Nifuroxazide-loaded cubosomes for pulmonary delivery attenuates bleomycin-induced lung fibrosis

By Sameh Saber, Mohamed Nasr, Simona Cavalu & al

This study highlights the importance of cubosomes as a drug delivery
system in enhancing the bioavailability of nifuroxazide (NXZD), a poorly soluble STAT3 inhibitor. NXZD loaded cubosomes (NXZD-LC) were in vitro and in vivo evaluated. In vitro, cubosomes presented a poly-angular
nanosized particles with a mean size and zeta potential of 223.73 ± 4.73 nm and 20.93 ± 2.38 mV, respectively. The entrapment efficiency of nifuroxazide was 90.56 ± 4.25%. The in vivo pharmacokinetic study and the
lung tissue accumulation of NXZD were performed by liquid chromatography-tandem mass spectrometry after oral administration to rats. The nanoparticles exhibited a two-fold increase and 1.33 times of bioavailability and lung tissue concentration of NXZD compared to NXZD dispersion, respectively. In view of this, NXZD-LC effectively
attenuated PF by targeting STAT3 and NF-κB signals. Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.

NXZD-loaded cubosomes; Mean plasma concentration-time profile (mean ± SD) after intra-gastric administration of NXZD suspension and
NXZD-loaded cubosomes. Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.
Effect of NXZD suspension and NXZD-loaded cubosomes on lung tissue histological features in intratracheal bleomycin-exposed rats. BLMC group exhibited a massive
inflammatory-cell infiltration (arrows), alveolar wall thickening (arrowhead), and the highest inflammation score. BLMC + NXZD showed moderate
inflammatory-cell infiltration (arrow) and alveolar wall thickening (arrowhead) and a non-significant difference in the inflammatory score compared with that of
BLMC group.Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.
Effect of NXZD suspension and NXZD-loaded cubosomes on lung tissue fibrotic changes in intratracheal bleomycin-exposed rats: significant decrease in the A% of
fibrosis compared with that of BLMC group.Copyright Sameh Saber, Mohamed Nasr,
Simona Cavalu & al.
Effect of NXZD suspension and NXZDloaded
cubosomes on the levels of LDH (a)
and BALF total protein (b) in intratracheal
bleomycin-exposed rats. Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.
Effect of NXZD suspension and NXZDloaded
cubosomes on MDA (a), NOx (b), GSH
(c) and SOD (d) in intratracheal bleomycinexposed
rats. Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.
Effect of NXZD suspension and NXZD-loaded cubosomes on COL1A1 mRNA expression (a), hydroxyproline (b) and ICAM-1 (c) in lung tissue in intratracheal
bleomycin-exposed rats. Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.
Effect of NXZD suspension and NXZD-loaded
cubosomes on TLR4 mRNA expression (a), TLR4 (b),
IL-6 (c), TNF-α (d) and MCP-1 (e) in lung tissue in
intratracheal bleomycin-exposed rats. Copyright Sameh Saber, Mohamed Nasr,
Simona Cavalu & al.
Effect of NXZD suspension and NXZDloaded
cubosomes on TGF-β1 mRNA expression
(a), TGF-β1 (b), PDGF-BB (c) and TIMP-1
(d) in intratracheal bleomycin-exposed rats. Copyright Sameh Saber, Mohamed Nasr,
Simona Cavalu & al.
Effect of NXZD suspension and NXZD-loaded cubosomes on NF-κB p65 DNA binding activity (a), STAT3 mRNA expression (b) and p-STAT3 (Tyr 705) (c) in
intratracheal bleomycin-exposed rats. Copyright Sameh Saber, Mohamed Nasr,
Simona Cavalu & al.

Nifuroxazide showed a potential anti-inflammatory effect, improved antioxidant defense, and suppressed fibrogenic mediators in the lung tissue. To conclude, cubosomes represent an advantageous pharmaceutical delivery system for enhancing pulmonary delivery of poorly soluble drugs. Additionally, since NXZD does induce cross-resistance to other antibacterial agents and does not adversely affect the physiological intestinal bacterial flora, repurposing NXZD as an antifibrotic agent is a promising challenge and new therapeutic approach for unmet therapeutic needs. Copyright Sameh Saber, Mohamed Nasr, Simona Cavalu & al.

Full text at

https://www.sciencedirect.com/science/article/pii/S0753332222001196

Novel Formulation Based on Chitosan-Arabic Gum Nanoparticles Entrapping Propolis Extract: Production, physico-chemical and structural characterization

By Simona Cavalu et al.

UV-Vis spectra of propolis extract and chitosan/Arabic gum
nanoparticles loaded with propolis. Copyright Simona Cavalu et al.
DLS analyses of colloidal chitosan/Arabic gum/propolis
mixture: a) Particle size distribution; b) Zeta potential. Copyright Simona Cavalu et al.
AFM images of chitosan/Arabic gum nanoparticles
entrapping propolis extract; a) 2D view; b) 3D topography; c)
Surface profile. Copyright Simona Cavalu et al.
AFM images of chitosan/Arabic gum nanoparticles
entrapping propolis extract; a) 2D view; b) 3D topography; c)
Surface profile. Copyright Simona Cavalu et al.
ATR FTIR spectra: a) raw propolis and powder chitosan/Arabic gum/propolis nanoparticles; b) powder chitosan and Arabic gum. Copyright Simona Cavalu et al.

Due to the limitation of chitosan in drug delivery systems, because of its hydrophilicity and solubility, chemical modification was performed in our study by combining with a second natural polymer, Arabic gum, in order to
improve the stability of nanoparticles. Copyright Simona Cavalu et al.

Morphological and structural characterization, using AFM, operating in tapping mode, along with the surface profile. Although the lateral dimensions are influenced by the shape of the probe, the height measurements can provide the height of nanoparticles with a high degree of accuracy and precision. However, larger particles are formed due to the aggregation during storage time. Copyright Simona Cavalu et al.

Structural characterization of polymeric powder
nanoparticles entrapping propolis was performed by ATR
FTIR spectroscopy, and compared with recorded spectrum of raw propolis, chitosan powder and Arabic gum as reference. In the same time, the
marker bands of propolis are well preserved in the polymeric mixture, indicating that the bioactive compounds are stable upon the encapsulation procedure. Copyright Simona Cavalu et al.

In this study we succeeded to prepare and characterize natural polymeric nanoparticles based on chitosan/Arabic gum, entrapping propolis extract. The physico-chemical properties of nanoparticles were assessed by UV-visible and FTIR spectroscopy, along with Dynamic Light Scattering, revealing that particle size obtained from highly dispersed mixture was in the range of 50-400 nm, with large Gaussian distribution, the maximum percentage of size distribution being at around 120 nm. In the same time,
an efficient encapsulation procedure was described using glutaraldehyde as cross-linking agent. The morpholological features of nanoparticles were emphasized by AFM microscopy, demonstrating a good correlation between
the results obtained by DLS technique. The FTIR analysis demonstrated that the marker bands of propolis are well preserved in the polymeric mixture, indicating that the bioactive compounds are stable upon the encapsulation
procedure. In our formulation, we consider that a balanced crosslinking toward electrostatic interaction was established. Propolis release from polymeric matrix was monitored in both simulated gastric acid and simulated intestinal fluids, concluding that our proposed formulation
is suitable for controlled release and pharmaceutical applications. Our results may provide a novel drug design, with improved bioavailability, stability and nutritional value of propolis bioactive compounds during processing and storage, with possible applications in food and nutraceutical industries. Copyright Simona Cavalu et al.

Full text at https://revistadechimie.ro/Articles.asp?ID=6836

Novel Hybrid Composites Based on PVA/SeTiO2 Nanoparticles and Natural Hydroxyapatite for Orthopedic Applications: Correlations between Structural, Morphological and Biocompatibility Properties

By Simona Cavalu et al.

The aim of our work was to develop and characterize a novel composition based on PVA reinforced with Se-doped TiO2 nanoparticles and natural hydroxyapatite (HA), for possible orthopedic applications. The PVA/Se-doped TiO2 composites with and without HA were structurally investigated by FTIR and XRD, in order to confirm the incorporation of the inorganic phase in the polymeric structure, and by SEM and XRF, to evidence the ultrastructural details and dispersion of nanoparticles in the PVA matrix. Both the mechanical and structural properties of the composites demonstrated a synergic reinforcing effect of HA and Se-doped TiO2 nanoparticles. Moreover, the tailorable properties of the composites were proved by the viability and differentiation potential of the bone marrow mesenchymal stem cells (BMMSC) to osteogenic, chondrogenic and adipogenic lineages. The novel hybrid PVA composites show suitable structural, mechanical and biological features to be considered as a promising biomaterial for articular cartilage and subchondral bone repair. (Copyright Simona Cavalu et al.)

SEM micrographs of hydroxyapatite (HA) crystals (a) and Se-doped TiO2 nanoparticles obtained from a TiO2 precursor calcinated at 400 (c), 600 (d) and 800 °C (e) along with the corresponding EDX spectra (b,f).
XRD pattern of precursor TiO2 particles calcinated at different temperatures (400 °C, 600 °C and 800 °C) (a) and corresponding Se-doped TiO2 particles (b). The symbols are: A—anatase, R—rutile, Se—elemental selenium, T—reduced titanate. Copyright Simona Cavalu et al.
Photographic images of poly(vinyl alcohol)/Se-doped TiO2 composites with and without HA and the reference PVA specimen (10%). The inset images present the powder of Se-doped TiO2 particles prepared from TiO2 precursor after calcination at 400, 600 and 800 °C, respectively. Copyright Simona Cavalu et al.
FTIR spectra of PVA/Se-doped TiO2 composites (a) and PVA/HA/Se-doped TiO2 composites (b). Copyright Simona Cavalu et al.
XRD patterns of PVA composites: (a) PVA-based composites with Se-doped TiO2 particles incorporated; (b) PVA-based composites with HA and Se-doped TiO2 particles incorporated. Copyright Simona Cavalu et al.
SEM images (cross section) of the PVA composites reinforced with Se-doped TiO2 nanoparticles and HA, with different details: (a) PVA 10%; (b,c) PVA HA; (d) PVA 400; (e,f) PVA 400HA; (g) PVA 600; (h,i) PVA 600HA; (j) PVA 800; (k,l) PVA 800HA.
Copyright Simona Cavalu et al.
Load–displacement curves recorded for the PVA samples with (right) and without (left) HA. Copyright Simona Cavalu et al.
Differentiation potential of bone marrow mesenchymal stem cells (BMMSCs) to adipogenic, osteogenic and chondrogenic lineages, after 72 h incubation time, in the presence of PVA-based composites. Copyright Simona Cavalu et al.
MTT assay of BMMSCs after 72 h incubation with PVA-based composites.
Copyright Simona Cavalu et al.

In our paper, Se-doped TiO2 nanoparticles were used as nanofiller, with the main goal of possible multiple advantages, such as osteogenic, anticancer and antimicrobial properties.We succeeded in preparing Se-doped TiO2 nanoparticles via a hydrothermal reaction, characterized by XRD and SEM, emphasizing their morphology and crystallinity. Depending on the calcination temperature of the TiO2 precursor, the morphology of the nanoparticles turns from nanorods to nanowires, while Se nanoparticles preserve their spherical shape.The morphology of the composites evidenced a good dispersion of both Se-doped TiO2 and HA particles within the polymeric hydrogel, resulting in a reinforced fibrous structure. Se-doped TiO2 nanoparticles were deeply embedded in the polymeric network, while the larger HA particles filled the porous architecture. It is obvious that the presence of HA particles influences the porosity of the PVA matrix. As an overall behavior, it seems that all the composites show better performance for the osteogenic and chondrogenic differentiation rather than for the adipogenic one. BMMSCs had fibroblast-like morphologies, maintaining their normal spindle shape in the early passages, while at later passages, exhibiting less concordant cell morphologies, with some cells characterized by an irregular flattened geometry and enlarged size. Particularly, the chondrogenic stimulation exhibited a distinct extracellular cartilage matrix stained with Alcian Blue (Sigma-Aldrich). At the same time, for osteogenic differentiation, Alizarin (Sigma-Aldrich) staining showed the formation of calcium oxalates on the differentiated BMMSCs, which was not observed in the undifferentiated cells. Intracellular lipid droplets staining using Oil Red-O (Sigma-Aldrich) proved the adipogenesis of BMSCs. Comparing the results obtained for different composites, it seems that PVA800 with or without HA shows the lowest differentiation potential in terms of adipogenic, osteogenic and chondrogenic stimulation. (Copyright Simona Cavalu et al.).

Full text at https://www.mdpi.com/1996-1944/13/9/2077/htm

Nanoparticles and Nanostructured Surface Fabrication for Innovative Cranial and Maxillofacial Surgery

By Simona Cavalu et al.

Titanium cranioplasty procedure in the case of a large defect. Copyright Simona Cavalu et al.

The Importance of Nano-Structured Surface on Titanium Implants. Titanium mesh or plates can be used in cranioplasty either alone or in conjunction with other synthetic materials, such as hydroxyapatite, calcium phosphate, and polyethylene.

Light microscopy image in phase contrast, longitudinal section, 500×, Kroll reagent; (b) Scanning Electron Microscopy 2000×; (c,d) 3D and 2D Atomic Force Microscopy images; (e) contact angle investigation on the surface of the titanium mesh. Copyright Simona Cavalu et al.
Surface properties of Ti mesh for cranioplasty evidenced by different microscopic techniques. Copyright Simona Cavalu et al.
The main sequence of events occurring in vivo, during interaction between Ti surface and biological environment. Copyright Simona Cavalu et al.
(a) The flow chart of SeNPs production via hydrothermal reaction using different saccharides as reducing agent; (b) TEM image of SeNPs used for the surface modifications of Ti mesh for cranioplasty, along with the surface morphology of the coating upon in situ SeNPs deposition and details of fibroblasts adhesion on the nanostructured Ti surface.
Copyright Simona Cavalu et al.

This review emphasized the main reasons why titanium mesh is preferred for skull reconstructions along with the importance of developing innovative surface structures with a dual benefit in terms of improved osteointegration and enhanced antibacterial activity to reduce the risk of post-surgical infection, knowing that infections are the main complication in cranioplasty surgeries.

The full text of this paper

https://www.mdpi.com/1996-1944/13/23/5391/htm