Engineered microparticles based on drug–polymer coprecipitates for ocular-controlled delivery of Ciprofloxacin: influence of technological parameters

Abstract

Ciprofloxacin is a drug active against a broad spectrum of aerobic Gram-positive and Gram-negative bacteria, for the therapy of ocular infections. It requires frequent administrations owing to rapid ocular clearance and it is a good candidate for ocular controlled release formulations. The preparation of such drug release systems is still a challenge. Ionic interactions between ciprofloxacin and the polyelectrolytes chondroitin sulfate or lambda carrageenan result in coprecipitates that can act as microparticulate controlled release systems from which the drug is released after being displaced by the medium’s ions. In some formulations, Carbopol was added to improve the mucoadhesive properties. The aim of this research was the study of the influence of the technological parameters of the preparation method of coprecipitates on their particle size, with the goal of achieving particles engineered with a size suitable for the ocular administration. Technological parameters taken into account were: concentration of drug and polymer solutions utilized for the preparation of interaction products, possible use of surfactants (kind and concentration), temperature of the solutions and stirring during the process of preparation of the coprecipitates. Preliminary stability study tests were carried out to further characterize the leader formulation. Particle size in suspensions for ocular drug delivery is a critical parameter influencing the quality of the formulation. The results obtained from this study show that chondroitin sulfate coprecipitates present the best characteristics in terms of particle size suitable for ocular administration. A further improvement of the particle size characteristics has been obtained with the addition of surfactants.     

Interaction of Langmuir–Blodgett and spin-coated films of μ-carbido-bridged ironphthalocyanine with NO2: Optical and conductimetric behaviour

The present study investigates the interaction of NO₂ gas and μ-carbido-bridged iron phthalocyanine (PcFeCFePc) films obtained by Langmuir–Blodgett (LB) and spin-coating (SC) techniques. The phthalocyanine bridged dimer under study belongs to the polynuclear unsubstituted phthalocyanines class and presents poor solubility: in contrast the corresponding N-base bis-adducts are soluble enough in organic solvents to be deposited by Langmuir–Blodgett and spin-coating techniques. The reaction with NO₂ is monitored by visible spectra variation that shows identical behaviour for both kinds of films, indicating that the chemical reaction between the gas and the films is independent of the deposition method. The electrical conductivity change as a function of time with NO₂ is instead dissimilar: for spin-coated films it shows a behaviour already observed for sandwich-type phthalocyanine whereas for LB films it resembles that of monomeric phthalocyanine. Such a response implies that the charges (holes) generated in the oxidation/reduction process are carried differently through the material, and we attempt to explain this behaviour taking into account the two different structural and morphological features induced by the two techniques.     

Development and Comprehensive Characteristics of Thermosensitive Liquid Suppositories of Metoprolol Based on Poly(lactide-co-glycolide) Nanoparticles

Thermosensitive liquid suppositories (LSs) carrying the model antihypertensive drug metoprolol tartrate (MT) were developed and evaluated. The fundamental purpose of this work was to produce, for the first time, liquid MT suppositories based on biodegradable nanoparticles and optimize their rheological and mechanical properties for prospective rectal administration. The nanoparticle system was based on a biodegradable copolymer synthesized by ring opening polymerization (ROP) of glycolide (GL) and L,L-lactide (LLA). Biodegradable nanoparticles loaded with the model drug were produced by the o/o method at the first stage of the investigation. Depending on the concentration of the drug in the sample, from 66 to 91% of MT was released over 12 h, according to first-order kinetics. Then, thermosensitive LSs with MT-loaded biodegradable nanoparticles were obtained by a cold method and their mechanical and rheological properties were evaluated. To adjust the thermogelling and mucoadhesive properties for rectal administration, the amounts of major formulation components such as poloxamers (P407, P188), Tween 80, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), and sodium alginate were optimized. The in vitro release results revealed that more than 80% of the MT was released after 12 h, following also first-order kinetics. It was discovered that the diffusion process was dominant. The drug release profile was mainly governed by the rheological and mechanical properties of the developed formulation. Such a novel, thermosensitive formulation might be an effective alternative to hypertension treatment, particularly for unconscious patients, patients with mental illnesses, geriatric patients, and children.     

Recent Advances in Hydroxyapatite-Based Biocomposites for Bone Tissue Regeneration in Orthopedics

Bone tissue is a nanocomposite consisting of an organic and inorganic matrix, in which the collagen component and the mineral phase are organized into complex and porous structures. Hydroxyapatite (HA) is the most used ceramic biomaterial since it mimics the mineral composition of the bone in vertebrates. However, this biomimetic material has poor mechanical properties, such as low tensile and compressive strength, which make it not suitable for bone tissue engineering (BTE). For this reason, HA is often used in combination with different polymers and crosslinkers in the form of composites to improve their mechanical properties and the overall performance of the implantable biomaterials developed for orthopedic applications. This review summarizes recent advances in HA-based biocomposites for bone regeneration, addressing the most widely employed inorganic matrices, the natural and synthetic polymers used as reinforcing components, and the crosslinkers added to improve the mechanical properties of the scaffolds. Besides presenting the main physical and chemical methods in tissue engineering applications, this survey shows that HA biocomposites are generally biocompatible, as per most in vitro and in vivo studies involving animal models and that the results of clinical studies on humans sometimes remain controversial. We believe this review will be helpful as introductory information for scientists studying HA materials in the biomedical field.     

Whole Body Vibration Improves Brain and Musculoskeletal Health by Modulating the Expression of Tissue-Specific Markers: FNDC5 as a Key Regulator of Vibration Adaptations

Whole body vibration (WBV) is well known to exert beneficial effects on multiple tissues, improving synaptic transmission, muscle mass, bone quality, and reducing anxiety and depressive behavior. However, the underlying molecular mechanisms are not yet fully understood, and organs and tissues may respond differently to the vibratory stimulus depending on multiple factors. Therefore, we investigated the WBV effects on the brain and musculoskeletal tissue of 4-month-old young mice, evaluating synaptic plasticity by electrophysiological recordings and tissue organization by histology and histomorphometric analysis. Specifically, WBV protocols were characterized by the same vibration frequency (45 Hz), but different in vibration exposure time (five series of 3 min for the B protocol and three series of 2 min and 30 s for the C protocol) and recovery time between two vibration sessions (1 min for the B protocol and 2 min and 30 s for the C protocol). In addition, immunohistochemistry was conducted to evaluate the expression of fibronectin type III domain-containing protein 5 (FNDC5), as well as that of tissue-specific markers, such as brain-derived neurotrophic factor (BDNF) in brain, myostatin in muscle and collagen I (COL-1) in bone. Our results suggest that the WBV effects depend closely on the type of protocol used and support the hypothesis that different organs or tissues have different susceptibility to vibration. Further studies will be needed to deepen our knowledge of physiological adaptations to vibration and develop customized WBV protocols to improve and preserve cognitive and motor functions.     

S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway

Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between Notch overexpression and tumor metastasis. MicroRNAs (miRNAs) have been reported to cross-talk with Notch for its regulation. Therefore, restoring underexpressed miRNAs targeting Notch could represent an encouraging therapeutic approach against CRC. In this context, S-adenosyl-L-methionine (AdoMet), the universal biological methyl donor, being able to modulate the expression of oncogenic miRNAs could act as a potential antimetastatic agent. Here, we showed that AdoMet upregulated the onco-suppressor miRNAs-34a/-34c/-449a and inhibited HCT-116 and Caco-2 CRC cell migration. This effect was associated with reduced expression of migration-/EMT-related protein markers. We also found that, in colorectal and triple-negative breast cancer cells, AdoMet inhibited the expression of Notch gene, which, by luciferase assay, resulted the direct target of miRNAs-34a/-34c/-449a. Gain- and loss-of-function experiments with miRNAs mimics and inhibitors demonstrated that AdoMet exerted its inhibitory effects by upregulating miRNAs-34a/-34c/-449a. Overall, these data highlighted AdoMet as a novel Notch inhibitor and suggested that the antimetastatic effects of AdoMet involve the miRNA-mediated targeting of Notch signaling pathway.     

Derivation of imperfect interface models coupling damage and temperature

In this paper we introduce a model describing a layered structure composed by two thermoelastic adherents and a thin adhesive subject to a degradation process. By an asymptotic expansion method, we derive a model of imperfect interface coupling damage and temperature evolution. Moreover, assuming that the behaviour of the adhesive is ruled by two different regimes, one in traction and one in compression, we derive a second limit model where unilateral contact conditions on the interface are also included.     

Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant

mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.     

Early Osteogenic Marker Expression in hMSCs Cultured onto Acid Etching-Derived Micro- and Nanotopography 3D-Printed Titanium Surfaces

Polyetheretherketone (PEEK) titanium composite (PTC) is a novel interbody fusion device that combines a PEEK core with titanium alloy (Ti6Al4V) endplates. The present study aimed to investigate the in vitro biological reactivity of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) to micro- and nanotopographies produced by an acid-etching process on the surface of 3D-printed PTC endplates. Optical profilometer and scanning electron microscopy were used to assess the surface roughness and identify the nano-features of etched or unetched PTC endplates, respectively. The viability, morphology and the expression of specific osteogenic markers were examined after 7 days of culture in the seeded cells. Haralick texture analysis was carried out on the unseeded endplates to correlate surface texture features to the biological data. The acid-etching process modified the surface roughness of the 3D-printed PTC endplates, creating micro- and nano-scale structures that significantly contributed to sustaining the viability of hBM-MSCs and triggering the expression of early osteogenic markers, such as alkaline phosphatase activity and bone-ECM protein production. Finally, the topography of 3D-printed PTC endplates influenced Haralick’s features, which in turn correlated with the expression of two osteogenic markers, osteopontin and osteocalcin. Overall, these data demonstrate that the acid-etching process of PTC endplates created a favourable environment for osteogenic differentiation of hBM-MSCs and may potentially have clinical benefit.