Modification of mesenchymal stromal cells with silibinin-loaded PLGA nanoparticles improves their therapeutic efficacy for cutaneous wound repair.

The use of mesenchymal stromal cells (MSCs) for treating chronic inflammatory disorders, wounds, and ischemia-reperfusion injuries has shown improved healing efficacy. However, the poor survival rate of transplanted cells due to oxidative stress in injured or inflamed tissue remains a significant concern for MSC-based therapies. In this study, we developed a new approach to protect MSCs from oxidative stress, thereby improving their survival in a wound microenvironment and enhancing their therapeutic effect. We produced PLGA nanoparticles loaded with the cytoprotective phytochemical silibinin (SBN), and used them to modify MSCs. Upon internalization, these nanoformulations released SBN, activating the Nrf2/ARE signaling pathway, resulting in threefold reduction in intracellular ROS content and improved cell survival under oxidative stress conditions. Modification of MSCs with SBN-loaded PLGA nanoparticles increased their survival upon transplantation to full-thickness cutaneous wounds and improved wound healing. This study suggests that MSC modification with cytoprotective nanoparticles could be a promising approach for improving wound healing.

Methylene Blue-Loaded NanoMOFs: Accumulation in Chlamydia trachomatis Inclusions and Light/Dark Antibacterial Effects.

Metal-organic framework nanoparticles (nanoMOFs) are promising nanomaterials for biomedical applications. Some of them, including biodegradable porous iron carboxylates are proposed for encapsulation and delivery of antibiotics. Due to the high drug loading capacity and fast internalization kinetics, nanoMOFs are more beneficial for the treatment of intracellular bacterial infections compared to free antibacterial drugs, which poorly accumulate inside the cells because of the inability to cross membrane barriers or have low intracellular retention. However, nanoparticle internalization does not ensure their accumulation in the cell compartment that shelters a pathogen. This study shows the availability of MIL-100(Fe)-based MOF nanoparticles to co-localize with Chlamydia trachomatis, an obligate intracellular bacterium, in the infected RAW264.7 macrophages. Furthermore, nanoMOFs loaded with photosensitizer methylene blue (MB) exhibit complete photodynamic inactivation of C. trachomatis growth. Simultaneous infection and treatment of RAW264.7 cells with empty nanoMOFs resulted in a bacterial load reduction from 100 to 36% that indicates an intrinsic anti-chlamydial effect of this iron-containing nanomaterial. Thus, our findings suggest the use of iron-based nanoMOFs as a promising drug delivery platform, which contributes to antibacterial effect, for the treatment of chlamydial infections.

Metal-Organic Framework-Based Nanomedicines for the Treatment of Intracellular Bacterial Infections.

Metal-organic frameworks (MOFs) are a highly versatile class of ordered porous materials, which hold great promise for different biomedical applications, including antibacterial therapy. In light of the antibacterial effects, these nanomaterials can be attractive for several reasons. First, MOFs exhibit a high loading capacity for numerous antibacterial drugs, including antibiotics, photosensitizers, and/or photothermal molecules. The inherent micro- or meso-porosity of MOF structures enables their use as nanocarriers for simultaneous encapsulation of multiple drugs resulting in a combined therapeutic effect. In addition to being encapsulated into an MOF's pores, antibacterial agents can sometimes be directly incorporated into an MOF skeleton as organic linkers. Next, MOFs contain coordinated metal ions in their structure. Incorporation of Fe2/3+, Cu2+, Zn2+, Co2+, and Ag+ can significantly increase the innate cytotoxicity of these materials for bacteria and cause a synergistic effect. Finally, abundance of functional groups enables modifying the external surface of MOF particles with stealth coating and ligand moieties for improved drug delivery. To date, there are a number of MOF-based nanomedicines available for the treatment of bacterial infections. This review is focused on biomedical consideration of MOF nano-formulations designed for the therapy of intracellular infections such as Staphylococcus aureus, Mycobacterium tuberculosis, and Chlamydia trachomatis. Increasing knowledge about the ability of MOF nanoparticles to accumulate in a pathogen intracellular niche in the host cells provides an excellent opportunity to use MOF-based nanomedicines for the eradication of persistent infections. Here, we discuss advantages and current limitations of MOFs, their clinical significance, and their prospects for the treatment of the mentioned infections.

Tissue-Oxygen-Adaptation of Bone Marrow-Derived Mesenchymal Stromal Cells Enhances Their Immunomodulatory and Pro-Angiogenic Capacity, Resulting in Accelerated Healing of Chemical Burns.

Transplantation of mesenchymal stromal cells (MSCs) provides a powerful tool for the management of multiple tissue injuries. However, poor survival of exogenous cells at the site of injury is a major complication that impairs MSC therapeutic efficacy. It has been found that tissue-oxygen adaptation or hypoxic pre-conditioning of MSCs could improve the healing process. Here, we investigated the effect of low oxygen tension on the regenerative potential of bone-marrow MSCs. It turned out that incubation of MSCs under a 5% oxygen atmosphere resulted in increased proliferative activity and enhanced expression of multiple cytokines and growth factors. Conditioned growth medium from low-oxygen-adapted MSCs modulated the pro-inflammatory activity of LPS-activated macrophages and stimulated tube formation by endotheliocytes to a much higher extent than conditioned medium from MSCs cultured in a 21% oxygen atmosphere. Moreover, we examined the regenerative potential of tissue-oxygen-adapted and normoxic MSCs in an alkali-burn injury model on mice. It has been revealed that tissue-oxygen adaptation of MSCs accelerated wound re-epithelialization and improved the tissue histology of the healed wounds in comparison with normoxic MSC-treated and non-treated wounds. Overall, this study suggests that MSC adaptation to 'physiological hypoxia' could be a promising approach for facilitating skin injuries, including chemical burns.

Comparison of EMT-Related and Multi-Drug Resistant Gene Expression, Extracellular Matrix Production, and Drug Sensitivity in NSCLC Spheroids Generated by Scaffold-Free and Scaffold-Based Methods.

Multicellular 3D tumor models are becoming a powerful tool for testing of novel drug products and personalized anticancer therapy. Tumor spheroids, a commonly used 3D multicellular tumor model, more closely reproduce the tumor microenvironment than conventional 2D cell cultures. It should be noted that spheroids can be produced using different techniques, which can be subdivided into scaffold-free (SF) and scaffold-based (SB) methods. However, it remains unclear, to what extent spheroid properties depend on the method of their generation. In this study, we aimed to carry out a head-to-head comparison of drug sensitivity and molecular expression profile in SF and SB spheroids along with a monolayer (2D) cell culture. Here, we produced non-small cell lung cancer (NSCLC) spheroids based on human lung adenocarcinoma cell line A549. Drug sensitivity analysis of the tested cell cultures to five different chemotherapeutics resulted in IC50 (A549-SB) > IC50 (A549-SF) > IC50 (A549-2D) trend. It was found that SF and SB A549 spheroids displayed elevated expression levels of epithelial-to-mesenchymal transition (EMT) markers and proteins associated with drug resistance compared with the monolayer A549 cell culture. Enhanced drug resistance of A549-SB spheroids can be a result of larger diameters and elevated deposition of extracellular matrix (ECM) that impairs drug penetration into spheroids. Thus, the choice of the spheroid production method can influence the properties of the generated 3D cell culture and their drug resistance. This fact should be considered for correct interpretation of drug testing results.

Surface modification of fibroblasts with peroxiredoxin-1-loaded polymeric microparticles increases cell mobility, resistance to oxidative stress and collagen I production.

Modification of the cell surface with artificial nano- and microparticles (also termed "cellular backpacks") containing biologically active payloads usually enables drug targeting via harnessing intrinsic cell tropism to the sites of injury. In some cases, using cells as delivery vehicles leads to improved pharmacokinetics due to extended circulation time of cell-immobilized formulations. Another rationale for particle attachment to cells is augmentation of desirable cellular functions and cell proliferation in response to release of the particle contents. In this study, we conjugated poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with multifunctional antioxidant enzyme peroxiredoxin-1 (Prx1) to the surface of fibroblasts. The obtained microparticles were uniform in size and demonstrated sustained protein release. We found that the released Prx1 maintains its signaling activity resulting in macrophage activation, as indicated by TNFα upregulation and increase in ROS generation. Functionalization of fibroblasts with PLGA/Prx1 microparticles via EDC/sulfo-NHS coupling reaction did not affect cell viability but increased cell migratory properties and collagen I production. Moreover, PLGA/Prx1 backpacks increased resistance of fibroblasts to oxidative stress and attenuated cell senescence. In summary, we have developed a novel approach of fibroblast modification to augment their biological properties, which can be desirable for wound repair, cosmetic dermatology, and tissue engineering.

Efficient degradation of 2,4-dichlorophenol in aqueous solution by peroxymonosulfate activated with magnetic spinel FeCo2O4 nanoparticles.

Magnetic spinel FeCo2O4 nanoparticles (NPs) were synthesized and proposed as a catalyst of peroxymonosulfate (PMS) for the degradation of 2,4-dichlorophenol (2,4-DCP). The catalyst was characterized by XRD, TEM, XPS, nitrogen adsorption-desorption isotherms, and magnetization curve. In addition, the effects of parameters, such as initial pH, PMS dosage, FeCo2O4 addition, and initial concentration of 2,4-DCP were studied. The results showed that FeCo2O4 NPs exhibit good properties for the degradation and mineralization of 2,4-DCP, achieving 95.8% and 44.7% removal of 2,4-DCP and TOC, respectively, within 90 min under reaction conditions of 4 mM PMS, 0.06 g L-1 FeCo2O4, 100 mg L-1 2,4-DCP, pH = 7.0, and T = 30 °C. Furthermore, SO4- and HO were main radical species in the reaction system was explored. The 2,4-DCP degradation efficiency could reach 91.8% even after FeCo2O4 NPs were used for the fifth run. Moreover, the degradation efficiencies of metronidazole (MNZ), methylene blue (MB), and rhodamine B (RhB) could reach 74.8%, 86.7%, and 96.1% under the same reaction conditions, respectively. Results revealed that the FeCo2O4/PMS system shows potential for degrading contaminants in the environment.