Fluorine-modified polymers reduce the adsorption of immune-reactive proteins to PEGylated gold nanoparticles.

Aim: To investigate the influence of fluorine in reducing the adsorption of immune-reactive proteins onto PEGylated gold nanoparticles. Methods: Reversible addition fragmentation chain transfer polymerization, the Turkevich method and ligand exchange were used to prepare polymer-coated gold nanoparticles. Subsequent in vitro physicochemical and biological characterizations and proteomic analysis were performed. Results: Fluorine-modified polymers reduced the adsorption of complement and other immune-reactive proteins while potentially improving circulatory times and modulating liver toxicity by reducing apolipoprotein E adsorption. Fluorine actively discouraged phagocytosis while encouraging the adsorption of therapeutic targets, CD209 and signaling molecule calreticulin. Conclusion: This study suggests that the addition of fluorine in the surface coating of nanoparticles could lead to improved performance in nanomedicine designed for the intravenous delivery of cargos.

Nanomedicines are based around the delivery of therapies by tiny, nanosized delivery vehicles. This method offers a much better way of specifically targeting life-threatening diseases. For fast delivery, nanomedicines can be injected into the blood (intravenously); however, this often leads to an unwanted and exaggerated immune response. The immune system is activated by proteins in the blood that attach themselves to nanoparticles through various chemical interactions (the protein corona effect). Fluorine is a chemical routinely used in surfactants such as firefighting foam and more recently in molecular imaging and nanoparticles designed for the delivery of therapies aimed at cancer. While fluorine has great potential to improve the cellular uptake of therapies, little is known about whether it can also help camouflage the nanoparticles against the immune system responses. Here, using fluorinated polymer-coated gold nanoparticles, the authors demonstrate that fluorine reduces uptake by immune cells and is highly effective at reducing the binding of immune system-initiating proteins. This work successfully illustrates the rationale for more widespread investigation of fluorine during the development of polymer-coated nanoparticles designed for the intravenous delivery of nanomedicines.

Multifunctional Fluoropolymer-Engineered Magnetic Nanoparticles to Facilitate Blood-Brain Barrier Penetration and Effective Gene Silencing in Medulloblastoma.

Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma.

3D-printed liquid metal polymer composites as NIR-responsive 4D printing soft robot.

4D printing combines 3D printing with nanomaterials to create shape-morphing materials that exhibit stimuli-responsive functionalities. In this study, reversible addition-fragmentation chain transfer polymerization agents grafted onto liquid metal nanoparticles are successfully employed in ultraviolet light-mediated stereolithographic 3D printing and near-infrared light-responsive 4D printing. Spherical liquid metal nanoparticles are directly prepared in 3D-printed resins via a one-pot approach, providing a simple and efficient strategy for fabricating liquid metal-polymer composites. Unlike rigid nanoparticles, the soft and liquid nature of nanoparticles reduces glass transition temperature, tensile stress, and modulus of 3D-printed materials. This approach enables the photothermal-induced 4D printing of composites, as demonstrated by the programmed shape memory of 3D-printed composites rapidly recovering to their original shape in 60 s under light irradiation. This work provides a perspective on the use of liquid metal-polymer composites in 4D printing, showcasing their potential for application in the field of soft robots.

Magnetic iron oxide nanoparticles for brain imaging and drug delivery.

Central nervous system (CNS) disorders affect as many as 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment of CNS disorders. With the advent of nanotechnologies, controlled delivery of drugs with nanoparticles holds great promise in CNS disorders for overcoming the blood-brain barrier (BBB) and improving delivery efficacy. In recent years, magnetic iron oxide nanoparticles (MIONPs) have stood out as a promising theranostic nanoplatform for brain imaging and drug delivery as they possess unique physical properties and biodegradable characteristics. In this review, we summarize the recent advances in MIONP-based platforms as imaging and drug delivery agents for brain diseases. We firstly introduce the methods of synthesis and surface functionalization of MIONPs with emphasis on the inclusion of biocompatible polymers that allow for the addition of tailored physicochemical properties. We then discuss the recent advances in in vivo imaging and drug delivery applications using MIONPs. Finally, we present a perspective on the remaining challenges and possible future directions for MIONP-based brain delivery systems.

Efficient Removal of Perfluorinated Chemicals from Contaminated Water Sources Using Magnetic Fluorinated Polymer Sorbents.

Efficient removal of per- and polyfluoroalkyl substances (PFAS) from contaminated waters is urgently needed to safeguard public and environmental health. In this work, novel magnetic fluorinated polymer sorbents were designed to allow efficient capture of PFAS and fast magnetic recovery of the sorbed material. The new sorbent has superior PFAS removal efficiency compared with the commercially available activated carbon and ion-exchange resins. The removal of the ammonium salt of hexafluoropropylene oxide dimer acid (GenX) reaches >99 % within 30 s, and the estimated sorption capacity was 219 mg g-1 based on the Langmuir model. Robust and efficient regeneration of the magnetic polymer sorbent was confirmed by the repeated sorption and desorption of GenX over four cycles. The sorption of multiple PFAS in two real contaminated water matrices at an environmentally relevant concentration (1 ppb) shows >95 % removal for the majority of PFAS tested in this study.

Low-Fouling Gold Nanorod Theranostic Agents Enabled by a Sulfoxide Polymer Coating.

Gold nanorods (GNRs) are widely used in various biomedical applications such as disease imaging and therapy due to their unique plasmonic properties. To improve their bioavailability, GNRs often need to be coated with hydrophilic polymers so as to impart stealth properties. Poly(ethylene glycol) (PEG) has been long used as such a coating material for GNRs. However, there is increasing acknowledgement that the amphiphilic nature of PEG facilitates its interaction with protein molecules, leading to immune recognition and consequent side effects. This has motivated the search for new classes of low-fouling polymers with high hydrophilicity as alternative low-fouling surface coating materials for GNRs. Herein, we report the synthesis, characterization, and application of GNRs coated with highly hydrophilic sulfoxide-containing polymers. We investigated the effect of the sulfoxide polymer coating on the cellular uptake and in vivo circulation time of the GNRs and compared these properties with pegylated GNR counterparts. The photothermal effect and photoacoustic imaging of these polymer-coated GNRs were also explored, and the results show that these GNRs are promising as nanotheranostic particles for the treatment of cancer.

Nanomaterial integrated 3D printing for biomedical applications.

3D printing technology, otherwise known as additive manufacturing, has provided a promising tool for manufacturing customized biomaterials for tissue engineering and regenerative medicine applications. A vast variety of biomaterials including metals, ceramics, polymers, and composites are currently being used as base materials in 3D printing. In recent years, nanomaterials have been incorporated into 3D printing polymers to fabricate innovative, versatile, multifunctional hybrid materials that can be used in many different applications within the biomedical field. This review focuses on recent advances in novel hybrid biomaterials composed of nanomaterials and 3D printing technologies for biomedical applications. Various nanomaterials including metal-based nanomaterials, metal-organic frameworks, upconversion nanoparticles, and lipid-based nanoparticles used for 3D printing are presented, with a summary of the mechanisms, functional properties, advantages, disadvantages, and applications in biomedical 3D printing. To finish, this review offers a perspective and discusses the challenges facing the further development of nanomaterials in biomedical 3D printing.

Engineering Polymers via Understanding the Effect of Anchoring Groups for Highly Stable Liquid Metal Nanoparticles.

Liquid metal nanoparticles (LMNPs) have recently attracted much attention as soft functional materials for various biorelated applications. Despite the fact that several reports demonstrate highly stable LMNPs in aqueous solutions or organic solvents, it is still challenging to stabilize LMNPs in biological media with complex ionic environments. LMNPs grafted with functional polymers (polymers/LMNPs) have been fabricated for maintaining their colloidal and chemical stability; however, to the best of our knowledge, no related work has been conducted to systematically investigate the effect of anchoring groups on the stability of LMNPs. Herein, various anchoring groups, including phosphonic acids, trithiolcarbonates, thiols, and carboxylic acids, are incorporated into brush polymers via reversible addition-fragmentation chain transfer (RAFT) polymerization to graft LMNPs. Both the colloidal and chemical stability of such polymer/LMNP systems are then investigated in various biological media. Moreover, the influence of multidentate ligands is also investigated by incorporating different numbers of carboxylic or phosphonic acid into the brush polymers. We discover that increasing the number of anchoring groups enhances the colloidal stability of LMNPs, while polymers bearing phosphonic acids provide the optimum chemical stability for LMNPs due to surface passivation. Thus, polymers bearing multidentate phosphonic acids are desirable to decorate LMNPs to meet complex environments for biological studies.

C-H Direct Arylation: A Robust Tool to Tailor the π-Conjugation Lengths of Non-Fullerene Acceptors.

Facile synthesis without involvement of toxic reagents is of great significance in the practical application of photovoltaic materials. In this work, four acceptor-donor-acceptor (A-D-A) type unfused-ring acceptors (UFRAs) with stepwise extension in π-conjugation, i. e., CPFB-IC-n (n=1-4), involving cyclopentadithiophene (CPDT) and 1,4-difluorobenzene (DFB) as cores, are facilely synthesized by an atom-, step-economic and labor-saving method through direct arylation of C-H bond (DACH). Among them, CPFB-IC-4 has the longest conjugation lengths among the molecular UFRA ever reported. The dependence of optoelectronic properties and photovoltaic performances of CPFB-IC-n (n=1-4) on conjugation length were systematically investigated. CPFB-IC-2 with near zero highest occupied molecular orbital (HOMO) offsets (ΔEHOMO =0.06 eV) achieves the highest power conversion efficiency (PCE), due to the significantly enhanced open voltage (VOC ) and short current (JSC ) caused by the balanced frontier molecular orbitals (FMOs) and complementary light absorption. Our work demonstrates that the optical properties and FMOs of UFRAs can be finely tuned by the stepwise elongation of conjugation lengths. Meanwhile, DACH coupling as a powerful tool here established will be a promising candidate for synthesizing high-performance oligomeric UFRAs.

Engineering macromolecular nanocarriers for local delivery of gaseous signaling molecules.

In addition to being notorious air pollutants, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have also been known as endogenous gaseous signaling molecules (GSMs). These GSMs play critical roles in maintaining the homeostasis of living organisms. Importantly, the occurrence and development of many diseases such as inflammation and cancer are highly associated with the concentration changes of GSMs. As such, GSMs could also be used as new therapeutic agents, showing great potential in the treatment of many formidable diseases. Although clinically it is possible to directly inhale GSMs, the precise control of the dose and concentration for local delivery of GSMs remains a substantial challenge. The development of gaseous signaling molecule-releasing molecules provides a great tool for the safe and convenient delivery of GSMs. In this review article, we primarily focus on the recent development of macromolecular nanocarriers for the local delivery of various GSMs. Learning from the chemistry of small molecule-based donors, the integration of these gaseous signaling molecule-releasing molecules into polymeric matrices through physical encapsulation, post-modification, or direct polymerization approach renders it possible to fabricate numerous macromolecular nanocarriers with optimized pharmacokinetics and pharmacodynamics, revealing improved therapeutic performance than the small molecule analogs. The development of GSMs represents a new means for many disease treatments with unique therapeutic outcomes.

Opposite Roles of Tumor Cell Proliferation and Immune Cell Infiltration in Postoperative Liver Metastasis of PDAC.

BACKGROUND: Recurrence of liver metastasis after pancreatectomy is often a predictor of poor prognosis. Comprehensive genomic analysis may contribute to a better understanding of the molecular mechanisms of postoperative liver metastasis and provide new therapeutic targets. METHODS: A total of 67 patients from The Cancer Genome Atlas (TCGA) were included in this study. We analyzed differentially expressed genes (DEGs) by R package "DESeq2." Weighted gene co-expression network analysis (WGCNA) was applied to investigate the key modules and hub genes. Immunohistochemistry was used to analyze tumor cell proliferation index and CD4+ T cells infiltration. RESULTS: Functional analysis of DEGs between the liver metastatic and recurrence-free groups was mainly concentrated in the immune response. The liver metastasis group had lower immune and stroma scores and a higher TP53 mutation rate. WGCNA showed that the genes in key modules related to disease-free survival (DFS) and overall survival (OS) were mainly enriched in the cell proliferation process and tumor immune response. Immunohistochemical analysis showed that the pancreatic cancer cells of patients with early postoperative liver metastasis had higher proliferative activity, while the infiltration of CD4+ T cells in tumor specimens was less. CONCLUSION: Our study suggested that increased immune cell infiltration (especially CD4+ T cells) and tumor cell proliferation may play an opposite role in liver metastasis recurrence after pancreatic cancer.

FUS-induced circRHOBTB3 facilitates cell proliferation via miR-600/NACC1 mediated autophagy response in pancreatic ductal adenocarcinoma.

BACKGROUND: Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation. METHODS: In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot. RESULTS: circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients. CONCLUSIONS: FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.

Prognostic impact of the ratio of preoperative CA19-9 to liver enzyme levels in pancreatic cancer patients with jaundice (predictability of combined CA19-9/AST and CA19-9/γ-GGT for jaundiced PDAC patients).

BACKGROUND: Carbohydrate antigen 19-9 (CA19-9) has been reported as the most significant survival predictor of patients with pancreatic ductal adenocarcinoma (PDAC). However, the elevation of CA19-9 could interfere with obstructive jaundice and the predictive value of CA19-9 in PDAC patients with jaundice remains to be analyzed and elucidated to find possible adjustments. OBJECTIVE: To evaluate the predictability of preoperative CA19-9 and its adjustments for the overall survival (OS) of PDAC patients by analyzing the relationship between preoperative serum CA19-9 and total bilirubin (TBIL). METHODS: A total of 563 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma in our center between January 2015 and September 2018 were retrospectively reviewed. Clinicopathologic information was collected and preoperative parameters such as CA19-9, CEA, TBIL, γ-GGT, AST, ALT, and ALP were recorded as well as overall survival rates, which began from the date of operation to that of death or the last follow-up. Kaplan-Meier survival curves with log-rank test and Cox regression models were applied using SPSS and the survival and survminer packages in R software. RESULTS: Using 39/390/1000 as the cut-off values for preoperative serum CA19-9, significant capability of OS stratification was found in the total cohort (p < 0.001, MST = 29.7/19.1/15.2/12.1 months) and patients with TBIL <102.6 µmol/L (p < 0.001, MST = 32.2/19.6/15.0/11.2 months). However, in the subgroup of TBIL≥102.6 µmol/L, this classification method was replaced by the combined scoring of CA19-9/AST and CA19-9/γ-GGT. CONCLUSIONS: As an independent predictor of overall survival of PDAC patients, preoperative serum CA19-9 is defective in survival stratification when TBIL≥102.6 µmol/L but a positive survival prognosis could be achieved with the application of combined preoperative CA19-9/AST and CA19-9/γ-GGT.

Effect of the transcription factor YY1 on the development of pancreatic endocrine and exocrine tumors: a narrative review.

Pancreatic tumors are classified into endocrine and exocrine types, and the clinical manifestations in patients are nonspecific. Most patients, especially those with pancreatic ductal adenocarcinoma (PDAC), have lost the opportunity to receive for the best treatment at the time of diagnosis. Although chemotherapy and radiotherapy have shown good therapeutic results in other tumors, their therapeutic effects on pancreatic tumors are minimal. A multifunctional transcription factor, Yin-Yang 1 (YY1) regulates the transcription of a variety of important genes and plays a significant role in diverse tumors. Studies have shown that targeting YY1 can improve the survival time of patients with tumors. In this review, we focused on the mechanism by which YY1 affects the occurrence and development of pancreatic tumors. We found that a YY1 mutation is specific for insulinomas and has a role in driving the degree of malignancy. In addition, changes in the circadian network are a key causative factor of PDAC. YY1 promotes pancreatic clock progression and induces malignant changes, but YY1 seems to act as a tumor suppressor in PDAC and affects many biological behaviors, such as proliferation, migration, apoptosis and metastasis. Our review summarizes the progress in understanding the role of YY1 in pancreatic endocrine and exocrine tumors and provides a reasonable assessment of the potential for therapeutic targeting of YY1 in pancreatic tumors.

CircNEIL3 regulatory loop promotes pancreatic ductal adenocarcinoma progression via miRNA sponging and A-to-I RNA-editing.

BACKGROUND: A growing number of studies have focused on investigating circRNAs as crucial regulators in the progression of multiple cancer types. Nevertheless, the biological effects and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unclear. METHODS: Differentially expressed circRNAs between cancerous tissue and adjacent normal tissues were identified by RNA sequencing in PDAC. Subsequently, in vitro and in vivo functional experiments were performed to investigate the functional roles of circNEIL3 in PDAC tumour growth and metastasis. Furthermore, RNA pull-down, dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH) and Sanger sequencing assays were performed to examine the circular interaction among circNEIL3, miR-432-5p and adenosine deaminases acting on RNA 1 (ADAR1). RESULTS: CircNEIL3 was upregulated in PDAC and promoted the progression of PDAC cells both in vitro and in vivo. Mechanistically, circNEIL3 was shown to regulate the expression of ADAR1 by sponging miR-432-5p to induce RNA editing of glioma-associated oncogene 1 (GLI1), ultimately influencing cell cycle progression and promoting epithelial-to-mesenchymal transition (EMT) in PDAC cells. Moreover, we discovered that the circNEIL3/miR-432-5p/ADAR1 axis was correlated with the PDAC clinical stage and overall survival of PDAC patients, while ADAR1 may reduce the biogenesis of circNEIL3. CONCLUSIONS: Our findings reveal that circNEIL3 facilitates the proliferation and metastasis of PDAC through the circNEIL3/miR-432-5p/ADAR1/GLI1/cell cycle and EMT axis and that its expression is regulated by ADAR1 through a negative feedback loop. Therefore, circNEIL3 may serve as a prognostic marker and a therapeutic target for PDAC.

Roundabout homolog 1 inhibits proliferation via the YY1-ROBO1-CCNA2-CDK2 axis in human pancreatic cancer.

Pancreatic cancer (PC) is highly malignant and has a high mortality with a 5-year survival rate of less than 8%. As a member of the roundabout immunoglobulin superfamily of proteins, ROBO1 plays an important role in embryogenesis and organogenesis and also inhibits metastasis in PC. Our study was designed to explore whether ROBO1 has effects on the proliferation of PC and its specific mechanism. The expression of ROBO1 was higher in cancer tissues than in matched adjacent tissues by immunohistochemistry (IHC) and qRT-PCR. Low ROBO1 expression is associated with PC progression and poor prognosis. Overexpression of ROBO1 can inhibit the proliferation of PC cells in vitro, and the S phase fraction can also be induced. Further subcutaneous tumor formation in nude mice showed that ROBO1 overexpression can significantly inhibit tumor growth. YY1 was found to directly bind to the promoter region of ROBO1 to promote transcription by a luciferase reporter gene assay, a chromatin immunoprecipitation (ChIP) and an electrophoretic mobility shift assay (EMSA). Mechanistic studies showed that YY1 can inhibit the development of PC by directly regulating ROBO1 via the CCNA2/CDK2 axis. Taken together, our results suggest that ROBO1 may be involved in the development and progression of PC by regulating cell proliferation and shows that ROBO1 may be a novel and promising therapeutic target for PC.

Antifouling Surfaces Enabled by Surface Grafting of Highly Hydrophilic Sulfoxide Polymer Brushes.

Antifouling surfaces are important in a broad range of applications. An effective approach to antifouling surfaces is to covalently attach antifouling polymer brushes. This work reports the synthesis of a new class of antifouling polymer brushes based on highly hydrophilic sulfoxide polymers by surface-initiated photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization. The sulfoxide polymer brushes are able to effectively reduce nonspecific adsorption of proteins and cells, demonstrating remarkable antifouling properties. Given the outstanding antifouling behavior of the sulfoxide polymers and versatility of surface-initiated PET-RAFT technology, this work presents a useful and general approach to engineering various material surfaces with antifouling properties, for potential biomedical applications in areas such as tissue engineering, medical implants, and regenerative medicine.

Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway.

Pancreatic cancer (PC) is a malignant cancer with high mortality and poor prognosis. In this study, we found that Linc01232 was significantly upregulated in PC tissues and cells and higher Linc01232 expression was associated with poorer prognosis. Linc01232 overexpression promoted and Linc01232 knockdown inhibited the migration and invasion of PC cells. The results of RNA pull-down, RNA Binding Protein Immunoprecipitation (RIP) assays revealed that Linc01232 physically interacted with Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) (680-890 nt fragment with the RNA recognition motif 2 domain) to inhibit its ubiquitin-mediated degradation in PC cells. RNA sequencing was performed to obtain the transcriptional profiles regulated by Linc01232 and we further demonstrated that Linc01232 participated in the alternative splicing of A-Raf by stabilizing HNRNPA2B1 and subsequently regulated the MAPK/ERK signaling pathway. Collected, our study showed that Linc01232/HNRNPA2B1/A-Raf/MAPK axis participated in the progression of PC and provided a potential therapeutic target for PC.