration (2.5% w/v). We then selected the optimal TOCNFs concentration (1% w/v) by evaluating the viability of cells embedded in the ink and eventually optimized the writing speed to be used to print accurate 3D grid structures. Bioinks were prepared by embedding L929 fibroblast cells in the ink printed by optimized printing parameters. The printed scaffolds were stable in a physiological-like environment and characterized by an elastic modulus of E = 1.8 ± 0.2 kPa. Cells loaded in the ink and printed were viable (cell viability >80%) and their metabolic activity increased in time during the in vitro culture, showing the potential use of the developed bioinks for biofabrication and tissue engineering applications.

The inclusion of physiologically active molecules into a naturally occurring polymer matrix can improve the degradation, absorption, and release profile of the drug, thus boosting the therapeutic impact and potentially even reducing the frequency of administration. The human body produces significant amounts of polysaccharide hyaluronic acid, which boasts exceptional biocompatibility, biodegradability, and one-of-a-kind physicochemical features. In this review, we will examine the clinical trials currently utilizing hyaluronic acid and address the bright future of this versatile polymer, as well as summarize the numerous applications of hyaluronic acid in drug delivery and immunomodulation.

Peptide functionalized hyaluronic acid (HA CF) cross-linked by cucurbit[8]uril (CB[8]), a new class of drug-delivery reservoirs, is used to enable improved drug bioavailability for glioblastoma tumors in patient-derived xenograft (PDX) models. The mechanical and viscoelastic properties of native human and mouse tissues are measured over 8 h via oscillatory rheology under physiological conditions . Treatment with drug–loaded hydrogels allowed for a significant survival impact of 45 % (55.5–80.5 days). A relationship between the type of PDX tumor formed—a consequence of the heterogeneic nature of GB tumors—and changes in the initial survival is observed owing to greater local pressure from stiffer tumors. These biocompatible and tailorable materials warrant use as drug delivery reservoirs in PDX resection models, where the mechanical properties can be readily adjusted to match the stiffness of local tissue and thus have potential to improve the survival of GB patients.

Conventional bivalent IgG antibodies targeting a subgroup of receptors of the TNF superfamily (TNFSF) including fibroblast growth factor-inducible 14 (anti-Fn14) typically display no or only very limited agonistic activity on their own and can only trigger receptor signaling by crosslinking or when bound to Fcγ receptors (FcγR). Both result in proximity of multiple antibody-bound TNFRSF receptor (TNFR) molecules, which enables engagement of TNFR-associated signaling pathways. Here, we have linked anti-Fn14 antibodies to gold nanoparticles to mimic the “activating” effect of plasma membrane-presented FcγR-anchored anti-Fn14 antibodies. We functionalized gold nanoparticles with poly-ethylene glycol (PEG) linkers and then coupled antibodies to the PEG surface of the nanoparticles. We found that Fn14 binding of the anti-Fn14 antibodies PDL192 and 5B6 is preserved upon attachment to the nanoparticles. More importantly, the gold nanoparticle-presented anti-Fn14 antibody molecules displayed strong agonistic activity. Our results suggest that conjugation of monoclonal anti-TNFR antibodies to gold nanoparticles can be exploited to uncover their latent agonism, e.g., for immunotherapeutic applications.

One of the great advantages of electrospun fibers is the large tridimensional area produced, capable of storing any type of material. The aim of our investigation is to study the electrospinning technique to produce polymer membranes for drug delivery applications, given their large surface area and ability to transport a bioactive compound. A mathematical modeling of the delivery system kinetics was also studied to find the mechanism that controls the releasing process. Results showed that electrospinning could provide regular and smooth membranes suitable for drug delivery processes. The choice of a proper solvent for this process was an important parameter analyzed, because it determined whether fibers were capable of forming, as well as influencing fiber porosity. The mathematical modeling also proved that thicker PLLA membranes exhibited a Fickian diffusion behavior during the drug transport, presenting better control in drug delivery processes The authors are grateful to CAPES for financial support

Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage's minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells.

Mesoporous silicon (PSi) is biocompatible and tailorable material with high potential in drug delivery applications. Here, we report of an evaluation of PSi as a carrier platform for theranostics by delivering a radioactive ion beam- (RIB-) based radioactive lanthanoid into tumors in a mouse model of prostate carcinoma. Thermally hydrocarbonized porous silicon (THCPSi) wafers were implanted with 159Dy at the facility for radioactive ion beams ISOLDE located at CERN, and the resulting [159Dy]THCPSi was postprocessed into particles. The particles were intratumorally injected into mice bearing prostate cancer xenografts. The stability of the particles was studied in vivo, followed by ex vivo biodistribution and autoradiographic studies. We showed that the process of producing radionuclide-implanted PSi particles is feasible and that the [159Dy]THCPSi particles stay stable and local inside the tumor over seven days. Upon release of 159Dy from the particles, the main site of accumulation is in the skeleton, which is in agreement with previous studies on the biodistribution of dysprosium. We conclude that THCPSi particles are a suitable platform together with RIB-based radiolanthanoids for theranostic purposes as they are retained after administration inside the tumor and the radiolanthanoid remains embedded in the THCPSi.

Hyaluronic acid (HA) is commonly used through intra-articular administration for viscosupplementation in osteoarthritis and other disorders. HA is generally supplied as an injection commonly reported as painful, with strong limitations after treatment. In this study, an alternative delivery system was constructed based on HA hydrogel and poly(lactic-co-glycolic acid) (PLGA) particles with oleic acid. Development studies included the determination of particle toxicity, hemolytic activity, in vitro and in vivo anti-inflammatory activity using macrophages and a murine model, respectively. This study showed that empty PLGA particles presented a mean size of 373 nm, while particles containing HA and oleic acid showed a marked particle size increase. The HA association efficiency was of 73.6% and 86.2% for PLGA particles without and with oleic acid, respectively. The in vitro HA release from PLGA particles revealed a sustained profile. Particles showed a good in vitro cell compatibility and the risk of hemolysis was less < 1%, ensuring their safety. The in vivo anti-inflammatory study showed a higher inhibition for HA-loaded PLGA particles when compared to HA solution (78% versus 60%) and they were not different from the positive control, clearly suggesting that this formulation may be a promising alternative to the current HA commercial dosage form. iMed.ULisboa [UID/DTP/04138/2013] CESAM [UID/AMB/50017/2019] FCT/MEC through Portuguese funds FEDER, within the PT2020 Partnership Agreement Compete 2020

Current nanomedicine suffers from a big challenge due to the fact that most of the nanocarrier systems lack the desired tumor penetration depth, thereby limiting their clinical translation. Unlike the nanomaterials with a similar size or shape, microgels display excellent softness, fluidity and deformability, as well as stimuli-responsiveness in the tumor microenvironment. Herein, we report the synthesis of temperature-responsive poly(N-vinylcaprolactam)/oligo (ethylene glycol) acrylate/glycidyl methacrylate (PVCL/OEGA/GMA) microgels with different hydrodynamic radii (100-500 nm), crosslinking densities, 2-methoxyethyl acrylate (MEA) contents and OEGA chain lengths using a precipitation polymerization method and the investigation of the microgels in terms of their tumor penetration capability using a multicellular tumor spheroid (MCTS) model. The prepared microgels were well characterized with different techniques. We show that regardless of the size, crosslinking density, MEA content and OEGA chain length, all microgels display the desired cytocompatibility in the given concentration range. In vitro cellular uptake data reveal that similar to 2-dimensional (2-D) adherent cells, microgels with a smaller size display more enhanced cellular uptake than those having a larger size in the 3-D MCTS model. Likewise, 3-D MCTS penetration results indicate that the PVCL/OEGA/GMA microgels with the smallest radius of 100 nm exhibit the deepest penetration length. We then selected the microgels with a radius of 200 nm but with different physicochemical parameters to investigate their cellular uptake and tumor penetration behavior. Our data show that microgels with varying crosslinking densities, MEA contents and OEGA chain lengths do not have any appreciable changes in terms of their cellular uptake and penetration in the 3-D MCTS model. Our study provides new insights for the design of different microgel-based systems for further cancer theranostic applications.

We report the formation of polymeric and nanocomposite capsules via droplet solvent extraction, focusing on the interplay between solvent exchange and removal, demixing and directional solidification kinetics. We investigate a model system of sodium poly(styrene sulfonate), NaPSS and silica nanoparticles in aqueous solution, whose phase behaviour is experimentally measured, and examine a series of selective extraction solvents (toluene, butyl acetate, ethyl acetate and methyl ethyl ketone), ranging from 0.04 to 11% v/v water solubility. Tuning the rate of solvent exchange is shown to provide an effective means of decoupling demixing and solidification timescales, and thereby tunes the internal microstructure of the capsule, including hollow, microporous, core–shell, and bicontinuous morphologies. In turn, these determine the capsule dissolution mechanism and kinetics, ranging from single to pulsed release profiles of nanoparticle clusters (at intermediate solubilities), to minimal dissolution (at either extremes). These findings provide facile design and assembly strategies for functional capsules with time-varying release profiles.

Carbon nanomaterials are attractive candidates for drug delivery due to their high surface area, ease of functionalisation and biocompatibility. This work describes the spectroscopic monitoring of the loading capacity of oxidised carbon nanohorns for two cationic porphyrins. Addition of the COOH functionalised carbon nanohorns to both meso-tetra(4-N-methylpyridyl) free base (H2TMPyP4) and platinum (PtTMPyP4) porphyrin in aqueous solution results in hypochromism of the Soret band and quenching of the porphyrin emission. These changes are used to monitor the non-covalent binding interactions with the nanohorn surface and determine the surface loading. The colloidal stability of the nanohorns to biologically relevant solution environments as a function of loading is also reported. Finally, we demonstrate photoactivated cell death upon uptake of a colloidally stable PtTMPyP4 CNH hybrid.

The skin surface, our first barrier against the external environment, is covered by the sebum oil, a lipid film composed of sebaceous and epidermal lipids, which is important in the regulation of the hydration level of our skin. Here, we investigate the pathways leading to the transfer of epidermal lipids from the skin lipid bilayer to the sebum. We show that the sebum triglycerides, a major component of sebum, interact strongly with the epidermal lipids and extract them from the bilayer. Using microsecond time scale molecular dynamics simulations, we identify and quantify the free energy associated with the skin lipid extraction process.

The state-of-the-art sustained drug delivery systems are related to features to improve pharmacological transport through a controlled ratio between drug release and the desired therapeutic effect. Microspheres of biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), play an important role in these approaches, directing the release in a specific region of interest. In this way, the encapsulation of doxycycline (DOX) as a microbial agent turns the PLGA microspheres into a potential device for the treatment of topic oral diseases. Thus, this work aimed to produce DOX-loaded PLGA microspheres and see how they interfered with mesenchymal stem cell viability and in the sustained release in antimicrobial assays. Scanning electron microscopy showed the spherical microstructured pattern, revealing assorted sized distribution, with major diameters ranging 1–3 µm. The encapsulation efficiency presented a mean of 80% in both methods to obtain the microspheres (sonication and magnetic rotation). The DOX release test revealed a gradual and continuous profile of 30–40% between 120 and 168 h. Mesenchymal stem cells cultured in PLGA with or without DOX at several concentrations revealed no effect on the cell metabolic activity. Striking morphology changes were observed by confocal microscopy after 1 to 3 days under culture. The live/dead assay indicated that when microsphere densities were increased (from 10 to 100 µg/mL) cultured cells presented an internalized pattern of microspheres in both groups of PLGA containing DOX or not, while slight cell death signals were identified nearby microsphere clusters. Microbiological assays performed by the agar diffusion test pointed out that an inhibition zone was identified in Staphylococcus aureus (S. aureus) cultures at earlier times of DOX release. Despite the well-known use of PLGA as a drug delivery vehicle, when synthesized with DOX, it presents both characteristics of the desired treatment to prevent healthy tissue damage while avoiding bacterial growth in a microenvironment with anatomical features, such as grooves, projections, and other tough conditions that favor the development of oral diseases.

Dietary supplements have extreme importance. Due to the easily degradable nature of these supplements, the development and application of carrier systems in food technologies seem to be extremely important. Today, oral film technologies have gained importance due to their rapid and high absorption properties. This study chose silk fibroin (SF) as the main component due to its high biocompatibility. Turmeric extract has been added to the oral films as an active agent. The prepared films were analyzed with atomic force microscopy (AFM) and scanning electron microscopy (SEM) to reveal their morphological properties, and at the same time, the film thickness was measured. It has been found that the increase in extract amount is a factor that causes an increase in film roughness while causing a decrease in phase separation. It was observed that the film roughness increased twice with the addition of extract. The roughness of the films formed with 15% extract was measured as 28.5. The average roughness of the films formed without the use of extracts was observed as 15.7 mm. It was also observed that the Trolox equivalent antioxidant capacity (TEAC) was doubled for films containing 15% turmeric extract after one hour of release. The films exhibited different weight loss profiles after release as the amount of turmeric extract was changed. Disc diffusion experiments revealed that films containing turmeric extract exhibited antimicrobial effects.