Poly(ethylene glycol) Methyl Ether Acrylate-Grafted Chitosan-Based Micro- and Nanoparticles as a Drug Delivery System for Antibiotics.

Nanotechnology is the science of creating materials at the nanoscale by using various devices, structures, and systems that are often inspired by nature. Micro- and nanoparticles (MPs, NPs) are examples of such materials that have unique properties and can be used as carriers for delivering drugs for different biomedical applications. Chitosan (CS) is a natural polysaccharide that has been widely studied, but it has a problem with low water solubility at neutral or basic pH, which limits its processability. The goal of this work was to use a chemically modified CS with poly(ethylene glycol) methyl ether acrylate (PEGA) to prepare CS micronic and submicronic particles (MPs/NPs) that can deliver different types of antibiotics, respectively, levofloxacin (LEV) and Ciprofloxacin (CIP). The particle preparation procedure employed a double crosslinking method, ionic followed by a covalent, in a water/oil emulsion. The studied process parameters were the precursor concentration, stirring speeds, and amount of ionic crosslinking agent. MPs/NPs were characterized by FT-IR, SEM, light scattering granulometry, and Zeta potential. MPs/NPs were also tested for their water uptake capacity in acidic and neutral pH conditions, and the results showed that they had a pH-dependent behavior. The MPs/NPs were then used to encapsulate two separate drugs, LEV and CIP, and they showed excellent drug loading and release capacity. The MPs/NPs were also found to be safe for cells and blood, which demonstrated their potential as suitable drug delivery systems for biomedical applications.

Magnetic Nanoparticle Coating Decreases the Senescence and Increases the Targeting Potential of Fibroblasts and Adipose-Derived Mesenchymal Stem Cells.

Magnetic nanoparticles (MNPs) are intensely scrutinized for applications in emerging biomedical fields. Their potential use for drug delivery, tracking, and targeting agents or for cell handling is tested for regenerative medicine and tissue engineering applications. The large majority of MNPs tested for biomedical use are coated with different lipids and natural or synthetic polymers in order to decrease their degradation process and to increase the ability to transport drugs or bioactive molecules. Our previous studies highlighted the fact that the as-prepared MNP-loaded cells can display increased resistance to culture-induced senescence as well as ability to target pathological tissues; however, this effect tends to be dependent on the cell type. Here, we assessed comparatively the effect of two types of commonly used lipid coatings, oleic acid (OA) and palmitic acid (PA), on normal human dermal fibroblasts and adipose-derived mesenchymal cells with culture-induced senescence and cell motility in vitro. OA and PA coatings improved MNPs stability and dispersibility. We found good viability for cells loaded with all types of MNPs; however, a significant increase was obtained with the as-prepared MNPs and OA-MNPs. The coating decreases iron uptake in both cell types. Fibroblasts (Fb) integrate MNPs at a slower rate compared to adipose-derived mesenchymal stem cells (ADSCs). The as-prepared MNPs induced a significant decrease in beta-galactosidase (B-Gal) activity with a nonsignificant one observed for OA-MNPs and PA-MNPs in ADSCs and Fb. The as-prepared MNPs significantly decrease senescence-associated B-Gal enzymatic activity in ADSCs but not in Fb. Remarkably, a significant increase in cell mobility could be detected in ADSCs loaded with OA-MNPscompared to controls. The OA-MNPs uptake significantly increases ADSCs mobility in a wound healing model in vitro compared to nonloaded counterparts, while these observations need to be validated in vivo. The present findings provide evidence that support applications of OA-MNPs in wound healing and cell therapy involving reparative processes as well as organ and tissue targeting.

Chitosan Grafted Poly (Ethylene Glycol) Methyl Ether Acrylate Particulate Hydrogels for Drug Delivery Applications.

Chitosan (CS) crosslinking has been thoroughly investigated, but the chemical reactions leading to submicronic hydrogel formulations pose problems due to various physical/chemical interactions that limit chitosan processability. The current study employs the chemical modification of chitosan by Michael addition of poly (ethylene glycol) methyl ether acrylate (PEGA) to the amine groups to further prepare chitosan particulate hydrogels (CPH). Thus, modified CS is subjected to a double crosslinking, ionic and covalent, in water/oil emulsion. The studied process parameters are polymer concentration, stirring speed, and quantity of ionic crosslinker. The CPH were structurally and morphologically characterized through infrared spectroscopy, scanning electron microscopy, light scattering granulometry, and zeta potential, showing that modified CS allows better control of dimensional properties and morphology as compared with neat CS. Swelling properties were studied in acidic and neutral pH conditions, showing that pH-dependent behavior was maintained after grafting and double crosslinking. The applicability of the prepared materials was further tested for drug loading and in vitro delivery of levofloxacin (LEV), showing excellent capacity. CPH were found to be cyto- and hemocompatible demonstrating their potential for effective use as a controlled release system for different biomedical applications.

Solid-Phase Synthesized Copolymers for the Assembly of pH-Sensitive Micelles Suitable for Drug Delivery Applications.

Diblock copolymers of polyhistidine are known for their self-assembly into micelles and their pH-dependent disassembly due to the amphiphilic character of the copolymer and the unsaturated imidazole groups that undergo a hydrophobic-to-hydrophilic transition in an acidic pH. This property has been largely utilized for the design of drug delivery systems that target a tumor environment possessing a slightly lower extracellular pH (6.8-7.2). The main purpose of this study was to investigate the possibility of designed poly(ethylene glycol)-polyhistidine sequences synthesized using solid-phase peptide synthesis (SPPS), to self-assemble into micelles, to assess the ability of the corresponding micelles to be loaded with doxorubicin (DOX), and to investigate the drug release profile at pH values similar to a malignant extracellular environment. The designed and assembled free and DOX-loaded micelles were characterized from a physico-chemical point of view, their cytotoxicity was evaluated on a human breast cancer cell line (MDA-MB-231), while the cellular areas where micelles disassembled and released DOX were assessed using immunofluorescence. We concluded that the utilization of SPPS for the synthesis of the polyhistidine diblock copolymers yielded sequences that behaved similarly to the copolymeric sequences synthesized using ring-opening polymerization, while the advantages of SPPS may offer facile tuning of the histidine site or the attachment of a large variety of functional molecules.

Conifer Essential Oils Reversed Amyloid Beta1-42 Action by Modulating BDNF and ARC Expression in The Rat Hippocampus.

BACKGROUND: The conifer species Pinus halepensis (Pinaceae) and Tetraclinis articulata (Cupressaceae) are widely used in traditional medicine due to their beneficial health properties. OBJECTIVE: This study aimed to investigate the mechanisms by which P. halepensis and T. articulata essential oils (1% and 3%) could exhibit neuroprotective effects in an Alzheimer's disease (AD) rat model, induced by intracerebroventricular (i.c.v.) administration of amyloid beta1-42 (Aß1-42). METHODS: The essential oils were administered by inhalation to the AD rat model, once daily, for 21 days. DNA fragmentation was assessed through a Cell Death Detection ELISA kit. Brainderived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (ARC), and interleukin-1ß (IL-1ß) gene expressions were determined by RT-qPCR analysis, while BDNF and ARC protein expressions were assessed using immunohistochemistry technique. RESULTS: Our data showed that both essential oils substantially attenuated memory impairments, with P. halepensis mainly stimulating ARC expression and T. articulata mostly enhancing BDNF expression. Also, the inhalation of essential oils reduced IL-1ß expression and induced positive effects against DNA fragmentation associated with Aß1-42-induced toxicity, further contributing to the cognitive improvement in the rats with the AD-like model Conclusion: Our findings provide further evidence that these essential oils and their chemical constituents could be natural agents of therapeutic interest against Aß1-42-induced neurotoxicity.

Exploring Hyperoxia Effects in Cancer-From Perioperative Clinical Data to Potential Molecular Mechanisms.

Increased inspiratory oxygen concentration is constantly used during the perioperative period of cancer patients to prevent the potential development of hypoxemia and to provide an adequate oxygen transport to the organs, tissues and cells. Although the primary tumours are surgically removed, the effects of perioperative hyperoxia exposure on distal micro-metastases and on circulating cancer cells can potentially play a role in cancer progression or recurrence. In clinical trials, hyperoxia seems to increase the rate of postoperative complications and, by delaying postoperative recovery, it can alter the return to intended oncological treatment. The effects of supplemental oxygen on the long-term mortality of surgical cancer patients offer, at this point, conflicting results. In experimental studies, hyperoxia effects on cancer biology were explored following multiple pathways. In cancer cell cultures and animal models, hyperoxia increases the production of reactive oxygen species (ROS) and increases the oxidative stress. These can be followed by the induction of the expression of Brain-derived neurotrophic factor (BDNF) and other molecules involved in angiogenesis and by the promotion of various degrees of epithelial mesenchymal transition (EMT).

NHF-derived carbon dots: prevalidation approach in breast cancer treatment.

Metastatic breast cancer dominates the female cancer-related mortality. Tumour-associated molecules represents a crucial for early disease detection and identification of novel therapeutic targets. Nanomaterial technologies provide promising novel approaches to disease diagnostics and therapeutics. In the present study we extend the investigations of antitumoral properties of Carbon Dots prepared from N-hydroxyphthalimide (CD-NHF) precursor. We evaluate the effect of CD-NHF on tumour cell migration and invasion in vitro and their impact on tumour progression using an in vivo model. Furthermore, we investigate the molecular mechanisms involved in CD-NHF antitumour effects. In vivo mammary tumours were induced in Balb/c female mice by injecting 4T1 cells into the mammary fat pad. Conditional treatment with CD-NHF significantly impair both migration and invasion of metastatic breast cancer cells. The presence of CD-NHF within the 3D cell cultures strongly inhibited the malignant phenotype of MDA-MB-231, 4T1 and MCF-7 cells in 3D culture, resulting in culture colonies lacking invasive projections and reduction of mammospheres formation. Importantly, breast tumour growth and metastasis dissemination was significantly reduced upon CD-NHF treatments in a syngeneic mouse model and is associated with down-regulation of Ki67 and HSP90 expression. CD-NHF nanostructures provide exciting perspective for improving treatment outcome in breast cancer.