Design of 3D Hybrid Plant Extract/Marine and Bovine Collagen Matrixes as Potential Dermal Scaffolds for Skin Wound Healing.

Tissue engineering involves the use of smart biomimetic hybrid matrices to reinforce the cellular interaction with the matrix and restore native properties after regeneration. In this study, we highlight the potential of 3D collagen sponges soaked with bioactive extract, to enhance the wound healing process in vivo. Acid-soluble collagen from two sources, marine and bovine, were extracted and characterized physiochemically using Fourier transform infrared spectroscopy (FTIR) and SDS-PAGE. Our results confirmed that the extracted collagens were mainly composed of collagen type I with slight molecular structure differences. Both collagens present two different α chains (α1 and α2) and one ß chain. Highly interconnected 3D scaffolds from collagen from the skin are designed and added by the widely known healing plants Pistacia lentiscus and Calendula officinalis. The resulting 3D collagen matrices possess fine biocompatibility with skin cells, Hacat (keratinocytes), and 3T3-L1 (fibroblasts) cells. To evaluate the potential wound healing effect, a collagen sponge soaked with the bioactive extract was tested on BALB/c mice. Our findings confirmed that sponges significantly improve animal re-epithelialization by increasing wound closure. Consequently, spongy collagen scaffolds loaded with Pistacia lentiscus and Calendula officinalis could be used as potential wound dressing material.

Chitosan-coated ultrapure silicon nanoparticles produced by laser ablation: biomedical potential in nano-oncology as a tumor-targeting nanosystem.

Ultrapure silicon nanoparticles (SiNPs) produced by femtosecond laser ablation in water have attracted great interest in the area of cancer therapy as they are efficient as photosensitizers in photodynamic therapy modality and can induce cell hyperthermia under radiofrequency radiation. Recently, we showed that these biocompatible nanoparticles were not able to reach tumors after intravenous injection in mice due to their rapid clearance from the bloodstream. In order to increase their half-life time and therefore their chances to reach and accumulate in tumors by an enhanced permeation retention (EPR) effect, a capping agent on SiNP surface acting as a colloidal stabilizer suspension is required. In this regard, this work focuses for the first time on the functionalization of SiNPs through the modification of their surface by chitosan (SiNPs-CH) in order to enhance their therapeutic properties in cancer therapy. Here, in vivo experiments were carried out during 15 days on nude mice developing a subcutaneously grafted malignant human brain tumor (glioblastoma). The characterization of SiNPs-CH showed an average hydrodynamic size of around 142 ± 65 nm as well as a relatively neutral charge (-5.2 mV) leading to a high colloidal suspension stability. The point of our work concerns the improvement of the biodistribution of SiNPs-CH with regard to tumors, the bloodstream, and organs. After the intravenous administration of 20 mg kg-1, all the studied parameters (animal behavior, organs' morphology, and histopathology) were in accord with the absence of toxicity due to SiNPs-CH, confirming their biocompatibility and even size and surface charge were modified compared to bare nanoparticles. Moreover an increased time in the bloodstream circulation of up to 7 days was observed, indicating the stealth of the nanoparticles, which could escape opsonization and premature elimination by macrophages and the reticuloendothelial system. As evidenced by silicon assessment, the interaction of the SiNPs-CH with the liver and spleen was significantly reduced compared to the bare nanoparticles. At the same time, SiNPs-CH were concentrated progressively in tumors from 12.03% after 1 day up to 39.55% after 7 days, confirming their uptake by the tumor microenvironment through the enhanced permeability retention effect. Subsequently, the silicon level declined progressively down to 33.6% after 15 days, evidencing the degradation of pH-sensitive SiNPs-CH under the acidic tumor microenvironment. Taken together, the stealthy SiNPs-CH exhibited an ideal biodistribution profile within the tumor microenvironment with a sustainable biodegradation and elimination profile, indicating their promising application in the nano-oncology field as a tumor-targeting system.

Titanate nanotubes as an efficient oral detoxifying agent against drug overdose: application in rat acetaminophen poisoning.

Voluntary drug intoxication is mainly due to drug overdose or the interaction of several drugs. Coma and its associated complications such as hypoventilation, aspiration pneumopathy, and heart rhythm disorders are the main hallmarks of drug intoxication. Conventional detoxification treatments, including gastric lavage or vomiting, administration of ipecac or activated charcoal (CH), and the use of antidotes, have proven to be inefficient and are generally associated with severe adverse effects. To overcome these limitations, titanate nanotubes (TiNTs) are proposed as an efficient emerging detoxifying agent because of their tubular shape and high adsorption capacity. In the present study, the detoxifying ability of TiNTs was evaluated on paracetamol (PR)-intoxicated rats. Results indicate that the loading ability of PR into TiNTs (70%) was significantly higher than that recorded for CH (38.6%). In simulated intestinal medium, TiNTs showed a controlled drug release of less than 10% after 72 h of incubation. In PR-intoxicated rats, TiNTs treatment resulted in a 64% decrease of PR after 4 h of poisoning versus 40% for CH. Concomitantly, TiNTs efficiently reduced PR absorption by 90% after 24 h of poisoning, attenuated the elevated levels of biochemical markers (i.e., alanine aminotransferase, aspartate aminotransferase, creatinine, and TNF-α) and mitigated oxidative stress by increasing the activity of superoxide dismutase and reducing the oxidized glutathione/total glutathione ratio, suggesting a histoprotective effect of TiNTs against paracetamol-induced toxicity in rats. In addition to their safety and high stability in the entire gastro-intestinal tract, biodistribution analysis revealed that TiNTs exhibited low intestinal absorption owing to their large cluster size of compact aggregate nanomaterials across the intestinal villi hindering the absorption of paracetamol. Collectively, these data provide a new and promising solution for in vivo detoxification. TiNTs are expected to have great potential for the treatment of voluntary and accidental intoxication in emergency care.

Thymoquinone-loaded lipid nanocapsules with promising anticancer activity for colorectal cancer.

Colorectal cancer (CRC) is the third most common worldwide. Depending on its stage, chemotherapy is usually given after surgery when CRC has already metastasized to other organs like the liver or lungs. Unfortunately, the current antineoplastics used for CRC therapies involve toxicity and side effects due to their lack of site-specificity. To overcome the drawbacks of heavy chemotherapy, this study proposes to assess the efficacy of thymoquinone (TQ), a bioactive constituent of black seeds (Nigella sativa), as an antiproliferative and pro-apoptotic agent on an experimental CRC model in mice. TQ was encapsulated in lipid nanocapsules (LNCs), used as nanocarriers, in order to increase its specificity and cell absorption. TQ-loaded LNCs (TQ-LNCs) have a diameter of 58.3 ± 3.7 nm and 87.7 ± 4.5% TQ encapsulation efficiency. In turn, in vivo studies showed that the intratumoral administration of TQ-LNCs decreased the tumor size in colorectal cancer bearing mice compared to the control group. TQ-LNCs were more effective than free TQ for inducing tumor cell death. These results highlight the potential of TQ entrapped in LNCs as an anticancer agent for CRC treatment.

Enhancement of the In Vitro Antitumor Effects of Berberine Chloride When Encapsulated within Small Extracellular Vesicles.

Berberine hydrochloride (BRB) is an isoquinoline alkaloid with promising anticancer efficacies. However, application of BRB had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism. The present study takes advantage of small extracellular vesicles (sEVs) to increase both stability and efficacy of BRB. sEVs from immature dendritic cells were produced and loaded with BRB. Proliferation, migration and Matrigel assay were performed, cycle arrest and nitric oxide (NO) production were evaluated in human breast cancer cell line (MDA-MB-231) and human umbilical vein endothelial cells (HUVECs). sEVs loaded with BRB formed a stable and homogenous population with a drug entrapment efficiency near to 42%. BRB loaded into sEVs was more potent than free BRB for MDA-MB-231 and endothelial proliferation, migration, and capillary-like formation in HUVECs. The mechanisms involved a blockade of cell cycle in G0/G1 phase, increased S phase and decreased of G2/M in MDA-MB-231 and HUVECs, and inhibition of NO production in HUVECs. Altogether, sEV-loaded BRB displayed higher effects than free BRB on different steps leading to its antitumor activity and anti-angiogenic properties in vitro. Thus, sEV formulation may be considered as an innovative approach and promising delivery of BRB to prevent tumorigenesis and angiogenesis.

Flumequine-loaded titanate nanotubes as antibacterial agents for aquaculture farms.

Flumequine (FLUM), a quinolone-derived antibiotic is one of the most prescribed drugs in aquaculture farms. However, its intensive use becomes worrisome because of its environmental risks and the emergence of FLUM-resistant bacteria. To overcome these problems we propose in this study the encapsulation and the delivery of FLUM by titanate nanotubes (TiNTs). Optimal FLUM loading was reached by suspending the dehydrated powder nanomaterials (FLUM : TiNTs ratio = 1 : 5) in ethanol. The drug entrapment efficiency was calculated to be 80% approximately with a sustained release in PBS at 37 °C up to 5 days. Then FLUM@TiNTs was evaluated for both its in vitro drug release and antimicrobial activity against Escherichia coli (E. coli). Spectacularly high antibacterial activity compared to those of free FLUM antibiotic was obtained confirming the efficiency of TiNTs to protect FLUM from rapid degradation and transformation within bacteria improving thereby its antibacterial effect. Indeed FLUM@TiNTs was efficient to decrease gradually the bacterial viability to reach ≈5% after 5 days versus ≈75% with free FLUM. Finally, the ex vivo permeation experiments on sea bass (Dicentrachus labrax) intestine shows that TiNTs act to increase the intestinal permeation of FLUM during the experiment. Indeed the encapsulated FLUM flux increased 12 fold (1.46 µg cm2 h-1) compared to the free antibiotic (0.18 µg cm2 h-1). Thanks to its physical properties (diameter 10 nm, tubular shape…) and its high stability in the simulated intestinal medium, TiNTs are easy internalized by enterocytes, thus involving an endocytosis mechanism, and then improve intestinal permeation of FLUM. Taken together, FLUM@TiNTs hold potential as an effective approach for enhancing the antimicrobial activity of FLUM and pave the way not only for future pharmacokinetic studies in the treatment and targeting of fish infections but also for instating of novel strategies that overcome the challenges associated with the abusive use of antibiotics in fish farming.

Tannic Acid, A Hydrolysable Tannin, Prevents Transforming Growth Factor-ß-Induced Epithelial-Mesenchymal Transition to Counteract Colorectal Tumor Growth.

Despite the medico-surgical progress that has been made in the management of patients with colorectal cancer (CRC), the prognosis at five years remains poor. This resistance of cancer cells partly results from their phenotypic characteristics in connection with the epithelial-mesenchymal transition (EMT). In the present study, we have explored the ability of a polyphenol, tannic acid (TA), to counteract CRC cell proliferation and invasion through an action on the EMT. We highlight that TA decreases human SW480 and SW620 CRC cell and murine CT26 CRC cell viability, and TA inhibits their adhesion in the presence of important factors comprising the extracellular matrix, particularly in the presence of collagen type I and IV, and fibronectin. Moreover, these properties were associated with TA's ability to disrupt CRC cell migration and invasion, which are induced by transforming growth factor-ß (TGF-ß), as evidence in the video microscopy experiments showing that TA blocks the TGF-ß1-induced migration of SW480 and CT26 cells. At the molecular level, TA promotes a reversal of the epithelial-mesenchymal transition by repressing the mesenchymal markers (i.e., Slug, Snail, ZEB1, and N-cadherin) and re-expressing the epithelial markers (i.e., E-cadherin and ß-catenin). These effects could result from a disruption of the non-canonical signaling pathway that is induced by TGF-ß1, where TA strongly decreases the phosphorylation of extracellular-signal regulated kinase ERK1/2, P38 and the AKT proteins that are well known to contribute to the EMT, the cell motility, and the acquisition of invasive properties by tumor cells. Very interestingly, a preclinical study of mice with subcutaneous murine tumor colon CT26 cells has shown that TA was able to significantly delay the growth of tumors without hepato- and nephrotoxicities.