To achieve a higher transfection efficiency and lower toxicity, a novel herringbone-like cationic lipid(2 ss HLL) composed of hydrophilic aspartic acid linked with two reduction-responsive cleavable hydrophobic olei...To achieve a higher transfection efficiency and lower toxicity, a novel herringbone-like cationic lipid(2 ss HLL) composed of hydrophilic aspartic acid linked with two reduction-responsive cleavable hydrophobic oleic acid tails was synthesized and assessed in this study. In our results, the cationic nanoplexes with a uniform spherical shape and a particle size of ~150 nm were successfully prepared by the electrostatic interaction between si RNAs and 2 ss HLL-based liposomes. From the results evaluated in Hep G2 cells, it was shown that the nanoplexes exhibited high cellular uptake of si RNA with a low cytotoxicity. Moreover, the significant down-regulation effects of 2 ss HLL/si EGFR nanoplexes on target m RNA were displayed by RT-PCR analysis, which were similar to those of Lipofectamine2000. It suggested that the enhanced si RNA gene silencing efficiency was probably attributed to the detachment of hydrophobic tail chains induced by reduction-responsive cleavage. This mechanism was also confirmed by the changes of size distribution and si RNA release of nanoplexes in the reductive environment and DTT-absence condition. Overall, we believed that the redox-active herringbone-like 2 ss HLL would be a potential nanocarrier towards si RNA delivery.展开更多
Tumor micro-environment responsive drug delivery systems (DDSs) have been developed as a potential approach to reduce the side effects of cancer chemotherapy. Glutathione (GSH) has been supposed to the most signif...Tumor micro-environment responsive drug delivery systems (DDSs) have been developed as a potential approach to reduce the side effects of cancer chemotherapy. Glutathione (GSH) has been supposed to the most significant signal of the difference between the normal tissue and the tumor cells, besides the media pH and temperature. In recent years, the reduction-responsive DDSs have attracted more and more attention for delivery of anti-cancer drugs, based on such physiological signal. Among them, disulfide bond-containing polymers have been designed as the main tool for the purpose. The recent progress in the synthesis strategies for the disulfide bond- containing polymer-based DDS is focused in the present review.展开更多
Breast cancer has become the most commonly diagnosed cancer type in the world.A combination of chemotherapy and photothermal therapy(PTT) has emerged as a promising strategy for breast cancer therapy.However,the intri...Breast cancer has become the most commonly diagnosed cancer type in the world.A combination of chemotherapy and photothermal therapy(PTT) has emerged as a promising strategy for breast cancer therapy.However,the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle.Therefore,to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect,a multifunctional nanoparticle system(PCRHNs) is developed,which is grafted onto the prussian blue nanoparticles(PB NPs) by reductionresponsive camptothecin(CPT) prodrug copolymer,and then modified with tumor-targeting peptide cyclo(Asp-D-Phe-Lys-Arg-Gly)(cRGD) and hyaluronic acid(HA).PCRHNs exhibited nano-sized structure with good monodispersity,high load efficiency of CPT,triggered CPT release in response to reduction environment,and excellent photothermal conversion under laser irradiation.Furthermore,PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT.In vivo studies indicate that PCRHNs exhibited excellent bio compatibility,prolonged blood circulation,enhanced tumor accumulation,allow tumor-specific che mo-photo thermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity.Moreover,hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT.Collectively,PCRHNs may be a promising therapeutic way for breast cancer therapy.展开更多
Drug delivery systems(DDSs)are of paramount importance to deliver drugs at the intended targets,e.g.,tumor cells or tissue by prolonging blood circulation and optimizing the pharmaceutical profiles.However,the therape...Drug delivery systems(DDSs)are of paramount importance to deliver drugs at the intended targets,e.g.,tumor cells or tissue by prolonging blood circulation and optimizing the pharmaceutical profiles.However,the therapeutic efficacy of DDSs is severely impaired by insufficient or non-specific drug release.Dynamic chemical bonds having stimuli-liable prope rties are the refore introduced into DDSs for regulating the drug release kinetics.This review summarizes the recent advances of dynamic covalent chemistry in the DDSs for improving cancer therapy.The review discusses the constitutions of the major classes of dynamic covalent bonds,and the respective applications in the tumor-targe ted DDSs which are based on the different responsive mechanisms,including acid-activatable and reduction-activatable.Furthermore,the review also discusses combination strategies of dual dynamic covale nt bonds which can response to the complex tumor microenvironment much more accurately,and then summarizes and analyzes the prospects for the application of dynamic covalent chemistry in DDSs.展开更多
Polymer systems can be designed into different structures and morphologies according to their physical and chemical performance requirements,and are considered as one of the most promising controlled delivery systems ...Polymer systems can be designed into different structures and morphologies according to their physical and chemical performance requirements,and are considered as one of the most promising controlled delivery systems that can effectively improve the cancer therapeutic index.However,the majority of the polymer delivery systems are designed to be simple spherical nanostructures.To explore morphology/size-oriented delivery performance optimization,here,we synthesized three novel cylindrical polymer brushes(CPBs)by atom transfer radical polymerization(ATRP),which were cellulose-g-(CPT-b-OEGMA)(CCO)with different lengths(~86,~40,and~21 nm).The CPBs are composed of bio-degradable cellulose as the carrier,poly(ethylene glycol)methyl ether methacrylate(OEGMA)as hydrophily block,and glutathione(GSH)-responsive hydrophobic camptothecin(CPT)monomer as loaded anticancer drug.By controlling the chain length of the initiator,three kinds of polymeric prodrugs with different lengths(CCO-1,CCO-2,and CCO-3)could be self-organized into unimolecular micelles in water.We carried out comparative studies of three polymers,whose results verified that the shorter CPBs exhibited higher drug release efficiency,more cellular uptake,and enhanced tumor permeability,accompanied by shortened blood circulation time and lower tumor accumulation.As evidenced by in vivo experiments,the shorter CPBs exhibited higher anti-tumor efficiency,revealing that the size advantage has a higher priority than the anisotropic structure advantage.This provided vital information as to design an anisotropic polymer-based drug delivery system for cancer therapy.展开更多
Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory resp...Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory responses. Herein, macrophage-targeting nanocomplexes (NCs) are developed to mediate efficient co-delivery of siRNA against MOF (siMOF) and microRNA-21 (miR21) into myocardial macrophages, cooperatively orches-trating the myocardial microenvironment against IR injury. Bioreducible, branched poly(β-amino ester) (BPAE-SS) is designed to co-condense siMOF and miR21 into NCs in a multivalency-reinforced approach, and they are surface-decorated with carboxylated mannan (Man-COOH) to shield the positive surface charges and enhance the serum stability. The final MBSsm NCs are efficiently internalized by myocardial macrophages after systemic administration, wherein BPAE-SS is degraded into small segments by intracellular glutathione to promote the siMOF/miR21 release, finally provoking efficient gene silencing. Thus, cardiomyocyte protection and macro-phage modulation are realized via the combined effects of ROS scavenging, inflammation inhibition, and autophagy attenuation, which ameliorates the myocardial microenvironment and restores the cardiac function via positive cellular crosstalk. This study renders promising solutions to address the multiple systemic barriers against in vivo nucleic acid delivery, and it also offers new options for IR injury by manipulating multiple reciprocal bio-reactions.展开更多
In this study, a networked swellable dextrin nanogel (DNG) was developed to achieve stimulated responsive small interfering RNA (siRNA) release for melanoma tumor therapy, siRNA was loaded into multidimensional de...In this study, a networked swellable dextrin nanogel (DNG) was developed to achieve stimulated responsive small interfering RNA (siRNA) release for melanoma tumor therapy, siRNA was loaded into multidimensional dextrin nanogels by charge condensation with positive arginine residues modified in the dextrin backbone. Moreover, the networked nanogel was destroyed and loosened based on its bioreducible responsive property to control accelerated siRNA release in a bioreducible intracellular environment, while it remained stable under normal physiological conditions. We demonstrated that DNGs had swellable and disassembly properties under reduced buffer condition by transmission electron microscopy evaluation. The DNGs achieved an endosomal escape followed by selective release of the cargo into the cytosol by glutathione- triggered disassembly according to confocal microscopy observation. Thus, this smart nanogel achieved outstanding luciferase gene silencing efficiency and decreased Bcl2 protein expression in vitro and in vivo based on western blot analysis. Moreover, this nanogel exhibited superior anti-tumor activity for B16F10 xenograft tumors in C57BL/6 mice. These results demonstrate that the networked DNGs are effective for gene condensation and controlled intracellular release for tumor therapy. Overall, these findings suggest that this multidimensional swellable stimuli-responsive dextrin nanogel is an innovative strategy with great promise for gene and drug delivery.展开更多
基金National Natural Science Foundation of China(Grant No.81473158,81690264 and 81773650)the New Drug R&D program of China(Grant No.2018ZX09721003-004)the Opening Project of Key Laboratory of Drug Targeting and Drug Delivery System,Ministry of Education(Sichuan University)
文摘To achieve a higher transfection efficiency and lower toxicity, a novel herringbone-like cationic lipid(2 ss HLL) composed of hydrophilic aspartic acid linked with two reduction-responsive cleavable hydrophobic oleic acid tails was synthesized and assessed in this study. In our results, the cationic nanoplexes with a uniform spherical shape and a particle size of ~150 nm were successfully prepared by the electrostatic interaction between si RNAs and 2 ss HLL-based liposomes. From the results evaluated in Hep G2 cells, it was shown that the nanoplexes exhibited high cellular uptake of si RNA with a low cytotoxicity. Moreover, the significant down-regulation effects of 2 ss HLL/si EGFR nanoplexes on target m RNA were displayed by RT-PCR analysis, which were similar to those of Lipofectamine2000. It suggested that the enhanced si RNA gene silencing efficiency was probably attributed to the detachment of hydrophobic tail chains induced by reduction-responsive cleavage. This mechanism was also confirmed by the changes of size distribution and si RNA release of nanoplexes in the reductive environment and DTT-absence condition. Overall, we believed that the redox-active herringbone-like 2 ss HLL would be a potential nanocarrier towards si RNA delivery.
基金Acknowledgements This project was granted financial support from the National Natural Science Foundation of China (Grant No. 20904017) and the Program for New Century Excellent Talents in University (Grant No. NCET-09-0441).
文摘Tumor micro-environment responsive drug delivery systems (DDSs) have been developed as a potential approach to reduce the side effects of cancer chemotherapy. Glutathione (GSH) has been supposed to the most significant signal of the difference between the normal tissue and the tumor cells, besides the media pH and temperature. In recent years, the reduction-responsive DDSs have attracted more and more attention for delivery of anti-cancer drugs, based on such physiological signal. Among them, disulfide bond-containing polymers have been designed as the main tool for the purpose. The recent progress in the synthesis strategies for the disulfide bond- containing polymer-based DDS is focused in the present review.
基金supported by the National Natural Science Foundation of China (NSFC31930067, NSFC31771096, and NSFC31700869)the National Key Research and Development Program of China (2017YFC1103502)+1 种基金the 135 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD18002, China)the Post-Doctor Research Project, West China Hospital, Sichuan University (No.19HXBH099, China)。
文摘Breast cancer has become the most commonly diagnosed cancer type in the world.A combination of chemotherapy and photothermal therapy(PTT) has emerged as a promising strategy for breast cancer therapy.However,the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle.Therefore,to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect,a multifunctional nanoparticle system(PCRHNs) is developed,which is grafted onto the prussian blue nanoparticles(PB NPs) by reductionresponsive camptothecin(CPT) prodrug copolymer,and then modified with tumor-targeting peptide cyclo(Asp-D-Phe-Lys-Arg-Gly)(cRGD) and hyaluronic acid(HA).PCRHNs exhibited nano-sized structure with good monodispersity,high load efficiency of CPT,triggered CPT release in response to reduction environment,and excellent photothermal conversion under laser irradiation.Furthermore,PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT.In vivo studies indicate that PCRHNs exhibited excellent bio compatibility,prolonged blood circulation,enhanced tumor accumulation,allow tumor-specific che mo-photo thermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity.Moreover,hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT.Collectively,PCRHNs may be a promising therapeutic way for breast cancer therapy.
基金Financial supports from the National Natural Science Foundation of China(Nos.31671024,51873228 and 31622025)the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2014218)+1 种基金the Fusion Grant between Fudan University and Shanghai Institute of Materia Medica,CAS(No.FU-SIMM20182006)the Open Project Program of Key Lab of Smart Drug Delivery(Ministry of Education),Department of Pharmaceutics,School of Pharmacy,Fudan University,China。
文摘Drug delivery systems(DDSs)are of paramount importance to deliver drugs at the intended targets,e.g.,tumor cells or tissue by prolonging blood circulation and optimizing the pharmaceutical profiles.However,the therapeutic efficacy of DDSs is severely impaired by insufficient or non-specific drug release.Dynamic chemical bonds having stimuli-liable prope rties are the refore introduced into DDSs for regulating the drug release kinetics.This review summarizes the recent advances of dynamic covalent chemistry in the DDSs for improving cancer therapy.The review discusses the constitutions of the major classes of dynamic covalent bonds,and the respective applications in the tumor-targe ted DDSs which are based on the different responsive mechanisms,including acid-activatable and reduction-activatable.Furthermore,the review also discusses combination strategies of dual dynamic covale nt bonds which can response to the complex tumor microenvironment much more accurately,and then summarizes and analyzes the prospects for the application of dynamic covalent chemistry in DDSs.
基金This work was financially supported by National Natural Science Foundation of China(51703187,31671037)the Basic and Frontier Research Project of Chongqing(cstc2018jcyjAX0104).
文摘Polymer systems can be designed into different structures and morphologies according to their physical and chemical performance requirements,and are considered as one of the most promising controlled delivery systems that can effectively improve the cancer therapeutic index.However,the majority of the polymer delivery systems are designed to be simple spherical nanostructures.To explore morphology/size-oriented delivery performance optimization,here,we synthesized three novel cylindrical polymer brushes(CPBs)by atom transfer radical polymerization(ATRP),which were cellulose-g-(CPT-b-OEGMA)(CCO)with different lengths(~86,~40,and~21 nm).The CPBs are composed of bio-degradable cellulose as the carrier,poly(ethylene glycol)methyl ether methacrylate(OEGMA)as hydrophily block,and glutathione(GSH)-responsive hydrophobic camptothecin(CPT)monomer as loaded anticancer drug.By controlling the chain length of the initiator,three kinds of polymeric prodrugs with different lengths(CCO-1,CCO-2,and CCO-3)could be self-organized into unimolecular micelles in water.We carried out comparative studies of three polymers,whose results verified that the shorter CPBs exhibited higher drug release efficiency,more cellular uptake,and enhanced tumor permeability,accompanied by shortened blood circulation time and lower tumor accumulation.As evidenced by in vivo experiments,the shorter CPBs exhibited higher anti-tumor efficiency,revealing that the size advantage has a higher priority than the anisotropic structure advantage.This provided vital information as to design an anisotropic polymer-based drug delivery system for cancer therapy.
基金This work was supported by the National Natural Science Foundation of China(82172076,51873142,and 52033006)Jiangsu Key Research and Development Plan(Social Development)Project(BE2020653 and BE2021642)+1 种基金Suzhou Science and Technology Development Project(SYS2019072)Collaborative Innovation Center of Suzhou Nano Science&Technology,the 111 project,Suzhou Key Laboratory of Nanotech-nology and Biomedicine,and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.
文摘Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory responses. Herein, macrophage-targeting nanocomplexes (NCs) are developed to mediate efficient co-delivery of siRNA against MOF (siMOF) and microRNA-21 (miR21) into myocardial macrophages, cooperatively orches-trating the myocardial microenvironment against IR injury. Bioreducible, branched poly(β-amino ester) (BPAE-SS) is designed to co-condense siMOF and miR21 into NCs in a multivalency-reinforced approach, and they are surface-decorated with carboxylated mannan (Man-COOH) to shield the positive surface charges and enhance the serum stability. The final MBSsm NCs are efficiently internalized by myocardial macrophages after systemic administration, wherein BPAE-SS is degraded into small segments by intracellular glutathione to promote the siMOF/miR21 release, finally provoking efficient gene silencing. Thus, cardiomyocyte protection and macro-phage modulation are realized via the combined effects of ROS scavenging, inflammation inhibition, and autophagy attenuation, which ameliorates the myocardial microenvironment and restores the cardiac function via positive cellular crosstalk. This study renders promising solutions to address the multiple systemic barriers against in vivo nucleic acid delivery, and it also offers new options for IR injury by manipulating multiple reciprocal bio-reactions.
文摘In this study, a networked swellable dextrin nanogel (DNG) was developed to achieve stimulated responsive small interfering RNA (siRNA) release for melanoma tumor therapy, siRNA was loaded into multidimensional dextrin nanogels by charge condensation with positive arginine residues modified in the dextrin backbone. Moreover, the networked nanogel was destroyed and loosened based on its bioreducible responsive property to control accelerated siRNA release in a bioreducible intracellular environment, while it remained stable under normal physiological conditions. We demonstrated that DNGs had swellable and disassembly properties under reduced buffer condition by transmission electron microscopy evaluation. The DNGs achieved an endosomal escape followed by selective release of the cargo into the cytosol by glutathione- triggered disassembly according to confocal microscopy observation. Thus, this smart nanogel achieved outstanding luciferase gene silencing efficiency and decreased Bcl2 protein expression in vitro and in vivo based on western blot analysis. Moreover, this nanogel exhibited superior anti-tumor activity for B16F10 xenograft tumors in C57BL/6 mice. These results demonstrate that the networked DNGs are effective for gene condensation and controlled intracellular release for tumor therapy. Overall, these findings suggest that this multidimensional swellable stimuli-responsive dextrin nanogel is an innovative strategy with great promise for gene and drug delivery.