Role and mechanism of IRF9 in promoting the progression of rheumatoid arthritis by regulating macrophage polarization via PSMA5.

Aim: To explore the mechanisms of IRF9 in the progression of rheumatoid arthritis(RA), and the effects of IRF9 on M1/M2 polarization. Methods: RA dataset (GSE55457) was downloaded from GEO. Correlation analysis between IRF9 and its downstream target protein PSMA5 was performed using bioinformatics analysis. The M1/M2 cell ratio of peripheral blood mononuclear cells which from 20 healthy specimen and 40 RA patients was determined. The expression of IRF9 and PSMA5 was detected using qPCR and Western blot. Then, knockdown IRF9 in RAW264.7 cell line (sh-IRF9 RAW264.7) was constructed. The effect of sh-IRF9 RAW264.7 on RA was explored by constructing a CIA mouse model. Results: IRF9 is upregulated in RA and is of good early screening effect. The results of pathway analysis showed that IRF9 targets and regulates the PSMA5 signaling pathway. IRF9 and PSMA5 were significantly elevated in RA patients, M1/M2 ratio was also increased. The effects of IRF9 on RAW264.7 macrophages were deeply explored in vitro, revealing that knockdown of IRF9 suppressed PSMA5, M1/M2 ratio and the secretion of pro-inflammatory factor in RAW264.7. In mouse in vivo experiments, sh-IRF9 RAW264.7 cells were found to modulate RA by downregulating PSMA5, modulating the M1/M2 ratio through enhancing the anti-inflammatory factor, and suppressing the pro-inflammatory factor. Conclusion: IRF9 promoted the progression of RA via regulating macrophage polarization through PSMA5.

AIBI Modified Mesoporous Copper Sulfide Nanocomposites for Efficient Non-Oxygen Dependent Free Radicals-Assisted Photothermal Therapy in Uveal Melanoma.

Uveal melanoma (UM) is an ocular cancer predominantly affecting adults, characterized by challenging diagnostic outcomes. This research endeavors to develop an innovative multifunctional nanocomposite system sensitive to near-infrared (NIR) radiation, serving as both a non-oxygen free-radical generator and a photothermal agent. The designed system combines azobis isobutyl imidazoline hydrochloride (AIBI) with mesoporous copper sulfide (MCuS) nanoparticles. MCuS harnesses NIR laser energy to induce photothermal therapy, converting light energy into heat to destroy cancer cells. Simultaneously, AIBI is activated by the NIR laser to produce alkyl radicals, which induce DNA damage in remaining cancer cells. This distinctive feature equips the designed system to selectively eliminate cancers in the hypoxic tumor microenvironment. MCuS is also beneficial to scavenge the overexpressed glutathione (GSH) in the tumor microenvironment. GSH generally consumes free radicals and hiders the PDT effect. To enhance control over AIBI release in cancer cells, 1-tetradecyl alcohol (TD), a phase-changing material, is introduced onto the surface of MCuS nanoparticles to create the final AMPT nanoparticle system. In vitro and in vivo experiments confirm the remarkable anti-tumor efficacy of AMPT. Notably, the study introduces an orthotopic tumor model for UM, demonstrating the feasibility of precise and effective targeted treatment within the ocular system.

Phenylboronic acid conjugated multifunctional nanogels with 131I-labeling for targeted SPECT imaging and radiotherapy of breast adenocarcinoma.

We report a new 131I-labeling functional platform for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of breast adenocarcinoma. In this study, polyethyleneimine (PEI) based nanogels (P.NH2 NGs) were prepared by water/oil polymerization, modified with targeted agent phenylboronic acid (PBA), and labeled with radionuclide 131I. The NGs without 131I-labeling own a spherical structure, uniform size distribution, and good cell viability. After 131I-labeling, the obtained 131I-PBA-PHP NGs displayed much higher cellular uptake than the non-targeted NGs due to the good softness and fluidity of NGs and the PBA targeting. The in vivo results demonstrated that 131I-PBA-PHP NGs could specifically target breast cancer cells and efficiently aggregate into xenograft breast adenocarcinoma for tumor SPECT imaging and specific radiotherapy. The developed 131I-labeling NGs may be used as a promising platform for efficient radioactive theranostic nanoplatform of tumor.

Safe and efficient 2D molybdenum disulfide platform for cooperative imaging-guided photothermal-selective chemotherapy: A preclinical study.

Introduction: The striking imbalance between the ever-increasing amount of nanomedicines and low clinical translation of products has become the focus of intense debate. For clinical translation, the critical issue is to select the appropriate agents and combination regimen for targeted diseases, not to prepare increasingly complex nanoplatforms. Objectives: A safe and efficient platform, α-tocopheryl succinate (α-TOS) married 2D molybdenum disulfide, was devised by a facile method and applied for cooperative imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Methods: A novel platform of PEGylated α-TOS and folic acid (FA) conjugated 2D MoS2 nanoflakes was fabricated  for the cooperative multimode computed tomography (CT)/photoacoustic (PA)/thermal imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Results: The photothermal efficiency (65.3%) of the platform under safe near-infrared irradiation is much higher than that of other photothermal materials reported elsewhere. Moreover, the covalently linked α-TOS renders platform with selective chemotherapy for cancer cells. Remarkably, with these excellent properties, the platform can be used to completely eliminate the solid tumor by safe photothermal therapy, and then kill the residual cancer cells by selective chemotherapy to prevent tumor recurrence. More significantly, barely side effects occur in the whole treatment process. The excellent efficacy and safety benefits in vivo lead to the prominent survival rate of 100% over 91 days. Conclusion: The safe and efficient platform might be a candidate of clinical nanomedicines for multimode theranostics. This study demonstrates an innovative thought in precise nanomedicine regarding the design of next generation of cancer theranostic protocol for potential clinical practice.

A novel Vancomycin-Functionalized-Magnetic Graphene Composite for Use as a Near-Infrared-Induced Synergistic Chemo-Photothermal Antibacterial.

Antibiotic-resistant bacterial strains are a major cause of disease. They continue to remain a challenge in the clinic particularly in the vision system. For example, infectious endophthalmitis is a major blind-causing disease caused by bacteria. A highly efficient synergistic antibacterial treatment that uses a photothermal antibacterial therapeutic with a chemo-antibacterial therapeutic in a multifunctional nanocomposite is reported. It is prepared by immobilizing vancomycin onto the surface of a magnetic chitosan-graphene (VCM-MCG) composite. An antibacterial effect is achieved when VCM-MCG is applied. This effect is enhanced when the nanocomposites are irradiated with a near-infrared laser. Growth of gram-positive methicillin-resistant Staphylococcus aureus and gram-negative Escherichia coli bacteria are suppressed efficiently. Such a composite can help manage the control of pathogenic bacteria growth in the clinic.

A Metal-Polymer Hybrid Biomimetic System for use in the Chemodynamic-Enhanced Photothermal Therapy of Cancers.

This article reports the fabrication of a smart biomimetic enzyme system, which incorporates a pH-responsive chemodynamic therapy (CDT) combined with a photothermal (PTT) therapy approach in resolving the high recurrence rate of deadly cancers. The resulting enzyme system comprises copper sulfide (CuS) nanoparticle (NP) cores as Fenton-like catalysts, and a photothermal-active generation 5 poly(amidoamine) (G5) dendrimer as a template for the entrapment of Cu NPs and the compression of glucose oxidase (GOD). GOD is introduced to produce H2 O2 necessary in the sequential Fenton-like reaction, and this generates hydroxyl radicals that kill the cancerous cells. Polyethylene glycol is added to the system to improve biocompatibility. Mechanism study suggests that the constructed CuS/G5-GOD-based system has a better Fenton-like catalytic activity than a Fe3 O4 -GOD-based system. This allows the further inhibition on the residual tumors from recurrence and metastasis through CDT after being treated by PTT. The developed smart nanoscale biomimetic system shows high efficiency for breast cancer suppression from recurrence and metastasis by combining PTT with a pH-responsive CDT. It has the potential to resolve the essential issue of cancer recurrence after its initial clinic treatment.

Functional LAPONITE Nanodisks Enable Targeted Anticancer Chemotherapy in Vivo.

Development of nanoplatforms for targeted anticancer drug delivery for effective tumor therapy still remains challenging in the development of nanomedicine. Here, we present a facile method to formulate a LAPONITE (LAP) nanodisk-based nanosystem for anticancer drug doxorubicin (DOX) delivery to folic acid (FA) receptor-overexpressing tumors. In the current work, aminated LAP nanodisks were first prepared through silanization, then functionalized with polyethylene glycol-linked FA (PEG-FA) via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) chemistry, and finally employed to physically encapsulate DOX. The formed functional LAP nanodisks (for short, LM-PEG-FA) possess a high DOX loading efficiency (88.6 ± 1.2%) and present a pH-dependent release feature with a quicker DOX release under acidic pH conditions (pH 5.0) than under physiological pH conditions (pH 7.4). In vitro flow cytometry, confocal microscopic observation, and cell viability assay show that the LM-PEG-FA/DOX complexes can be specifically taken up by FAR-overexpressing human ovarian cancer cells (SK-OV-3 cells) and present a specific cancer cell therapeutic effect. Further tumor treatment results reveal that the LM-PEG-FA/DOX complexes can exert a specific therapeutic efficacy to a xenografted SK-OV-3 tumor model in vivo when compared with nontargeted LM-mPEG/DOX complexes. Therefore, the developed LM-PEG-FA nanodisks could be employed as a potential platform for targeted cancer chemotherapy.

Magnetic Resonance Imaging of the Human Ferritin Heavy Chain Reporter Gene Carried by Dendrimer-Entrapped Gold Nanoparticles.

This paper aimed to find an effective method to destroy cancer cells by targeting breast cancer cells with natural killer (NK) cells transfected with the human ferritin heavy chain (hFTH1) gene by polyethylene glycol (PEG)-modified dendrimerentrapped gold nanoparticles (Au DENPs). In this study, fifth-generation polyamidoamine (G5 PAMAM) dendrimers modified with PEG were used as templates to entrap gold nanoparticles to transfect hFTH1 into NK cells. Our results revealed that the prepared Au DENPs/FTH1 provided high-quality imaging performance (hypointensity on T2-weighted MR imaging) and efficient transfection efficiency (reaching 80.2%) at a N/P ratio (ratio of the number of surface primary amines on {(Au0)25-G5 · NH2-mPEG17} to the number of phosphate groups in the hFTH1 backbone) of 5:1. Interestingly, the results showed that Au DENPs/FTH1 effectively guided NK-92 cells to concentrate around tumor cells for effective gene therapy without severely impacting their activity. This work will provide a new research platform for immunotherapy based on NK cells and lead to the optimization and even individualization of breast cancer immunotherapy through nanomolecular visualization research, which has a broad scope for future clinical applications.

The impact of sexual intercourse during pregnancy on obstetric and neonatal outcomes: a cohort study in China.

The reports about the effects of sexual attitudes and activities on obstetric outcomes were inconsistent or even contradictory. This study aims to investigate the patterns of sexual intercourse during pregnancy and its impact on obstetric and neonatal outcomes. All of the participants delivered their babies between September 2016 and June 2017 at Peking Union Medical College Hospital (PUMCH). An online questionnaire was sent to postpartum women with singleton deliveries at least 6 months after their deliveries. The perinatal outcome data were collected by reviewing the maternal and neonatal medical records. The obstetric and neonatal outcomes were compared between the women without and with sexual intercourse. Five hundred fifty questionnaires were sent out, and 406 (73.8%) women responded. A total of 211 (52%) women had sexual intercourse during pregnancy. There were 113, 67, 22, and 9 women reporting frequencies of sexual intercourse of less than once per month, 1-2 times/month, 3-4 times/month, and >4 times/month, respectively, and 49, 199, and 59 women reported sexual intercourse during their first, second, and third trimesters. The most common complaint was a lack of sexual interest. The experiences, frequency, and timing of sexual intercourse had no significant impact on any obstetric or neonatal outcome compared with those of the women without sexual intercourse. Impact statement What is already known on this subject? The reports about the effects of sexual attitudes and activities on obstetric outcomes were inconsistent. What do the results of this study add? In our study, the experiences, frequency, and the timing of sexual intercourse had no significant impact on any obstetric or neonatal outcome compared with those of women without sexual intercourse. What are the implications of these findings for clinical practice and/or further research? Sexual intercourse is generally safe in healthy pregnant women.

Enhanced Delivery of Therapeutic siRNA into Glioblastoma Cells Using Dendrimer-Entrapped Gold Nanoparticles Conjugated with ß-Cyclodextrin.

We describe a safe and highly effective non-viral vector system based on ß-cyclodextrin (ß-CD)-modified dendrimer-entrapped gold nanoparticles (Au DENPs) for improved delivery small interfering RNA (siRNA) to glioblastoma cells. In our approach, we utilized amine-terminated generation 5 poly(amidoamine) dendrimers partially grafted with ß-CD as a nanoreactor to entrap Au NPs. The acquired ß-CD-modified Au DENPs (Au DENPs-ß-CD) were complexed with two different types of therapeutic siRNA (B-cell lymphoma/leukemia-2 (Bcl-2) siRNA and vascular endothelial growth factor (VEGF) siRNA). The siRNA compression ability of the Au DENPs-ß-CD was evaluated by various methods. The cytocompatibility of the vector/siRNA polyplexes was assessed by viability assay of cells. The siRNA transfection capability of the formed Au DENPs-ß-CD vector was evaluated by flow cytometric assay of the cellular uptake of the polyplexes and Western blot assays of the Bcl-2 and VEGF protein expression. Our data reveals that the formed Au DENPs-ß-CD carrier enables efficiently delivery of siRNA to glioma cells, has good cytocompatibility once complexed with the siRNA, and enables enhanced gene silencing to inhibit the expression of Bcl-2 and VEGF proteins. The developed Au DENPs-ß-CD vector may be used for efficient siRNA delivery to different biosystems for therapeutic purposes.

Dendrimer-Modified MoS2 Nanoflakes as a Platform for Combinational Gene Silencing and Photothermal Therapy of Tumors.

Exploitation of novel hybrid nanomaterials for combinational tumor therapy is challenging. In this work, we synthesized dendrimer-modified MoS2 nanoflakes for combinational gene silencing and photothermal therapy (PTT) of cancer cells. Hydrothermally synthesized MoS2 nanoflakes were modified with generation 5 (G5) poly(amidoamine) dendrimers partially functionalized with lipoic acid via disulfide bond. The formed G5-MoS2 nanoflakes display good colloidal stability and superior photothermal conversion efficiency and photothermal stability. With the dendrimer surface amines on their surface, the G5-MoS2 nanoflakes are capable of delivering Bcl-2 (B-cell lymphoma-2) siRNA to cancer cells (4T1 cells, a mouse breast cancer cells) with excellent transfection efficiency, inducing 47.3% of Bcl-2 protein expression inhibition. In vitro cell viability assay data show that cells treated with the G5-MoS2/Bcl-2 siRNA polyplexes under laser irradiation have a viability of 21.0%, which is much lower than other groups of single mode PTT treatment (45.8%) or single mode of gene therapy (68.7%). Moreover, the super efficacy of combinational therapy was further demonstrated by treating a xenografted 4T1 tumor model in vivo. These results suggest that the synthesized G5-MoS2 nanoflakes may be employed as a potential nanoplatform for combinational gene silencing and PTT of tumors.

Construction of core-shell tecto dendrimers based on supramolecular host-guest assembly for enhanced gene delivery.

Design of dendrimer-based nanoarchitectures for enhanced gene delivery still remains a great challenge. Here, we report the design of core-shell tecto dendrimers using a supramolecular assembly approach for enhanced gene delivery applications. Firstly, ß-cyclodextrin (CD)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers (G5-CD) and adamantine (Ad)-modified generation 3 (G3) PAMAM dendrimers (G3-Ad) both having amine termini were synthesized. Through the supramolecular recognition of CD and Ad, G5-CD/Ad-G3 core-shell tecto dendrimers with a G5 core and G3 shell were formed. The formed G5-CD/Ad-G3 core-shell tecto dendrimers with a size of 8.4 nm possess good monodispersity, well-defined three-dimensional structure, and quite low cytotoxicity. Importantly, with the abundant amines on the surface, the core-shell tecto dendrimers are able to transfect the luciferase (Luc) gene with an efficiency 20 times and 170 times higher than the G5-CD and G3-Ad dendrimers, respectively. The higher gene transfection efficiency can also be qualitatively confirmed by transfection of plasmid DNA encoding enhanced green fluorescence protein. Our results suggest that the developed G5-CD/Ad-G3 core-shell tecto dendrimers may be used as a promising vehicle for enhanced gene transfection applications.

Multifunctional PEI-entrapped gold nanoparticles enable efficient delivery of therapeutic siRNA into glioblastoma cells.

RNA interference (RNAi) has been considered as a promising strategy for effective treatment of cancer. However, the easy degradation of small interfering RNA (siRNA) limits its extensive applications in gene therapy. For safe and effective delivery of siRNA, a novel vector system possessing excellent biocompatibility, highly efficient transfection efficiency and specific targeting properties has to be considered. In this study, we report the use of polyethyleneimine (PEI)-entrapped gold nanoparticles (Au PENPs) modified with an arginine-glycine-aspartic (Arg-Gly-Asp, RGD) peptide via a poly(ethylene glycol) (PEG) spacer as a vector for Bcl-2 (B-cell lymphoma-2) siRNA delivery to glioblastoma cells. The synthesized Au PENPs were well characterized. The efficiency of siRNA delivery was appraised by flow cytometry, confocal microscopy imaging, and the protein expression level. Our results revealed that the Au PENPs were capable of delivering Bcl-2 siRNA to glioblastoma cells with an excellent transfection efficiency, leading to specific gene silencing in the target cells (22% and 25.5% Bcl-2 protein expression in vitro and in vivo, respectively) thanks to the RGD peptide-mediated targeting pathway. The designed RGD-targeted Au PENPs may hold great promise to be used as a novel vector for specific cancer gene therapy applications.

Efficient delivery of therapeutic siRNA into glioblastoma cells using multifunctional dendrimer-entrapped gold nanoparticles.

AIM: To synthesize the arginine-glycine-aspartic (RGD) functionalized dendrimer-entrapped gold nanoparticles (Au DENPs) for siRNA delivery to induce gene silencing of cancer cells in vitro and in vivo. MATERIALS & METHODS: Au DENPs modified with RGD peptide via a polyethylene glycol spacer were used as a vector of two distinct small interfering RNAs (siRNAs) (VEGFvascular endothelial growth factor siRNA and B-cell lymphoma/leukemia-2 siRNA), and the physicochemical properties, cytocompatibility and transfection efficiency of Au DENP/siRNA polyplexes were characterized. RESULTS: The Au DENP/siRNA polyplexes with good cytocompatibility and highly efficient transfection capacity can be used for the transfection of siRNAs. CONCLUSION: The developed functional RGD-modified Au DENPs may be used for efficient gene therapy of different types of cancer.

Partially PEGylated dendrimer-entrapped gold nanoparticles: a promising nanoplatform for highly efficient DNA and siRNA delivery.

Exploring a plasmid DNA (pDNA)/small interfering RNA (siRNA) delivery vector with excellent biocompatibility and high gene transfection efficiency still remains a great challenge. In this research, generation 5 (G5) dendrimer-entrapped gold nanoparticles (Au DENPs) partially modified with polyethylene glycol monomethyl ether (mPEG) were designed as non-viral pDNA/siRNA delivery vectors. The pDNA that can encode luciferase (Luc) or enhanced green fluorescent protein (EGFP) and the Bcl-2 siRNA that can knockdown the expression of the Bcl-2 protein were successfully packaged by the partially PEGylated Au DENPs and effectively delivered into HeLa cells. The length of the surface conjugated mPEG chains and the composition of the entrapped Au NPs were systematically altered to explore their influences on the structure, cytotoxicity, and pDNA or siRNA delivery efficiency. We show that the modified mPEG and entrapped Au NPs can significantly improve the encoding of Luc and EGFP or silence the Bcl-2 protein expression, and the {(Au0)50-G5.NH2-mPEG2K} DENPs display the best DNA or siRNA delivery efficiency among all the designed partially PEGylated Au DENPs. The Luc transfection efficiency of the {(Au0)50-G5.NH2-mPEG2K} was about 292 times higher than that of the G5.NH2 dendrimers at an N/P ratio of 5 : 1, and the Bcl-2 protein was silenced to 15% using the {(Au0)50-G5.NH2-mPEG2K} as a vector relative to the expression level transfected using the G5.NH2 dendrimers (100%). With enhanced pDNA/siRNA transfection efficiency and less cytotoxicity, the PEGylated Au DENPs may hold great promise to be used in pDNA and siRNA delivery applications.

RGD peptide-modified dendrimer-entrapped gold nanoparticles enable highly efficient and specific gene delivery to stem cells.

We report the use of arginine-glycine-aspartic (Arg-Gly-Asp, RGD) peptide-modified dendrimer-entrapped gold nanoparticles (Au DENPs) for highly efficient and specific gene delivery to stem cells. In this study, generation 5 poly(amidoamine) dendrimers modified with RGD via a poly(ethylene glycol) (PEG) spacer and with PEG monomethyl ether were used as templates to entrap gold nanoparticles (AuNPs). The native and the RGD-modified PEGylated dendrimers and the respective well characterized Au DENPs were used as vectors to transfect human mesenchymal stem cells (hMSCs) with plasmid DNA (pDNA) carrying both the enhanced green fluorescent protein and the luciferase (pEGFPLuc) reporter genes, as well as pDNA encoding the human bone morphogenetic protein-2 (hBMP-2) gene. We show that all vectors are capable of transfecting the hMSCs with both pDNAs. Gene transfection using pEGFPLuc was demonstrated by quantitative Luc activity assay and qualitative evaluation by fluorescence microscopy. For the transfection with hBMP-2, the gene delivery efficiency was evaluated by monitoring the hBMP-2 concentration and the level of osteogenic differentiation of the hMSCs via alkaline phosphatase activity, osteocalcin secretion, calcium deposition, and von Kossa staining assays. Our results reveal that the stem cell gene delivery efficiency is largely dependent on the composition and the surface functionality of the dendrimer-based vectors. The coexistence of RGD and AuNPs rendered the designed dendrimeric vector with specific stem cell binding ability likely via binding of integrin receptor on the cell surface and improved three-dimensional conformation of dendrimers, which is beneficial for highly efficient and specific stem cell gene delivery applications.