Cationic Polymer Polyethylenimine Research Articles

Ursodeoxycholic acid loaded dual-modified graphene oxide nanocomposite alleviates cholestatic liver injury through inhibiting hepatocyte apoptosis

Ursodeoxycholic acid (UDCA) is the preferred treatment for various types of cholestasis, however, its effectiveness is limited because of its insolubility in water. We used polyethylene glycol (PEG) and cationic polymer polyethylenimine (PEI) to double-modify graphite oxide (PPG) as a drug delivery system. UDCA was successfully loaded onto PPG through intermolecular interactions to form UDCA-PPG nanoparticles. UDCA-PPG nanoparticles not only improve the solubility and dispersibility of UDCA, but also have good biocompatibility and stability, which significantly improve the delivery rate of UDCA. The results indicated that UDCA-PPG significantly reduced ROS levels, promoted cell proliferation, protected mitochondrial membrane potential, reduced DNA damage and reduced apoptosis in the DCA-induced cell model. In a mouse cholestasis model established by bile duct ligation (BDL), UDCA-PPG improved liver necrosis, fibrosis, and mitochondrial damage and reduced serum ALT and AST levels, which were superior to those in the UDCA-treated group. UDCA-PPG reduced the expression of the apoptosis-related proteins, Caspase-3 and Bax, increased the expression of Bcl-2, and reduced the expression of the oxidative stress-related proteins, NQO and HO-1, as well as the autophagy-related proteins LC3, p62 and p-p62. Therefore, UDCA-PPG can enhance the therapeutic effect of UDCA in cholestasis, by significantly improving drug dispersibility and stability, extending circulation time in vivo, promoting absorption, decreasing ROS levels, enhancing autophagy flow and inhibiting apoptosis via the Bcl-2/Bax signaling pathway.

Efficient polymeric nanoparticles for RNAi in macrophage reveal complex effects on polarization markers upon knockdown of STAT3/STAT6

Tumor associated macrophages (TAMs) are the most abundant immune cell type in the tissue microenvironment, affecting tumor progression, metastasis and therapeutic response. Different macrophage activation (“polarization”) states can be distinguished: resting (M0; non-activated), pro-inflammatory/anti-tumorigenic (M1) and anti-inflammatory/pro-tumorigenic (M2). When exploring macrophages as targets in novel cancer immunotherapy approaches, TAM repolarization from the M2 into the M1 phenotype is an intriguing strategy to block their pro-tumoral and enhance their anti-tumoral properties.In the context of RNAi-based gene knockdown of M2 promoting genes, major bottlenecks include cellular siRNA delivery and correct intracellular processing. This is particularly true in case of macrophages as a cell type well-known to be notoriously hard-to-transfect. Among polymeric nanocarriers, the cationic polymer polyethylenimine (PEI) is widely explored for delivering nucleic acids. Further advanced nanocarriers are tyrosine-modified polymers based on PEI or polypropylenimine dendrimers (PPI) for highly efficient siRNA delivery in vitro and in vivo.In this paper, we explored a panel of PEI- or PPI-based nanoparticle systems for siRNA-mediated gene knockdown efficacy in macrophages and subsequent TAM repolarization. The tyrosine-modified linear 10 kDa PEI (LP10Y) or branched 5 kDa PEI (P5Y) as well as a tyrosine-modified PPI (PPI-Y) were found most efficient for gene knockdown in macrophage cell lines or primary macrophages, independent of their polarization. Knockdown of STAT6 or STAT3 led to repolarization of M2 macrophages, as indicated by alterations in various M2 and M1 marker levels. This highly specific approach also demonstrated non-redundant functions of STAT3 and STAT6. Importantly, macrophage re-polarization from M2 to M1 upon PPI-Y/siRNA-mediated STAT6 knockdown increased tumor cell phagocytosis in a co-culture model.In conclusion, we identify certain tyrosine-modified PEI- or PPI-based nanoparticles as particularly efficient for macrophage transfection, and the specific, siRNA-mediated STAT6 knockdown as a promising approach for macrophage repolarization and enhancement of their tumor cell suppressive role.

The 25-kDa linear polyethylenimine exerts specific antiviral activity against pseudorabies virus through interferencing its adsorption via electrostatic interaction.

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which is responsible for enormous economic losses to the global pig industry. Although vaccination has been used to prevent PRV infection, the effectiveness of vaccines has been greatly diminished with the emergence of PRV variants. Therefore, there is an urgent need to develop anti-PRV drugs. Polyethylenimine (PEI) is a cationic polymer and has a wide range of antibacterial and antiviral activities. This study found that a low dose of 1 µg/mL of the 25-kDa linear PEI had significantly specific anti-PRV activity, which became more intense with increasing concentrations. Mechanistic studies revealed that the viral adsorption stage was the major target of PEI without affecting viral entry, replication stages, and direct inactivation effects. Subsequently, we found that cationic polymers PEI and Polybrene interfered with the interaction between viral proteins and cell surface receptors through electrostatic interaction to exert the antiviral function. In conclusion, cationic polymers such as PEI can be a category of options for defense against PRV. Understanding the anti-PRV mechanism also deepens host-virus interactions and reveals new drug targets for anti-PRV.IMPORTANCEPolyethylenimine (PEI) is a cationic polymer that plays an essential role in the host immune response against microbial infections. However, the specific mechanisms of PEI in interfering with pseudorabies virus (PRV) infection remain unclear. Here, we found that 25-kDa linear PEI exerted mechanisms of antiviral activity and the target of its antiviral activity was mainly in the viral adsorption stage. Correspondingly, the study demonstrated that PEI interfered with the virus adsorption stage by electrostatic adsorption. In addition, we found that cationic polymers are a promising novel agent for controlling PRV, and its antiviral mechanism may provide a strategy for the development of antiviral drugs.

Enhancing the safety and effectiveness of polyethylenimine gene delivery through cell membrane encapsulation

Due to the powerful DNA loading capacity and excellent proton sponge effect, the cationic polymer polyethyleneimine (PEI) has been demonstrated as a versatile, efficient DNA delivery tool both in vitro and in vivo. However, the excess surface positive charge of PEI and the common capture/clearance of PEI/DNA complex by the immune system limit its further clinical applications. To reduce the cytotoxicity resulting from surface charge and avoid the clearance of nanoparticles interacting with proteins and circulating immune cells in the blood, a bionic gene delivery system was developed by coating PEI/DNA complexes with natural cell membranes. The obtained RAW Cell membrane-coated PEI/DNA capsules (RAWm-PDc) and Red blood Cell membrane-coated PEI/DNA capsules (RBCm-PDc) complex showed excellent dispersibility and stability with an average particle size of 200–300 nm. Moreover, the RAWm-PDc/RBCm-PDc complex had great DNA loading capacity and protected the bound DNA effectively from nuclease hydrolysis. Most importantly, the RAWm-PDc/RBCm-PDc complex exhibited low protein adsorption, reduced cytotoxicity and high gene delivery efficiency. All the results demonstrated the potential of RAWm-PDc/RBCm-PDc as a promising non-viral gene delivery vector.

Polyethyleneimine-mediated assembly of DNA nanotubes for KRAS siRNA delivery in lung adenocarcinoma therapy.

Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.

Implication of the Autophagy-Related Protein Beclin1 in the Regulation of EcoHIV Replication and Inflammatory Responses.

The protein Beclin1 (BECN1, a mammalian homologue of ATG6 in yeast) plays an important role in the initiation and the normal process of autophagy in cells. Moreover, we and others have shown that Beclin1 plays an important role in viral replication and the innate immune signaling pathways. We previously used the cationic polymer polyethyleneimine (PEI) conjugated to mannose (Man) as a non-viral tool for the delivery of a small interfering (si) Beclin1-PEI-Man nanoplex, which specifically targets mannose receptor-expressing glia (microglia and astrocytes) in the brain when administered intranasally to conventional mice. To expand our previous reports, first we used C57BL/6J mice infected with EcoHIV and exposed them to combined antiretroviral therapy (cART). We show that EcoHIV enters the mouse brain, while intranasal delivery of the nanocomplex significantly reduces the secretion of HIV-induced inflammatory molecules and downregulates the expression of the transcription factor nuclear factor (NF)-kB. Since a spectrum of neurocognitive and motor problems can develop in people living with HIV (PLWH) despite suppressive antiretroviral therapy, we subsequently measured the role of Beclin1 in locomotor activities using EcoHIV-infected BECN1 knockout mice exposed to cART. Viral replication and cytokine secretion were reduced in the postmortem brains recovered from EcoHIV-infected Becn1+/- mice when compared to EcoHIV-infected Becn1+/+ mice, although the impairment in locomotor activities based on muscle strength were comparable. This further highlights the importance of Beclin1 in the regulation of HIV replication and in viral-induced cytokine secretion but not in HIV-induced locomotor impairments. Moreover, the cause of HIV-induced locomotor impairments remains speculative, as we show that this may not be entirely due to viral load and/or HIV-induced inflammatory cytokines.

An efficient silica scale inhibiting strategy for geothermal systems: Combination of cationic and anionic polymers

AbstractCationic silica scale inhibitors are widely used, but are prone to precipitation and exhibit poor performance in geothermal systems. In this study, the cationic polymer polyethyleneimine ethoxylate (PEIE) was first found to have high silica scale inhibition efficiency. Three anionic polymers were added separately to PEIE solutions to alleviate the precipitation and scaling. The inhibition effect of PEIE alone and PEIE with anionic polymers were measured at 40°C without salt and 136.7°C with salt. Molecular dynamics simulation was used to investigate the inhibition mechanism. The results showed that PEIE exhibited good inhibition efficiency of 62% at 40°C without salt and 48% at 136.7°C with salt, while the addition of the anionic polymer acrylic acid‐2‐acrylamide‐2‐methylpropanesulfonic acid (AA/AMPS) to PEIE further improved to 71% and 62%. Compared with commercial inhibitors, the PEIE + AA/AMPS enhanced at least 15% scale inhibition efficiency. This is because the addition of AA/AMPS: (1) enhances the attraction of PEIE to silicic acid and inhibits the silicic acid condensation process; (2) chelates metal ions that promote condensation; and (3) enhances dispersion ability, stabilizing the colloid formed by PEIE and silicic acid. This study provides a promising new inhibitor and efficient strategy for inhibiting silica scale in geothermal systems.

Novel bionic inspired nanosystem construction for precise delivery of mRNA.

The intracellular delivery of messenger (m)RNA holds great potential for the discovery and development of vaccines and therapeutics. Yet, in many applications, a major obstacle to clinical translation of mRNA therapy is the lack of efficient strategy to precisely deliver RNA sequence to liver tissues and cells. In this study, we synthesized virus-like mesoporous silica (V-SiO2) nanoparticles for effectively deliver the therapeutic RNA. Then, the cationic polymer polyethylenimine (PEI) was included for the further silica surface modification (V-SiO2-P). Negatively charged mRNA motifs were successfully linked on the surface of V-SiO2 through electrostatic interactions with PEI (m@V-SiO2-P). Finally, the supported lipid bilayer (LB) was completely wrapped on the bionic inspired surface of the nanoparticles (m@V-SiO2-P/LB). Importantly, we found that, compared with traditional liposomes with mRNA loading (m@LNPs), the V-SiO2-P/LB bionic-like morphology effectively enhanced mRNA delivery effect to hepatocytes both in vitro and in vivo, and PEI modification concurrently promoted mRNA binding and intracellular lysosomal escape. Furthermore, m@V-SiO2-P increased the blood circulation time (t1/2 = 7h) to be much longer than that of the m@LNPs (4.2h). Understanding intracellular delivery mediated by the V-SiO2-P/LB nanosystem will inspire the next-generation of highly efficient and effective mRNA therapies. In addition, the nanosystem can also be applied to the oral cavity, forehead, face and other orthotopic injections.

Molecularly imprinted self-buffering double network hydrogel containing bi-amidoxime functional groups for the rapid hydrolysis of organophosphates.

The development of high-performance catalyst materials with high catalytic activity for the hydrolysis of organophosphorus toxicants without additional pH buffer conditions has become an urgent need for practical application. Here, a multifunctional molecularly imprinted polymer double network hydrogel (MIP-DN) material has been prepared by integrating the first polymer network containing the functional group of bi-amidoxime as the catalytic active center and the cationic polymer polyethyleneimine (PEI) with pH buffer function as the main component of the second network. Advantageously, the resultant MIP-DN hydrogel showed excellent catalytic performance without additional pH buffer conditions, exhibiting a half-life of 25min for the hydrolysis of paraoxon in pure water. Together with multi-functions of high catalytic activity, self-buffering function and excellent processability, the MIP-DN hydrogel prepared in this work provides a new strategy for the preparation of catalytic materials with practical application value toward toxic organophosphates.

Mucoadhesive Nanoparticles Enhance the Therapeutic Effect of Dexamethasone on Experimental Ulcerative Colitis by the Local Administration as an Enema

As the first-line drug to treat ulcerative colitis (UC), long-term use of glucocorticoids (GCs) produces severe toxic and side effects. Local administration as enema can increase the local GCs concentrations and reduce systemic exposure to high oral doses by directly delivering GCs to the inflammation site in the distal colorectum. However, UC patients are often accompanied by diarrhea, leading to the short colonic residence time of GCs and failure to exert their function fully. A kind of mucoadhesive nanoparticles (NPs) loading different dexamethasone derivatives (DDs) were developed, which could attach to the positively charged inflammatory colonic mucosa through electrostatic adsorption after administered by enema, thereby improving the local concentration and achieving effective targeted therapy for UC. Two DDs, dexamethasone hemisuccinate and dexamethasone phosphate, were synthesized. In NPs preparation, The core PEI-DDs NPs were built by the electrostatic adsorption of DDs and the cationic polymer polyethyleneimine (PEI). Then, the natural polyanionic polysaccharide sodium alginate (SA) was electronically coated around NPs to construct the final SA-PEI-DDs NPs, followed by the in vitro stability and release tests, in vitro and in vivo colonic mucosal adhesion tests. In the in vivo anti-UC test, the experimental colitis mice were induced by 2,4,6-trinitrobenzenesulfonic acid. The body weight and disease activity index changes were measured, and the myeloperoxidase activity, pro-inflammatory cytokines concentration, and hematoxylin and eosin staining were also investigated to evaluate the therapeutic effect of NPs. The structures of two DDs were demonstrated by 1H-NMR and MS. Both NPs were negatively charged and achieved high loading efficiency of DDs, while their particle sizes were significantly different. NPs showed good stability and sustained release properties in the simulated colonic environment. Moreover, the negative charge on the of NPs surface made them easier to adhere to the positively charged inflammatory colonic mucosa, thereby enhancing the enrichment and retention of DDS in the colitis site. Furthermore, the NPs exhibited better therapeutic effects than free Dex on the experimental colitis mice induced by TNBS through the enema rectal. These results indicated the mucoadhesive NPs as a kind of novel nano-enema showed great potential to achieve efficient treatment on UC.

Lentiviral Mediated Delivery of shRNAs to hESCs and NPCs Using Low-cost Cationic Polymer Polyethylenimine (PEI)

Lentiviral Mediated Delivery of shRNAs to hESCs and NPCs Using Low-cost Cationic Polymer Polyethylenimine (PEI)

Lentiviral Mediated Delivery of shRNAs to hESCs and NPCs Using Low-cost Cationic Polymer Polyethylenimine (PEI).

The current protocol describes the use of lentiviral particles for the delivery of short hairpin RNAs (shRNAs) to both human embryonic stem cells (hESCs) as well as neural progenitor cells (NPCs) derived from hESCs at high efficiency. Lentiviral particles were generated by co-transfecting HEK293T cells using entry vectors (carrying shRNAs) along with packaging plasmids (pAX and pMD2.G) using the low-cost cationic polymer polyethylenimine (PEI). Viral particles were concentrated using ultracentrifugation, which resulted in average titers above 5 x 107. Both hESCs and NPCs could be infected at high efficiencies using these lentiviral particles, as shown by puromycin selection and stable expression in hESCs, as well as transient GFP expression in NPCs. Furthermore, western blot analysis showed a significant reduction in the expression of genes targeted by shRNAs. In addition, the cells retained their pluripotency as well as differentiation potential, as evidenced by their subsequent differentiation into different lineages of CNS. The current protocol deals with the delivery of shRNAs; however, the same approach could be used for the ectopic expression of cDNAs for overexpression studies.

Specific Tumor Cell Detection by a Metabolically Targeted Aggregation-Induced Emission-Based Gold Nanoprobe.

Detection of circulating tumor cells (CTCs) could be widely used for early diagnosis and real-time monitoring of tumor progression in liquid biopsy samples. Compared with normal cells, tumor cells exhibit relatively strong negative surface charges due to the high rate of glycolysis. In this study, a cationic fluorescence “turn-on” aggregation-induced emission (AIE) nanoprobe based on gold nanorods (GNRs) was designed and tested to detect tumor cells specifically. In brief, tetraphenylethene (TPE), an AIE dye, was conjugated to the cationic polymer polyethylenimine (PEI) yielding TPEI. TPEI-PEG-SH was obtained by further functionalizing TPEI with a thiol group. TPEI-PEG-SH was grafted to the surface of GNRs, yielding the cationic AIE nanoprobe, named as GNRs-PEG-TPEI. The nanoprobe was characterized to have a uniform particle size of 172 nm, a strong positive surface charge (+54.87 mV), and a surface modification load of ∼40%. The in vitro stability of GNRs-PEG-TPEI was verified. The cellular imaging results demonstrated that the nanoprobe could efficiently recognize several types of tumor cells including MCF-7, HepG2, and Caco-2 while exhibiting specific fluorescence signals only after interacting with tumor cells and minimal background interference. In addition, the study investigated the toxicity of the nanoprobe to the captured cells and proved the safety of the nanoprobe. In conclusion, a specific and efficient nanoprobe was developed for capture and detection of different types of tumor cells based on their unique metabolic characteristics. It holds great promise for achieving early diagnosis and monitoring the tumor progression by detecting the CTCs in clinical liquid biopsy samples.

ROS responsive polyethylenimine-based fluorinated polymers for enhanced transfection efficiency and lower cytotoxicity.

Cationic polymer polyethylenimine (PEI) plays a crucial role in gene delivery. However, high molecular weight PEI leads to higher efficient transfection efficacy and higher cytotoxicity, while low molecular weight PEI exhibits lower transfection performance with lower toxicity. Therefore, effective chemical modification of PEI is required to enhance transfection activity and improve biocompatibility. Here, reactive oxygen species (ROS) responsive PEI-based fluorinated polymers (TKPF) with three degrees of fluorination (TKPF 12.5%, TKPF 25%, and TKPF 50%) were designed and synthesized by crosslinking low molecular weight PEI (PEI 1.8K) with a thioketal (TK) linker and then modifying heptafluorobutyric anhydride onto their surface. Fluorination reduced the positive charge density and endowed hydrophobic and lipophobic characteristics to resist serum interactions. The fluorophilic effect mediated efficient cellular uptake and endosomal escape while ROS-responsive TK linker allowed the polyplex disassembly to decrease the cytotoxicity of the polycations and improve the release of payloads at specific sites. TKPFs attained superior transfection efficiency in multiple cell lines (293TN cells and B16F10 cells) in vitro and showed excellent biocompatibility. TKPFs also exhibited great serum resistance in gene delivery and TKPF 50% transfected nearly 80% cells in the presence of 70% FBS. These results demonstrate that the fluorination and ROS responsiveness combined polycations are excellent gene-delivery vectors with serum-resistant capacity for further application.

Efficient Transient Expression of Plasmid DNA Using Poly (2-(N,N-Dimethylamino) Ethyl Methacrylate) in Plant Cells.

Nanomaterials have been widely studied for their potential to become the new generation of nanocarriers in gene transfection, yet it remains still difficult to apply them efficiently and succinctly to plant cells. Poly (2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA), which possesses temperature and pH dual-sensitivity, has largely been applied in animal cells, but it is rarely involved in plant cells. As a proof of concept, PDMAEMA as a gene carrier is incubated with plasmid GFP (pGFP) to explore its transfection ability in plants, and cationic polymer polyethylenimine (PEI) is used as a control. pGFP was efficiently condensed into the nanostructure by electrostatic interactions at an N/P (amino group from cationic polymers/phosphate group from plasmid DNA (pDNA)) ratio of 15; after complexation into nanocarriers, pGFP was protected from endonuclease degradation according to the DNase I digestion assay. After incubation with protoplasts and leaves, GFP was observed with confocal microscopy in plant cells. Western blot experiments confirmed GFP expression at the protein level. Toxicity assay showed PDMAEMA had a lower toxicity than PEI. These results showed that transient expression of pGFP was readily achieved in Arabidopsis thaliana and Nicotiana benthamiana. Notably, PDMAEMA showed lower cytotoxicity than PEI upon incubation with Nicotiana benthamiana leaves. PDMAEMA exhibited great potency for DNA delivery in plant cells. This work provides us with new ideas of more concise and more effective methods for plant transformation.

Optical properties of formation of gold nanoparticle aggregates deposited on quartz glass and application to SPR sensing

The sensing of surrounding medium is a research focus, which is highly dependent on the nanotechnology that exhibits typical features of technical difficulty and high price. In this work, a surrounding medium sensor based on gold nanoparticles (Au NPs) is fabricated. The formation of Au NP aggregates is deposited on quartz glass by alternately immerses the glass sheet in positive charged cationic polymer polyethyleneimine and negative charged citrate coated Au NPs. The formation of Au NP aggregates with different numbers of NPs is fabricated controlling numbers of deposition and deposition time. The formation of aggregates contains less NPs exhibit ability of refractive index sensing by monitoring the surface plasmon resonance (SPR) of Au NPs. The formation of Au NP aggregates can be used as a substitute of Au NPs array for the application of SPR sensing for the merits of easy fabrication and low cost.

Rapid photocatalytic inactivation of E. coli by polyethyleneimine grafted O-doped g-C3N4: Synergetic effects of the boosted reactive oxygen species production and adhesion performance

Previous studies have proved that the promoted interactions with bacteria was closely responsible for the improved inactivation efficiency of photocatalysts. Herein, for the first time, the cationic polymer polyethyleneimine (PEI) grafted O-doped g-C3N4 (denoted as PEI/OCN) was successfully fabricated by combination one-pot thermal-polymerization and subsequent covalent cross-linking reaction. Benefiting from the synergistic effect of O-doping and PEI-grafting, the obtained PEI/OCN possessed an extended and intensive visible light response, accelerated photogenerated charge transport, good hydrophilicity as well as enough electrostatic adhesion to bacteria. As a result, PEI/OCN exhibited a dramatically boosted reactive oxygen species (ROS) generation and outstanding rapid photocatalytic bactericidal capability, achieving 7.0 log CFU mL−1 inactivation efficiency of Escherichia coli (E. coli) within 30 min visible light exposure. Radical trapping and electron spin resonance (ESR) experiments revealed that superoxide radicals (•O2−) were crucially dominated the superior photocatalytic disinfection activity. Overall, the presented work provided a rationally designing of novel metal-free g-C3N4-based photocatalysts for efficient elimination of bacterial contaminations.

PH-responsive black phosphorus quantum dots for tumor-targeted photodynamic therapy

Black phosphorus quantum dots(BPQDs) have shown a good application prospect in the field of tumor therapy due to their photoelectric effect and good biodegradability. Due to the active endocytosis and fast metabolic efficiency of tumor cells, BPQDs are easy to be absorbed by tumor cells. However, this does not guarantee that BPQDs will be completely targeted to tumor cells, and normal cells will also absorb BPQDs. Because the cell membrane is negatively charged, BPQDs are also negatively charged and are not easily absorbed by cells under the action of electrostatic repulsion. Surface pegylation is the most common modification method of black phosphorus at present. However, surface pegylation can reduce the uptake of BPQDs by tumor cells. Positive PEG is also easy to be recognized and swallowed by the reticuloendothelial system. The inherent instability and poor tumor targeting of BPQDs under physiological conditions limit further research and clinical application. For this purpose, we selected cationic polymer polyethylenimine (PEI) to modify BPQDs and then added RGD peptides targeting tumor cells. An outer layer of negatively charged PEG+DMMA makes the nanosystem more stable . In the acidic environment of the tumor, the PEG layer has a charge reversal, and the positively charged PEI and the RGD polypeptide BPQDs targeted by the tumor cells are released into the tumor cells. It provides a new method for efficiently and accurately transporting BPQDs, a novel photosensitive nanomaterial, into tumor cells for photodynamic therapy.

Ultrasound-assisted C3F8-filled PLGA nanobubbles for enhanced FGF21 delivery and improved prophylactic treatment of diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. Fibroblast growth factor 21 (FGF21) has been proved to have cardioprotective effect in DCM. However, the insufficient cardiac delivery effect of FGF21 limits its application in DCM. Therefore, to improve the therapeutic efficacy of FGF21 in DCM, an effective drug delivery system is urgently required. In this study, perfluoropropane (C3F8) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles (CPPNBs) were synthesized via double-emulsion evaporation and FGF21 was efficiently absorbed (CPPNBs@FGF21) via the electrostatic incorporation effect. CPPNBs@FGF21 could effectively deliver FGF21 to the myocardial tissue through the cavitation effect under low-frequency ultrasound (LFUS). The as-prepared CPPNBs@FGF21 could efficiently load FGF21 after doping with the cationic polymer PEI, and displayed uniform dispersion and favorable biosafety. After filling with C3F8, CPPNBs@FGF21 could be used for distribution monitoring through ultrasound imaging. Moreover, CPPNBs@FGF21 significantly downregulated the expression of ANP, CTGF, and caspase-3 mRNA via the action of LFUS owing to increased FGF21 release, therefore exhibiting enhanced inhibition of myocardial hypertrophy, apoptosis, and interstitial fibrosis in DCM mice. In conclusion, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM. Statement of significanceDiabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks effective clinical treatments. Fibroblast growth factor 21 (FGF21) can protect cardiomyocytes from diabetic damage, but insufficient cardiac drug delivery limits the application of FGF21 in DCM. In this study, perfluoropropane (C3F8) and polyethylenimine (PEI)-doped poly (lactic-co-glycolic acid) (PLGA) nanobubbles loaded with FGF21 (CPPNBs@FGF21) were developed for the prophylactic treatment of DCM. CPPNBs@FGF21 could effectively deliver the FGF21 to the myocardial tissue through the cavitation effect of low-frequency ultrasound (LFUS). Our results indicated that CPPNBs@FGF21 combined with LFUS could significantly down-regulate the expressions of ANP, CTGF, and caspase-3 mRNA, and as a result, it prevented the myocardial hypertrophy, apoptosis, and interstitial fibrosis of DCM mice. Overall, we established an effective protein delivery nanocarrier for the diagnosis and prophylactic treatment of DCM.

A Label-Free Diamond Microfluidic DNA Sensor Based on Active Nitrogen-Vacancy Center Charge State Control.

We propose a label-free biosensor concept based on the charge state manipulation of nitrogen-vacancy (NV) quantum color centers in diamond, combined with an electrochemical microfluidic flow cell sensor, constructed on boron-doped diamond. This device can be set at a defined electrochemical potential, locking onto the particular chemical reaction, whilst the NV center provides the sensing function. The NV charge state occupation is initially prepared by applying a bias voltage on a gate electrode and then subsequently altered by exposure to detected charged molecules. We demonstrate the functionality of the device by performing label-free optical detection of DNA molecules. In this experiment, a monolayer of strongly cationic charged polymer polyethylenimine is used to shift the charge state of near surface NV centers from negatively charged NV- to neutral NV0 or dark positively charged NV+. Immobilization of negatively charged DNA molecules on the surface of the sensor restores the NV centers charge state back to the negatively charged NV-, which is detected using confocal photoluminescence microscopy. Biochemical reactions in the microfluidic channel are characterized by electrochemical impedance spectroscopy. The use of the developed electrochemical device can also be extended to nuclear magnetic resonance spin sensing.