Fabrication and characterization of metformin-loaded PLGA/Collagen nanofibers for modulation of macrophage polarization for tissue engineering and regenerative medicine.

In tissue engineering (TE) and regenerative medicine, the accessibility of engineered scaffolds that modulate inflammatory states is extremely necessary. The aim of the current work was to assess the efficacy of metformin (MET) incorporated in PLGA/Collagen nanofibers (Met-PLGA/Col NFs) to modulate RAW264.7 macrophage phenotype from pro-inflammatory status (M1) to anti-inflammatory status (M2). Given this, MET-PLGA/Col NFs were fabricated using an electrospinning technique. Structural characterization such as morphology, chemical and mechanical properties, and drug discharge pattern were assessed. MTT assay test exposed that MET-PLGA/Col NFs remarkably had increased cell survival in comparison with pure PLGA/Collagen NFs and control (p < 0.05) 72 h after incubation. Based on the qPCR assay, a reduction in the expression of iNOS-2 and SOCS3 was found in the cells seeded on MET-PLGA/Col NFs, demonstrating the substantial modulation of the M1 phenotype to the M2 phenotype. Moreover, it was determined a main decrease in the pro-inflammatory cytokines and mediator's expression but the growth factors amount related to anti-inflammatory M2 were meaningfully upregulated. Finally, MET-PLGA/Col NFs possibly will ensure a beneficial potential for effective variation of the macrophage response from an inflammatory phase (M1) to a pro-regenerative (M2) phase.

Oral targeted delivery of Imatinib by pH responsive copolymer modulates liver fibrosis in the mice model.

Liver fibrosis is a significant cause of morbidity and mortality without approved treatment. The therapeutic effects of Imatinib as a tyrosine kinase inhibitor on reversing liver fibrosis have already been shown. However, considering the conventional route of Imatinib administration, the amount of drug to be used is very high, and its side effects are raised. Therefore, we designed an efficient pH-sensitive polymer for the targeted delivery of Imatinib in treating a carbon tetrachloride (CCl4)-induced liver fibrosis. This nanotherapeutic system-based Vitamin A (VA)-modified Imatinib-loaded poly (lactic-co-glycolic acid)/Eudragit S100 (PLGA-ES100) has been successfully fabricated by adapting the solvent evaporation technique. The applying ES100 on the surface of our desired nanoparticles (NPs) protects drug release at the acidic pH of the gastric and guarantees the effective release of Imatinib at a higher pH of the intestine. Besides, VA-functionalized NPs could be an ideal efficient drug delivery system due to the high capacity of hepatic cell lines to absorb VA. For induction of liver fibrosis, CCL4 was intraperitoneally (IP) injected twice a week for six weeks in BALB/c mice. Oral administration of VA-targeted PLGA-ES100 NPs loaded with Rhodamine Red™ by live animal imaging showed a preferential accumulation of the selected NPs in the liver of mice. Besides, administrating targeted Imatinib-loaded NPs significantly decreased serum levels of ALT, and AST, and also reduced the expression of extracellular matrix components, including collagen I, collagen III, and α-SMA, considerably. Interestingly, histopathological evaluation of liver tissues through H&E and Masson's trichrome staining showed that oral administration of targeted Imatinib-loaded NPs reduced hepatic damage by enhancing hepatic structure condition. Also, the Sirius-red staining indicated a reduction in collagen expression during treatment with targeted NP containing Imatinib. The immunohistochemistry result on liver tissue shows a significant decrease in the expression of α-SMA in groups treated with targeted NP. In the meantime, administration of a very scarce dose of Imatinib via targeted NP caused a substantial decline in the expression of fibrosis marker genes (Collagen I, Collagen III, α-SMA). Our results confirmed that novel pH-sensitive VA-targeted PLGA-ES100 NPs could efficiently deliver Imatinib to the liver cells. Loading Imatinib in the PLGA-ES100/VA might overcome many challenges facing conventional Imatinib therapy, including gastrointestinal pH, the low concentration at the target region, and toxicity.

Graphene-MoS2 polyfunctional hybrid hydrogels for the healing of transected Achilles tendon.

Healing of injured tendon is a major clinical challenge in orthopaedic medicine, due to the poor regenerative potential of this tissue. Two-dimensional nanomaterials, as versatile scaffolds, have shown a great potential to support, trigger and accelerate the tendon regeneration. However, weak mechanical properties, poor functionality and low biocompatibility of these scaffolds as well as post-surgery infections are main drawbacks that limit their development in the higher clinical phases. In this work, a series of hydrogels consisting polyglycerol functionalized reduced graphene oxide (PG), polyglycerol-functionalized molybdenum disulfide (PMoS2) and PG/PMoS2 hybrid within the gelatin matrix are formulated in new scaffolds and their ability for the healing of injured Achilles tendon, due to their high mechanical properties, low toxicity, cell proliferation enhancement, and antibacterial activities is investigated. While scaffolds containing PG and PMoS2 showed a moderate tendon regeneration and anti-inflammatory effect, respectively, their hybridization into PG/PMoS2 demonstrated a synergistic healing efficiency. Along the same line, an accelerated return of tendon function with low peritendinous adhesion and low cross-sectional area in animal group treated with scaffold containing PG/PMoS2 was observed. Taking advantage of the high biocompatibility, high strength, straightforward construction and fast tendon regeneration, PG/PMoS2 can be used as a new scaffold for the future tissue engineering.

Osteogenic differentiation of adipose-derived stem cells on dihydroartemisinin electrospun nanofibers.

BACKGROUND: Adipose tissue-derived stem cells (ASCs) are promising candidate in stem cell therapies, and maintaining their stemness potential is vital to achieve effective treatment. Natural-based scaffolds have been recently attracted increasing attention in nanomedicine and drug delivery. In this study, Dihydroartemisinin (DHART)-loaded polycaprolactone collagen nanofibers (PCL/Col NFs) were constructed as effective biocompatible scaffolds through adjusting the proportions of hydrophobic/ hydrophilic polymers for enhanced osteoblastic differentiation of human adipose-derived stem cells (hADSCs). RESULTS: The designed NFs were characterized through FTIR, XRD, TGA, FE-SEM, and tensile testing. DHART-loaded PCL/Col electrospun NFs provide an ideal solution, with the potential of sustained drug release as well as inhibition of drug re-crystallization. Interestingly, inhibiting DHART re-crystallization can improve its bioavailability and provide a more effective therapeutic efficacy. Besides, the data set found through FE-SEM, MTT, PicoGreen, qPCR, and alkaline phosphatase (ALP) assays revealed the improved adhesion and proliferation rate of hADSCs cultured on PCL/Col/DHART (5%) NFs after 14 and 21 days of incubation. CONCLUSIONS: These findings confirmed the potential of the designed NF scaffolds for sustained/controlled release of DHART therapeutic molecules toward bone tissue regeneration and engineering.

Development of a Magnetic Nanostructure for Co-delivery of Metformin and Silibinin on Growth of Lung Cancer Cells: Possible Action Through Leptin Gene and its Receptor Regulation.

OBJECTIVE: Chemotherapeutic combinational approaches would be more efficient in decreasing toxicity of drug, preventing tumor progression in relation to either drug alone. Hence, the aim of this study is to constract magnetic PLGA/PEG nanoparticles (NPs) co-loaded with Metformin (Met) and Silibinin (Sil) to investigate their cytotoxicity as well as their impact on  mRNA expression levels of leptin and leptin receptor genes in A549 lung cancer cells. MATERIALS AND METHODS: The synthesized NPs were characterized by FTIR, FE-SEM, and VSM and then, MTT assay was utilized to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Moreover, the mRNA levels of leptin and its receptor genes expression were studied by quantitative real-time PCR. By co-encapsulation of Met and Sil into PLGA/PEG/ Fe3O4, cytotoxic efficiency of the compounds considerably augmented for all concentrations. RESULTS: Cytotoxicity assay displayed that combination of Met and Sil had a synergistic concentration-dependent effect on A549 lung cancer cells. Moreover, qPCR data revealed that the expression levels of the leptin and leptin receptor was considerably reduced with increasing concentrations of drug-encapsulated magnetic NPs, especially Met/Sil-encapsulated PLGA/PEG/ Fe3O4 NPs. CONCLUSION: Present preliminary study shows that co-incorporating Met, Sil, Fe3O4 into PLGA/PEG NPs might provide a more promising and safe treatment strategy for lung cancer.

Stimulus-responsive drug/gene delivery system based on polyethylenimine cyclodextrin nanoparticles for potential cancer therapy.

Combination therapy through simultaneous delivery of anti-cancer drugs and genes with nano-assembled structure has been proved to be a simple and effective approach for treating breast cancer. In this study, redox-sensitive folate-appended-polyethylenimine-ß-cyclodextrin (roFPC) host-guest supramolecular nanoparticles (HGSNPs) were developed as a targeted co-delivery system of doxorubicin (Dox) and Human telomerase reverse transcriptase-small interfering RNA) hTERT siRNA) for potential cancer therapy. The nanotherapeutic system was prepared by loading adamantane-conjugated doxorubicin (Ad-Dox) into roFPC through the supramolecular assembly, followed by electrostatically-driven self-assembly between hTERT siRNA and roFPC/Ad-Dox. The roFPC' host-guest structures allow pH-dependent intracellular drug release in a sustained manner, as well as simultaneous and effective gene transfection. This co-delivery vector displayed combined anti-tumor properties of the Dox-enhanced gene transfection, good water-solubility, and biocompatibility, possesses considerably enhanced hemocompatibility, and especially targets folate receptor-positive cells only at low N/P levels to prompt effective cell apoptosis for cancer treatment.

Cyclodextrin based natural nanostructured carbohydrate polymers as effective non-viral siRNA delivery systems for cancer gene therapy.

Short interfering RNAs (siRNAs), as small non-coding RNA fragments, are one of the widely studied RNAi inducers for gene modulations. The reasonably designed siRNA probes provide a novel potential therapeutic strategy for cancer therapy via silencing the specific cancer-promoting gene. The optimization of physicochemical properties of delivery vectors, such as stability, the possibility of surface functionalization, size, charge, biocompatibility, biodegradability, and non-immunogenicity with receptor-mediated targeting ligands, is necessary for effective intracellular siRNA delivery. The present review is focused on the recent progress of the non-viral nanocarriers for siRNA cancer treatment based on synthetic approaches associated with cyclodextrin (CD)-based carbohydrate polymers, i.e. CD-cationic polymers, CD-polyrotaxanes, CD-dendrimers, and CD-modified tumor-specific targeting ligands. Besides, the efficiency of nanocarriers-based stimuli-responsive CDs is described for the simultaneous delivery of siRNAs and chemotherapeutic drugs. Further, theranostic CD compounds are introduced for the specific diagnosis and cargo-targeting delivery to the specific disease sites. In the meantime, the development of the inherent fluorescent CD-based supramolecular biomaterials without formal chromophores will open up a new strategy to design an effective theranostic non-viral carrier system.

An implantable smart hyperthermia nanofiber with switchable, controlled and sustained drug release: Possible application in prevention of cancer local recurrence.

Temperature-responsive drug-loaded electrospun nanofibers have gained huge critical attention as efficient localized implantable devices in preventing cancer local recurrence. In this regard, a smart hyperthermia nanofiber with the simultaneous heat-generation and dual-stage drug release ability in response to 'ON-OFF' switching of an alternating magnetic field (AMF) for improved hyperthermic chemotherapy has been developed. The smart hyperthermia nanofibrous scaffolds are fabricated via electrospinning a temperature-responsive copolymer blended with iron oxide (II, III) magnetic nanoparticles (MNPs, 10 nm), metformin (MET), and mesoporous silica nanoparticles (MSNs) loaded with MET (MSNs@MET). It was found that all the magnetic nanofibers (MNFs) possess heat generation property and 'ON-OFF' switchable heating ability. The swelling ratio with reversible alterations and the corresponding drug discharge in response to AMF application with 'ON-OFF' switching was also demonstrated. MET-MNFs showed an initial rapid discharge in the 1st cycle of AMF application while MET released from MET@MSNs-MNFs exhibited a sustained release without the initial rapid discharge. It was found that MET-MET@MSNs-MNFs displayed a blend of initial rapid discharge and late prolonged drug discharge. In a magnetic field for 300 s during the second and third days, the metabolic activity of B16F10 skin melanoma cells incubated with all types of MNFs was decreased. Importantly, MET-MET@MSNs-MNFs had enhanced cytotoxicity than the MET-MNFs and MET@MSNs-MNFs (P < .05), due to the double effects of heat and dual-stage drug release. These results demonstrated that the proposed two-stage drug discharge approach plus hyperthermia is more desirable to standard chemotherapy regimens and might effectively induce cytotoxicity via a synergistic effect over a relatively long time.

Study of the Cytotoxic and Bactericidal Effects of Sila-substituted Thioalkyne and Mercapto-thione Compounds based on 1,2,3-Triazole Scaffold.

A series of sila-organosulphur compounds containing 1,2,3-triazole cores were screened for their cytotoxic activity on human breast cancer cell line MCF-7. Most of the tested compounds exhibited moderate-to-good activity against the cancer cells. Especially, the compound 4-((2-(trimethylsilyl)ethynylthio)methyl)-1-benzyl-1H-1,2,3-triazole (3a) from series of sila-substituted thioalkyne 1,2,3-triazoles (STATs) and the compounds 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-mercapto-1,1-bis(trimethylsilyl)propane-2-thione (4a) and 1-mercapto-1,1-bis(trimethylsilyl)-3-(1-phenethyl-1H-1,2,3-triazol-4-yl)propane-2-thione (4e) from series of sila-substituted mercapto-thione 1,2,3-triazoles (SMTTs) exhibited promising cytotoxicity against MCF-7 with IC50 values of 35.17, 32.63 and 30.3 µg/mL, respectively. In addition, the possible mechanisms for inhibition of cell growth and induction of apoptotic cell death were explored by DAPI staining, cell cycle analysis and qRT-PCR. The synthetic compounds were evaluated for their in vitro antibacterial activities, and as a result, the most prominent effects were observed for 3e and 4e. Especially, 3e was found to be quite active against all the tested strains with the MIC values ranging from 15 to 62 µg/mL, except P. aeruginosa. The results of the time-kill assay suggested that the compound of 3e completely inhibited the growth of both gram-negative bacteria, A. baumannii, and gram-positive bacteria, S. aureus. In addition, SEM analysis confirmed morphostructural damage of the bacteria. Our findings could be applicable for developing dual-targeting anticancer/antibacterial therapeutics.