SARS-CoV-2 has triggered a public health outbreak across the world, resulting in almost 5 million deaths as of January 2022. The arrival of vaccines has provided temporary relief, but these vaccines target the spike p...SARS-CoV-2 has triggered a public health outbreak across the world, resulting in almost 5 million deaths as of January 2022. The arrival of vaccines has provided temporary relief, but these vaccines target the spike protein, which is highly prone to mutation, making it impossible to develop a long-term cure for the coronavirus. As such, there is an urgent need for site-specific inhibition of the virus in the respiratory tract, as well as targeting the internal proteins of the virus itself. Past literature has identified 3CLpro and PLpro as enzymes essential to the replication of the virus, as they assemble almost the entirety of the viral genome;as such, inhibiting the activity of these enzymes can stymie the spread of the virus. This project proposes the use of inhaled drug delivery to inhibit Covid-19 by synthesizing a formulation that can travel directly to the lungs via inhalation. In order to streamline synthesis, existing FDA-approved drugs were analyzed using computational docking software and in vitro assays for inhibitory activity against these two enzymes. High-performing drugs were then encapsulated in PLGA nanoparticles to synthesize a drug delivery system, which was tested and characterized in vitro. Furthermore, in an effort to improve this drug delivery system relative to other drug delivery systems, the use of enzyme nanomotors was explored as a way to increase the accuracy of delivery by using computational simulations that mimicked conditions in the human body to model the velocity and trajectory of the nanomotors.展开更多
Vascular endothelial growth factor receptor 2(VEGFR-2)and neuropilin-1(NRP-1)are two prominent antiangiogenic targets.They are highly expressed on vascular endothelial cells and some tumor cells.Therefore,targeting VE...Vascular endothelial growth factor receptor 2(VEGFR-2)and neuropilin-1(NRP-1)are two prominent antiangiogenic targets.They are highly expressed on vascular endothelial cells and some tumor cells.Therefore,targeting VEGFR-2 and NRP-1 may be a potential antiangiogenic and antitumor strategy.A7R,a peptide with sequence of Ala-Thr-Trp-Leu-Pro-Pro-Arg that was found by phage display of peptide libraries,can preferentially target VEGFR-2 and NRP-1 and destroy the binding between vascular endothelial growth factor 165(VEGF165)and VEGFR-2 or NRP-1.This peptide is a new potent inhibitor of tumor angiogenesis and a targeting ligand for cancer therapy.This review describes the discovery,function and mechanism of the action of A7R,and further introduces the applications of A7R in antitumor angiogenic treatments,tumor angiogenesis imaging and targeted drug delivery systems.In this review,strategies to deliver different drugs by A7R-modified liposomes and nanoparticles are highlighted.A7R,a new dual targeting ligand of VEGFR-2 and NRP-1,is expected to have efficient therapeutic or targeting roles in tumor drug delivery.展开更多
Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug deliv...Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.展开更多
Rheumatoid arthritis(RA)is a common autoimmune disease characterized by joint inflammation and immune dysfunction.Although various therapeutic approaches have been utilized for the treatment of RA in clinical applicat...Rheumatoid arthritis(RA)is a common autoimmune disease characterized by joint inflammation and immune dysfunction.Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications,the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems.Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation.Ac2–26,a 25-amino acid peptide derived from Annexin A(a pro-resolving mediator),has shown good efficacy in the treatment of inflammatory disorders.However,the low bioavailability of Ac2–26 peptides hinders their efficacy in vivo.In this paper,we formed PEGylated lipid nanoparticles(LDNPs)by the co-assembly of l-ascorbyl palmitate(L-AP)and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn–glycero-3-phosphoethanolamine(DSPE-PEG 2 k)to encapsulate and deliver Ac2–26 peptides to the arthritic rats.They showed good stability and biocompatibility.After being intravenously administrated,Ac2–26 peptide-loaded PEGylated lipid nanoparticles(ADNPs)showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites.In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology.Therefore,the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.展开更多
In the present work an attempt has been made to design the antibiotic drug loaded carbopolpoly( NVP) based hydrogel wound dressings for better wound care. The polymer films were characterized by SEM-EDX, AFM, FTIR, 13...In the present work an attempt has been made to design the antibiotic drug loaded carbopolpoly( NVP) based hydrogel wound dressings for better wound care. The polymer films were characterized by SEM-EDX, AFM, FTIR, 13CNMR, TGA/DTA/DTG, DSC, and swelling studies. Besides drug release, various biomedical properties (viz. blood compatibility, mucoadhesion, oxygen permeability, water vapour transmission rate, microbial penetration, tensile strength, bursting strength, resilience, stress relaxation, and folding endurance) have also been studied. The polymer films have been observed to be biocompatible, permeable to oxygen and water vapour and have absorbed simulated wound fluid 11.37±0.31g/g of polymer film. The drug release profile followed the Case-II diffusion mechanism and release profile best fitted in Hixson-Crowell’s kinetic models. Mechanical properties results showed that the polymer film had 0.65±0.12 Nmm??2 tensile strength, 119.38±14.26% elongationand 25.49±0.72% resilience.展开更多
Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases,immune cell infiltration and protease-driven tissue damages....Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases,immune cell infiltration and protease-driven tissue damages.It is an urgent need to explore potential drug strategies for mitigating lung inflammation.Protease-activated receptor 2(PAR2)as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction.However,it has been rarely reported about the role of PAR2 in lung inflammation.This study applied CRISPR-Cas9 system encoding Cas9 and sg RNA(p Cas9-PAR2)for PAR2 knockout and fabricated an anionic human serum albuminbased nanoparticles to deliver p Cas9-PAR2 with superior inflammation-targeting efficiency and stability(TAP/p Cas9-PAR2).TAP/p Cas9-PAR2 robustly facilitated p Cas9-PAR2 to enter and transfect inflammatory cells,eliciting precise gene editing of PAR2 in vitro and in vivo.Importantly,PAR2 deficiency by TAP/p Cas9-PAR2 effectively and safely promoted macrophage polarization,suppressed proinflammatory cytokine releases and alleviated acute lung inflammation,uncovering a novel value of PAR2.It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/p Cas9-PAR2was mainly dependent on ERK-mediated NLRP3/IL-1β and NO/i NOS signalling.Therefore,this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.展开更多
Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure(ALF).Hence,reprogramming pro-inflammatory M1 into anti-inflammatory M2 ph...Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure(ALF).Hence,reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting inflammation.Our group found Carvedilol possessed potential anti-inflammatory property previously,which had been scarcely reported in ALF.We present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4(IL-4)and IL-10 at first.Then Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform(termed as M2M@CNP)to evade reticuloendothelial system(RES)and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species(ROS),further prolonging its circulation and accumulation.Sustainably released Carvedilol produced anti-inflammatory,antioxidant and anti-apoptosis effects,combining local M2-type cell membranes(M2-CM)inhibited pro-inflammatory cytokines and ROS levels,which in turn promoted and amplified M1 to M2 phenotype polarization efficiency.This study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.展开更多
Infectious diseases caused by bacteria are a global threat to the human health. Here, we propose a solvent “irrigation” technique to endow TiO_(2) nanotubes (NTs) to precisely modify with functional nanomaterials, a...Infectious diseases caused by bacteria are a global threat to the human health. Here, we propose a solvent “irrigation” technique to endow TiO_(2) nanotubes (NTs) to precisely modify with functional nanomaterials, and apply them in constructing a near-infrared (NIR) light controlled drug-delivery system for rapid necrosis of bacteria. In this design, the NIR stimuli-responsive functional shell is located on the external tube wall of TiO_(2) NT;the internal tube wall offers sufficient binding sites for drug loading. Using kanamycin as a model drug, we demonstrate that the reactive oxygen species generated in photocatalysis not only controllably release the loaded drug by scissoring the linked chains, but also effectively compromise bacteria membrane integrity by damaging the cell wall. Benefiting from the damages, antibiotics rapidly enter the bacteria and reach ≥99.9% reduction in Escherichia coli colony within only 2 h. Importantly, such a covalently conjugation-based delivery system can efficiently relieve radical-induced inflammation and cytotoxicity. This study provides an innovative design strategy for engineering delivery systems with tailorable components, enduring stimuli-response by multiple triggers.展开更多
文摘SARS-CoV-2 has triggered a public health outbreak across the world, resulting in almost 5 million deaths as of January 2022. The arrival of vaccines has provided temporary relief, but these vaccines target the spike protein, which is highly prone to mutation, making it impossible to develop a long-term cure for the coronavirus. As such, there is an urgent need for site-specific inhibition of the virus in the respiratory tract, as well as targeting the internal proteins of the virus itself. Past literature has identified 3CLpro and PLpro as enzymes essential to the replication of the virus, as they assemble almost the entirety of the viral genome;as such, inhibiting the activity of these enzymes can stymie the spread of the virus. This project proposes the use of inhaled drug delivery to inhibit Covid-19 by synthesizing a formulation that can travel directly to the lungs via inhalation. In order to streamline synthesis, existing FDA-approved drugs were analyzed using computational docking software and in vitro assays for inhibitory activity against these two enzymes. High-performing drugs were then encapsulated in PLGA nanoparticles to synthesize a drug delivery system, which was tested and characterized in vitro. Furthermore, in an effort to improve this drug delivery system relative to other drug delivery systems, the use of enzyme nanomotors was explored as a way to increase the accuracy of delivery by using computational simulations that mimicked conditions in the human body to model the velocity and trajectory of the nanomotors.
基金funded by National Natural Science Foundation of China(No.81302686)Primary Research&Developement Plan of Shandong Province(No.2016GSF201083)
文摘Vascular endothelial growth factor receptor 2(VEGFR-2)and neuropilin-1(NRP-1)are two prominent antiangiogenic targets.They are highly expressed on vascular endothelial cells and some tumor cells.Therefore,targeting VEGFR-2 and NRP-1 may be a potential antiangiogenic and antitumor strategy.A7R,a peptide with sequence of Ala-Thr-Trp-Leu-Pro-Pro-Arg that was found by phage display of peptide libraries,can preferentially target VEGFR-2 and NRP-1 and destroy the binding between vascular endothelial growth factor 165(VEGF165)and VEGFR-2 or NRP-1.This peptide is a new potent inhibitor of tumor angiogenesis and a targeting ligand for cancer therapy.This review describes the discovery,function and mechanism of the action of A7R,and further introduces the applications of A7R in antitumor angiogenic treatments,tumor angiogenesis imaging and targeted drug delivery systems.In this review,strategies to deliver different drugs by A7R-modified liposomes and nanoparticles are highlighted.A7R,a new dual targeting ligand of VEGFR-2 and NRP-1,is expected to have efficient therapeutic or targeting roles in tumor drug delivery.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2023MC168the National Natural Science Foundation of China,No.31670989the Key R&D Program of Shandong Province,No.2019GSF107037(all to CS).
文摘Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.
基金supported by the National Natural Science Foundation of China(No.82003661)。
文摘Rheumatoid arthritis(RA)is a common autoimmune disease characterized by joint inflammation and immune dysfunction.Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications,the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems.Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation.Ac2–26,a 25-amino acid peptide derived from Annexin A(a pro-resolving mediator),has shown good efficacy in the treatment of inflammatory disorders.However,the low bioavailability of Ac2–26 peptides hinders their efficacy in vivo.In this paper,we formed PEGylated lipid nanoparticles(LDNPs)by the co-assembly of l-ascorbyl palmitate(L-AP)and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn–glycero-3-phosphoethanolamine(DSPE-PEG 2 k)to encapsulate and deliver Ac2–26 peptides to the arthritic rats.They showed good stability and biocompatibility.After being intravenously administrated,Ac2–26 peptide-loaded PEGylated lipid nanoparticles(ADNPs)showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites.In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology.Therefore,the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.
文摘In the present work an attempt has been made to design the antibiotic drug loaded carbopolpoly( NVP) based hydrogel wound dressings for better wound care. The polymer films were characterized by SEM-EDX, AFM, FTIR, 13CNMR, TGA/DTA/DTG, DSC, and swelling studies. Besides drug release, various biomedical properties (viz. blood compatibility, mucoadhesion, oxygen permeability, water vapour transmission rate, microbial penetration, tensile strength, bursting strength, resilience, stress relaxation, and folding endurance) have also been studied. The polymer films have been observed to be biocompatible, permeable to oxygen and water vapour and have absorbed simulated wound fluid 11.37±0.31g/g of polymer film. The drug release profile followed the Case-II diffusion mechanism and release profile best fitted in Hixson-Crowell’s kinetic models. Mechanical properties results showed that the polymer film had 0.65±0.12 Nmm??2 tensile strength, 119.38±14.26% elongationand 25.49±0.72% resilience.
基金supported by the National Natural Science Foundation of China(Nos.82003784 and 81872789)the Fundamental Research Funds for the Central Universities(No.2682022ZTPY037,China)Large Instruments Open Foundation of Southwest Jiaotong University(No.2022SRII-046,China)。
文摘Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases,immune cell infiltration and protease-driven tissue damages.It is an urgent need to explore potential drug strategies for mitigating lung inflammation.Protease-activated receptor 2(PAR2)as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction.However,it has been rarely reported about the role of PAR2 in lung inflammation.This study applied CRISPR-Cas9 system encoding Cas9 and sg RNA(p Cas9-PAR2)for PAR2 knockout and fabricated an anionic human serum albuminbased nanoparticles to deliver p Cas9-PAR2 with superior inflammation-targeting efficiency and stability(TAP/p Cas9-PAR2).TAP/p Cas9-PAR2 robustly facilitated p Cas9-PAR2 to enter and transfect inflammatory cells,eliciting precise gene editing of PAR2 in vitro and in vivo.Importantly,PAR2 deficiency by TAP/p Cas9-PAR2 effectively and safely promoted macrophage polarization,suppressed proinflammatory cytokine releases and alleviated acute lung inflammation,uncovering a novel value of PAR2.It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/p Cas9-PAR2was mainly dependent on ERK-mediated NLRP3/IL-1β and NO/i NOS signalling.Therefore,this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.
基金supported by grants from the Research Unit Project of Chinese Academy of Medical Sciences(No.2019-I2M-5-030)the Research Project of Jinan Microecological Biomedicine Shandong Laboratory(No.JNL-2022002A)the Zhejiang Provincial Natural Science Foundation of China(No.LQ22H030009).
文摘Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure(ALF).Hence,reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting inflammation.Our group found Carvedilol possessed potential anti-inflammatory property previously,which had been scarcely reported in ALF.We present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4(IL-4)and IL-10 at first.Then Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform(termed as M2M@CNP)to evade reticuloendothelial system(RES)and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species(ROS),further prolonging its circulation and accumulation.Sustainably released Carvedilol produced anti-inflammatory,antioxidant and anti-apoptosis effects,combining local M2-type cell membranes(M2-CM)inhibited pro-inflammatory cytokines and ROS levels,which in turn promoted and amplified M1 to M2 phenotype polarization efficiency.This study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.
基金This research is supported by the National Natural Science Foundation of China (Nos. 21874013, 22074013, and 21775016)the Research Funds for the Central Universities (Nos. N182410008-1 and N2005027)+1 种基金the Talent Project of Revitalizing Liaoning (No. XLYC1807165)Special thanks are due to the instrumental or data analysis from Analytical and Testing Center, Northeastern University.
文摘Infectious diseases caused by bacteria are a global threat to the human health. Here, we propose a solvent “irrigation” technique to endow TiO_(2) nanotubes (NTs) to precisely modify with functional nanomaterials, and apply them in constructing a near-infrared (NIR) light controlled drug-delivery system for rapid necrosis of bacteria. In this design, the NIR stimuli-responsive functional shell is located on the external tube wall of TiO_(2) NT;the internal tube wall offers sufficient binding sites for drug loading. Using kanamycin as a model drug, we demonstrate that the reactive oxygen species generated in photocatalysis not only controllably release the loaded drug by scissoring the linked chains, but also effectively compromise bacteria membrane integrity by damaging the cell wall. Benefiting from the damages, antibiotics rapidly enter the bacteria and reach ≥99.9% reduction in Escherichia coli colony within only 2 h. Importantly, such a covalently conjugation-based delivery system can efficiently relieve radical-induced inflammation and cytotoxicity. This study provides an innovative design strategy for engineering delivery systems with tailorable components, enduring stimuli-response by multiple triggers.
