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1.
Asian J Pharm Sci ; 19(2): 100891, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38584690

RESUMO

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvß3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

2.
Pharmaceutics ; 16(2)2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38399358

RESUMO

The Pharmaceutics Editorial Office retracts the article, "A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy" [...].

3.
Adv Mater ; 36(18): e2311350, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38221798

RESUMO

The discovery of the topological transition in twisted bilayer (tBL) materials has attracted considerable attention in nano-optics. In the analogue of acoustics, however, no such topological transition has been found due to the inherent nondirectional scalar property of acoustic pressure. In this work, by using a theory-based nonlocal anisotropic design, the in-plane acoustic pressure is transformed into a spatially distributed vector field using twisted multilayer metasurfaces. So-called "acoustic magic angle"-related acoustic phenomena occur, such as nonlocal polariton hybridization and the topological Lifshitz transition. The dispersion becomes flat at the acoustic magic angle, enabling polarized excitations to propagate in a single direction. Moreover, the acoustic topological transition (from hyperbolic to elliptic dispersion) is experimentally observed for the first time as the twist angle continuously changes. This unique characteristic facilitates low-loss tunable polariton hybridization at the subwavelength scale. A twisted trilayer acoustic metasurface is also experimentally demonstrated, and more possibilities for manipulating acoustic waves are found. These discoveries not only enrich the concepts of moiré physics and topological acoustics but also provide a complete framework of theory and methodologies for explaining the phenomena that are observed.

4.
Biochem Biophys Res Commun ; 680: 135-140, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37738903

RESUMO

Venous malformations are a vascular disorder. Currently, the use of chemical sclerosing agents is a common clinical approach for the treatment of venous malformations. However, the effectiveness of existing sclerosing agents is unsatisfactory and often accompanied by severe side effects. In this study, we have developed a novel cationic surfactant-based sclerosing agent (POL-TA) by conjugating the plasmin inhibitor tranexamic acid (TA) with a nonionic surfactant polidocanol (POL) through an ester bond. POL-TA induces endothelial cell damage, triggering the coagulation cascade and thrombus formation. Moreover, it releases TA in vivo, which inhibits plasmin activity and the activation of matrix metalloproteinase (MMPs), thereby stabilizing the fibrin network of the thrombus and promoting vascular fibrosis. We have established a cell model using venous malformation endothelial cells and assessed the cellular damage and underlying mechanisms of POL-TA. The inhibitory effects of POL-TA on the plasmin-MMPs system were evaluated using MMP-9 activity assay kit. Additionally, the mice tail vein model was employed to investigate the vascular sclerosing effects and mechanisms of POL-TA.

5.
Colloids Surf B Biointerfaces ; 222: 113103, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36571980

RESUMO

This investigation aimed to use CRISPR-Cas9 gene-editing to knock down P-glycoprotein (P-gp) expression and then establish a feasible cell line to evaluate the potential pharmacoresistance of therapeutic agents mediated by efflux. A cationic liposome was prepared as a "smart bomb" by conjugating with a peptide-based targeting ligand (THRPPMWSPVWP), specifically binding to transferrin receptors at the blood-brain barrier (BBB), and then formed a nanocomplex with P-gp knockdown CRISPR/Cas9 plasmid. Higher uptakes of targeted and stable liposomes in bEND.3 cells were observed compared to non-peptide conjugated ones (p < 0.05). The P-gp transporters were successfully knocked down by the cell-nontoxic CRISPR/Cas9 targeted liposomes and P-gp associated ATP activities were higher in the transfected cells (p < 0.05). Functional studies of knocked down cells were evaluated by using prototypical P-gp substrates rhodamine 123 and doxorubicin. More accumulation of rhodamine 123 and higher cytotoxic sensitivity of doxorubicin was observed in the transfected cells as compared with those in the wild-type cells.


Assuntos
Células Endoteliais , Lipossomos , Animais , Camundongos , Células Endoteliais/metabolismo , Sistemas CRISPR-Cas/genética , Rodamina 123 , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Doxorrubicina/farmacologia
6.
Small ; 18(30): e2201933, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35789094

RESUMO

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.


Assuntos
Nanopartículas , Neoplasias , Acústica , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Endotélio Vascular , Membrana Eritrocítica , Humanos , Infarto/tratamento farmacológico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico
7.
Int J Pharm ; 623: 121890, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35690307

RESUMO

It is well known that the difficulty of siRNA therapeutic application is the lack of safe and effective delivery vector. Virosome is a nano vesicle composed of lipid membrane and membrane protein. It retains fusion protein without virus genetic material, and therefore has the reduced immunogenicity compared with viral vector. Virosomes have the potential to deliver protein and nucleic acid drugs, but the traditional preparation method of virosomes is quite limited. In this study, we firstly proposed to synthesize influenza virus hemagglutinin HA2 virosomes by cell-free protein synthesis. In this study, liposomes provided the hydrophobic lipid bilayer environment for the formation of HA2 protein multimer, which inhibited the aggregation of hydrophobic HA2 and improved HA2 protein expression. Chitosan as a rigid core adsorbed siRNA and improved the encapsulation efficiency of siRNA. In conclusion, the cell-free protein synthesis was used to prepare HA2 virosomes, which paves the way for constructing a novel nano vector with high delivery efficiency and biosafety for the delivery of siRNA.


Assuntos
Orthomyxoviridae , Virossomos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Hemaglutininas , Lipossomos , Orthomyxoviridae/genética , Orthomyxoviridae/metabolismo , RNA Interferente Pequeno/genética
8.
J Food Biochem ; 46(8): e14196, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35527362

RESUMO

Oxidative stress-induced dysfunction of nerve cells has been implicated as a crucial cause of cell death in neurodegenerative diseases. In Asian countries, herbs, such as Angelica sinensis (Oliv.) Diels (DG) and Rehmannia glutinosa (Gaertn.) DC. (SDH), have long be considered to have antiaging abilities. The herbs act as neuro protectants that rescue nerve cells from oxidative stress damage and apoptosis. Thus, developing herbal formulas can potentially lead to new treatments for neurodegenerative diseases. In this study, we compared the effective active components and antioxidant properties of extractive of DG and SDH (DG-SDH) when formulated at different ratios. DG-SDH formulated at a ratio of 3:2 (DG-SDH [3:2]) produced the highest content of polysaccharides, polyphenols, and flavonoids. It also showed the best ability in removing DPPH and hydroxyl free radicals compared to single herb or other compounding ratio. The antioxidant activity of DG-SDH (3:2) showed best synergistic effects in scavenging activity assays of DPPH free radicals and hydroxyl free radicals. DG-SDH (3:2) could increase the cell viability of SHSY-5Y cells, PC-12 cells, and BV-2 cells. In particular, DG-SDH (3:2) protected SHSY-5Y cells from H2 O2 -induced cell injury by inhibiting excessive expression of reactive oxygen species (ROS), reducing the rate of apoptosis and restoring mitochondrial membrane potential. Actin-Tracker Green and DAPI staining and fluorescence microscope observation confirmed that DG-SDH (3:2) helped in preserving cell morphology under oxidative stress. These findings support that DG-SDH (3:2) promote the neuroprotection against hydrogen peroxide and can serve as a novel therapy for neurodegenerative diseases. PRACTICAL APPLICATIONS: This is the first study to investigate DG and SDH interaction between effective ingredients. These findings support that DG-SDH (3:2) has the best synergistic effects in antioxidant activity and promote the neuroprotection against hydrogen peroxide. Hence, DG-SDH (3:2) will be an excellent candidate to be developed as a functional food ingredients or nutraceuticals for neurodegenerative diseases.


Assuntos
Angelica sinensis , Rehmannia , Angelica sinensis/química , Antioxidantes/farmacologia , Peróxido de Hidrogênio/toxicidade , Radical Hidroxila , Substâncias Protetoras
9.
Adv Sci (Weinh) ; 9(20): e2200257, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35561061

RESUMO

Acoustic resonant cavities play a vital role in modern acoustical systems. The ultrahigh quality-factor resonances are highly desired for some applications such as high-resolution acoustic sensors and acoustic lasers. Here, a class of supercavity resonances is theoretically proposed and experimentally demonstrated in a coupled acoustic resonator system, arising from the merged bound states in the continuum (BICs) in geometry space. Their topological origin is demonstrated by explicitly calculating their topological charges before and after BIC merging, accompanied by charges annihilation. Compared with other types of BICs, they are robust to the perturbation brought by fabrication imperfection. Moreover, it is found that such supercavity modes can be linked with the Friedrich-Wintgen BICs supported by an entire rectangular (cuboid) resonator sandwiched between two rectangular (or circular) waveguides and thus more supercavity modes are constructed. Then, these coupled resonators are fabricated and such a unique phenomenon-moving, merging, and vanishing of BICs-is experimentally confirmed by measuring their reflection spectra, which show good agreement with the numerical simulation and theoretical prediction of mode evolution. The results may find exciting applications in acoustic and photonics, such as enhanced acoustic emission, filtering, and sensing.

10.
Pharmaceutics ; 14(2)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35214075

RESUMO

Venous malformation (VM), which causes severe damage to patients' appearance and organ function, is one of the most common vascular malformations. At present, many drugs in clinical treatment cause various adverse reactions. Herein, we synthesized cationic amphiphilic gelators (TA6, TA8, and TA9) by introducing saturated carbon chains of different lengths to tranexamic acid (TA), which could self-assemble into low-molecular-weight gels (LMWGs) as drug delivery carriers by hydrogen bonds, van der Waals forces, and hydrophobic interactions. The rheological properties, gelation driving force and drug release profiles of TA6, TA8, and TA9 hydrogels were characterized, and the results indicated that the hydrogels prepared in this study possessed the typical characteristics of a gel and could release drugs slowly. More importantly, the TA9 gelator showed significant pharmacological activity, in that it served as both an active drug compound and a drug carrier. The in vitro experiments demonstrated that TA9 induced HUVECs death and hemolysis by destroying cell membranes in a dose-dependent manner, and caused cell death and hemolysis at a concentration of 0.09 µM/mL. Meanwhile, we found TA9 could interact not only with fibrinogen, but also with other endogenous molecules in the blood. After the administration of TA9 hydrogel for 15 days, macroscopic imaging and histological evaluation in mice and rabbits displayed obvious thrombi, inflammatory reactions, and venous embolization, indicating that the mechanism of the TA9 hydrogel in treating VM was involved in two processes. Firstly, the TA9 hydrogel relied on its mechanical strength to physically block veins and continuously release TA9, in situ, for targeted therapy. Then, TA9 destroyed endothelial cells and damaged venous walls critically, causing thrombi. Most excitingly, TA9 was hydrolyzed to TA by enzymes that inhibited the degradation of thrombi by plasmin to prolong the embolization time and to promote venous fibrosis. Compared with other clinically available sclerosants, the degradation of TA9 also empowered a better biocompatibility and biodegradability for the TA9 hydrogel. In conclusion, we synthesized a potentially safe and effective derivative of TA and developed a low-molecular-weight gel as a self-delivery system for TA in treating VM.

11.
J Hazard Mater ; 423(Pt B): 127241, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-34844359

RESUMO

At present, the uptake and accumulation of nanoplastics by plants have raised particular concerns. However, molecular mechanisms underlying nanoplastic phytotoxicity are still vague and insufficient. To address this scientific gap, we analyzed the transcriptome response of hydroponically grown wheat (Triticum aestivum L.) to polystyrene nanoplastics (PSNPs) (100 nm) by integrating the differentially expressed gene analysis (DEGA) and the weighted gene correlation network analysis (WGCNA). PSNPs could significantly shape the gene expression patterns of wheat in a tissue-specific manner. Four candidate modules and corresponding hub genes associated with plant traits were identified using WGCNA. PSNPs significantly altered carbon metabolism, amino acid biosynthesis, mitogen-activated protein kinase (MAPK) signaling pathway-plant, plant hormone signal transduction, and plant-pathogen interaction Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In addition, some Gene Ontology (GO) terms associated with the metal ion transport were further screened. These findings shed new light on the phytotoxic mechanism and environmental implication behind the interaction of nanoplastics and crop plants, and advance our understanding of the potential adverse effect induced by the presence of nanoplastics in agricultural systems.


Assuntos
Microplásticos , Triticum , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Poliestirenos/toxicidade , Transcriptoma , Triticum/genética
12.
Inorg Chem ; 60(6): 3741-3748, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33641331

RESUMO

Mechanochromic luminescent (MCL) materials are promising in pressure sensors, security papers, photoelectric devices and optical data recording. Although some kinds of MCL-active iridium(III) complexes with various soft substituent functional ligands (e.g., dendritic carbazole, flexible chains, and Schiff base ligands) were reported, the MCL mechanism is still not clear and mainly ascribes to the physical phase transformations from crystalline state to amorphous state in response to force stimulus at present stage, and deserves further study in order to obtain more intelligent MCL materials. Herein, two new iridium(III) complex isomers are tactfully constructed and show distinctly opposite MCL properties in spite of the same physical phase transformations happening on them. The absolutely out of the ordinary MCL mechanism has been presented on account of molecular level for the first time via the comparative study of photophysical properties based on isomers 1 and 2 with the help of crystal structure analysis, room/low temperature emission spectra, NMR, PXRD, and TD-DFT calculations. All of these results suggest that the emitting state dominated by the triplet charge transfer excited state (3CT) plays a key role in achieving mechanochromic luminescence in iridium(III) complex systems.

13.
Adv Mater ; 33(4): e2003084, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33306245

RESUMO

Janus metamaterials, metasurfaces, and monolayers have received intensive attention in nanophotonics and 2D materials. Their core concept is to introduce asymmetry along the wave propagation direction, by stacking different materials or layers of meta-atoms, or breaking out-of-plane mirror asymmetry with external biases. Nevertheless, it has been hitherto elusive to realize a diffusive Janus metadevice, since scalar diffusion systems such as heat conduction normally operate in the absence of polarization control, spin manipulation, or electric-field stimuli, which all are widely used in achieving optical Janus devices. It is even more challenging, if not impossible, for a single diffusive metadevice to exhibit more than two thermal functions. Here a path-dependent thermal metadevice beyond Janus characteristics is proposed, which can exhibit three distinct thermal behaviors (cloaking, concentrating, and transparency) under different directions of heat flow. The rotation transformation mechanism of thermal conductivity provides a robust platform to assign a specific thermal behavior in any direction. The proof-of-concept experiment of anisotropic in-plane conduction successfully validates such a path-dependent trifunction thermal metamaterial device. It is anticipated that this path-dependent strategy can provide a new dimension for multifunctional metamaterial devices in the thermal field, as well as for a more general diffusion process.

14.
Adv Mater ; 32(42): e2003823, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32902007

RESUMO

The emerging thermal metamaterials and metadevices demonstrate significant potential to transform thermal conduction. However, the thermal conductivities of existing devices are all restricted at fixed values if the configuration or constituent materials are static. Thermal convection provides an additional tool to boost and flexibly modify the heat transfer in moving matter, but it is essentially distinct from thermal conduction since the Onsager reciprocity is generally broken in the former but preserved in the latter. Therefore, it is difficult to use convective components for sophisticated control of conductive heat. Here, it is shown that a convective system can be made undistinguishable from a conductive one in principle, by discovering and operating on the reciprocal line of mechanically rotating systems. The realized thermal metadevice can thus mimic a solid-like material whose thermal conductivity dynamically covers a wide range. It offers great possibilities of real-time smooth control over heat transfer for broad applications.

15.
J Drug Target ; 28(9): 923-932, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32312081

RESUMO

Biguanides (i.e. metformin, phenformin and buformin) are antidiabetic drugs with potential antitumor effects. Herein, a polycationic polymer, N,N'-bis(cystamine)acrylamide-buformin (CBA-Bu), containing multiple biodegradable disulphide bonds and buformin-mimicking side chains was synthesised. CBA-Bu was equipped with high efficiency and safety profile for gene delivery, meanwhile exhibiting potential antitumor efficacy. As a gene vector, CBA-Bu was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>30 mV) uniform polyplexes that were well resistant to heparin and DNase I. Due to the reduction responsiveness of the disulphide bonds, CBA-Bu/pDNA polyplexes could release the loaded pDNA in the presence of dithiothreitol, and induce extremely low cytotoxicity in NIH/3T3 and U87 MG cells. The transfection results showed that CBA-Bu had a cellular uptake efficiency comparable to 25 kDa PEI, while a significantly higher gene expression level. Additionally, CBA-Bu had a lower IC50 value than its non-biguanide counterpart in two cancer cell lines. Furthermore, CBA-Bu could activate AMPK and inhibit mTOR pathways in U87 MG cells, a mechanism involved in the antitumor effect of biguanides. Taken together, CBA-Bu represented an advanced gene vector combining desirable gene delivery capability with potential antitumor activity, which was promising to achieve enhanced therapeutic efficacy in antitumor gene therapy.


Assuntos
Buformina/química , Buformina/farmacologia , Terapia Genética/métodos , Neoplasias/terapia , Poliaminas/química , Poliaminas/farmacologia , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Buformina/administração & dosagem , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Vetores Genéticos , Humanos , Concentração Inibidora 50 , Camundongos , Células NIH 3T3 , Nanopartículas , Plasmídeos , Poliaminas/administração & dosagem
16.
J Hazard Mater ; 385: 121620, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31744724

RESUMO

Microplastics and nanoplastics are emerging pollutants of global concern. However, the understanding of their ecological effects on terrestrial plants is still limited. We conducted the systematic research to reveal the impact of polystyrene nanoplastics (PSNPs) (0.01-10 mg/L) on seed germination and seedling growth of wheat (Triticum aestivum L.). The results showed that PSNPs had no discernible effect on seed germination rate whereas significantly (p < 0.01) increased root elongation by 88.6 %-122.6 % when compared with the control. Similarly, remarkable increases in carbon, nitrogen contents, and plant biomass were also observed after exposure to PSNPs. Moreover, PSNPs could reduce the shoot to root biomass ratio (S:R ratio) of wheat seedlings. Furthermore, the imagings of a 3D laser confocal scanning microscopy (LCSM) and scanning electron microscopy (SEM) indicated that PSNPs were taken up and subsequently down-top transported to shoot. The absorption and accumulation of four micronutrients (Fe, Mn, Cu and Zn) in wheat were generally reduced in varying degrees. Notably, metabolomics analysis revealed that all PSNPs treatments altered the leaf metabolic profiles mainly by regulating energy metabolisms and amino acid metabolisms. These findings are expected to provide new insights into the effects of PSNPs on crop plants.


Assuntos
Germinação/efeitos dos fármacos , Microplásticos/toxicidade , Poliestirenos/toxicidade , Plântula/efeitos dos fármacos , Sementes/efeitos dos fármacos , Triticum/efeitos dos fármacos , Biomassa , Clorofila/metabolismo , Fotossíntese , Raízes de Plantas/metabolismo , Brotos de Planta/metabolismo , Plântula/genética , Triticum/embriologia , Triticum/genética
17.
Chem Commun (Camb) ; 55(97): 14582-14585, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31750477

RESUMO

On the basis of rational molecular design, the tricolour luminescence switching of an Ir(iii) complex is achieved for the first time. The transformation between two crystalline states and an amorphous state is responsible for the switching behaviour of this complex between blue, green and yellow states. Solvent molecules are shown to play a crucial role in the crystallization and luminescence processes.

18.
Colloids Surf B Biointerfaces ; 182: 110355, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306828

RESUMO

Inspired by the excellent membrane affinity of antimicrobial polymers, we synthesized a novel biodegradable poly(amino amine) polymer with pendent side chains that mimic the widely used biocide polyhexamethylene biguanide (PHMB) for gene delivery. Michael addition polymerization was utilized to form the polymer scaffold between N,N'-cystaminebisacrylamide (CBA) and N-Boc-1,6-diaminohexane (Boc-DAH) followed by N-Boc deprotection. Then the exposed primary amino groups were partly (about 75%) transformed into biguanide by an addition reaction with dicyandiamide to obtain the final product CBA-DAH-biguanide (CBA-DAH-BG). The polymer CBA-DAH-BG was able to condense plasmid DNA (pDNA) into nano-sized (<200 nm), positively-charged (>35 mV) polyplexes that were well resistant to heparin and DNase I. Rapid DNA release was observed in the presence of dithiothreitol (DTT), indicating that CBA-DAH-BG was equipped with biodegradability by the cleavage of disulfide bonds, which was helpful for unpacking DNA and decreasing cytotoxicity. CBA-DAH-BG/pDNA polyplexes were characterized by efficient cellular uptake efficacy, extremely low cytotoxicity, and high transfection efficiency in two cell lines (i.e., NIH/3T3 and U87 MG), compared to 25 kDa polyethyleneimine (PEI) and the intermediate product CBA-DAH that were both devoid of biguanide groups. Of note, clathrin-mediated endocytosis and lipid rafts played an important role in the internalization of the polyplexes. Taken together, this strategy described herein may represent an innovative avenue for the design of more advanced nonviral gene vectors with high transfection efficiency and biocompatibility.


Assuntos
Anti-Infecciosos/síntese química , Biguanidas/síntese química , Técnicas de Transferência de Genes , Plasmídeos/metabolismo , Polietilenoimina/química , Acrilamidas/química , Animais , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Biguanidas/metabolismo , Biguanidas/farmacologia , Linhagem Celular Tumoral , Desoxirribonuclease I/química , Diaminas/química , Ditiotreitol/química , Endocitose , Genes Reporter , Heparina/química , Hexanos/química , Humanos , Hidrólise , Luciferases/genética , Luciferases/metabolismo , Camundongos , Células NIH 3T3 , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Plasmídeos/química , Polietilenoimina/toxicidade
19.
Acta Biomater ; 96: 517-536, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31284098

RESUMO

Exosomes are naturally secreted nanovesicles that have emerged as a promising therapeutic nanodelivery platform, due to their specific composition and biological properties. However, challenges like considerable complexity, low isolation yield, drug payload, and potential safety concerns substantially reduce their pharmaceutical acceptability. Given that the nano-bio-interface is a crucial factor for nanocarrier behavior and function, modification of synthetic nanoparticles with the intrinsic hallmarks of exosomes' membrane to create exosome mimetics could allow for siRNA delivery in a safer and more efficient manner. Herein, connexin 43 (Cx43)-embedded, exosome-mimicking lipid bilayers coated chitosan nanoparticles (Cx43/L/CS NPs) were constructed by using cell-free (CF) synthesis systems with plasmids encoding Cx43 in the presence of lipid-coated CS NPs (L/CS NPs). The integration of de novo synthesized Cx43 into the lipid bilayers of L/CS NPs occurred cotranslationally during one-pot reaction and, more importantly, the integrated Cx43 was functionally active in transport. In addition to considerably lower cytotoxicity (

Assuntos
Materiais Biomiméticos , Conexina 43 , Sistemas de Liberação de Medicamentos , Exossomos/química , Nanopartículas/química , RNA Interferente Pequeno , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Materiais Biomiméticos/farmacologia , Sistema Livre de Células , Conexina 43/biossíntese , Conexina 43/química , Conexina 43/farmacocinética , Conexina 43/farmacologia , Células HEK293 , Humanos , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/farmacologia
20.
J Cell Biochem ; 120(10): 16967-16977, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31099062

RESUMO

At present, nonviral gene vectors develop rapidly, especially cationic polymers. A series of bioreducible poly(amide amine) (PAA) polymers containing guanidino groups have been synthesized by our research team. These novel polymer vectors demonstrated significantly higher transfection efficiency and lower cytotoxicity than polyethylenimine (PEI)-25kDa. However, compared with viral gene vectors, relatively low transfection efficiency, and high cytotoxicity are still critical problems confronting these polymers. In this study, poly(agmatine/N,N'-cystamine-bis-acrylamide) p(AGM-CBA) was selected as a model polymer, nuclear localization signal (NLS) peptide PV7 (PKKKRKV) with good biocompatibility and nuclear localization effect was introduced to investigate its impact on transfection efficiency and cytotoxicity. NLS peptide-mediated in vitro transfection was performed in NIH 3T3 cells by directly incorporating NLS peptide with the complexes of p(AGM-CBA)/pDNA. Meanwhile, the transfection efficiency and cytotoxicity of these complexes were evaluated. The results showed that the transfection efficiency could be increased by 5.7 times under the appropriate proportion, and the cytotoxicity brought by the polymer vector could be significantly reduced.


Assuntos
Acrilamidas/toxicidade , Agmatina/toxicidade , DNA/química , Sinais de Localização Nuclear/farmacologia , Poliaminas/toxicidade , Células 3T3 , Animais , Linhagem Celular , Membrana Celular/fisiologia , Camundongos , Sinais de Localização Nuclear/química , Transfecção
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