Active target time projection chambers are state-of-the-art tools in the field of low-energy nuclear physics and are particularly suitable for experiments using low-intensity radioactive ion beams or gamma rays.The Fu...Active target time projection chambers are state-of-the-art tools in the field of low-energy nuclear physics and are particularly suitable for experiments using low-intensity radioactive ion beams or gamma rays.The Fudan multi-purpose active target time projection chamber(fMeta-TPC)with 2048 channels was developed to studyα-clustering nuclei.This study focused on the photonuclear reaction with a laser Compton scattering gamma source,particularly for the decay of the highly excitedαcluster state.The design of fMeta-TPC is described in this paper.A comprehensive evaluation of its offline performance was conducted using an ultraviolet laser and ^(241)Amαsource.The results showed that the intrinsic angular resolution of the detector was within 0.30°,and the detector had an energy resolution of 6.85%for 3.0 MeVαparticles.The gain uniformity of the detector was approximately 10%(RMS/Mean),as tested by the ^(55)Fe X-ray source.展开更多
Targeting drug delivery systems mediated by nanoparticles has shown great potential in the diagnosis and treatment of cancer.However,influences of different tumor progressions on the accumulation of nanoparticles,espe...Targeting drug delivery systems mediated by nanoparticles has shown great potential in the diagnosis and treatment of cancer.However,influences of different tumor progressions on the accumulation of nanoparticles,especially the ligand-modified active targeting nanoparticles are seldom exploited.In this work,the accumulation and penetration of RGD-modified gold nanoparticles(active AuNPs)with different sizes were investigated in orthotopic breast cancer with different tumor progressions.The results showed that the smallest active AuNPs had better accumulation and permeation effects in early tumor tissues with the relatively looser extracellular matrix,larger gaps,lower interstitial fluid pressure,and less receptor expression,which was due to size effects.However,the larger active AuNPs had better accumulation and penetration effects in late tumor tissues with highly expressed target receptors integrinαvβ3 because of the multivalent interactions between larger active nanoparticles and integrinαvβ3.In the midterm,tumor accumulation of active AuNPs was equally influenced by size effects and multivalent interactions.Therefore,RGD-modified nanoparticles with sizes of 7 and 90 nm accumulated more in tumors.This study will guide a rational design of active targeting nanoparticles for enhancing the diagnosis and treatment of tumors based on their progressions.展开更多
This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by ...This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.展开更多
The ^(12)C+^(12)C fusion reaction was studied in the range of E_(c.m.)=8.9 to 21 MeV using the active-target Time Projection Chamber.With full information on all tracks of the reaction products,cross sections of the^(...The ^(12)C+^(12)C fusion reaction was studied in the range of E_(c.m.)=8.9 to 21 MeV using the active-target Time Projection Chamber.With full information on all tracks of the reaction products,cross sections of the^(12)C(^(12)C,^(8)Be)^(16)O_(g.s.)channel and the ^(12)C(^(12)C,3a)^(12)C channel could be measured down to the level of a few milibarns.The ^(12)C(^(12)C,^(8)Be)^(16)O_(g.s.)reaction channel was determined to be 10_(-8)^(+24) mb at E_(c.m.)=11.1 MeV,supporting the direct a transfer reaction mechanism.The ^(12)C(^(12)C,3α)^(12)C reaction channel was studied for the first time using an exclusive measurement.Our result does not confirm the anomaly behavior reported in the previous inclusive measurement by Kolata et al.[Phys.Rev.C 21,579(1980)].Our comparisons with statistical model calculations suggest that the 3 a channel is dominated by the fusion evaporation process at E_(c.m.)>19 MeV.The additional contribution of the 3 a channel increases the fusion reaction cross section by 10% at energies above 20 MeV.We also find that an additional reaction mechanism is needed to explain the measured cross section at E_(c.m.)<15 MeV at which point the statistical model prediction vanishes.展开更多
This article mainly introduced novel carrier-modified methods for active targeting antitumor preparation as well as their evaluation methodology in recent years. By reviewing related domestic and overseas literatures,...This article mainly introduced novel carrier-modified methods for active targeting antitumor preparation as well as their evaluation methodology in recent years. By reviewing related domestic and overseas literatures, the up-to-date scientific researches concerning active targeting antitumor preparation were elaborated and the problems existing in present studies were discussed. Numerous valid vector- embellished methods had been discovered with excellent targeting effects, and the significant progress was acquired for the evaluation tools in vitroand in vivo. The active targeting agent would be a major direction in prospective tumor or cancer therapeutic regimen.展开更多
Brain metastasis is a major cause of death in patients with solid cancers. Breast cancer cells have high tendency to migrate towards brain. Cancer cells within brain are characterized by severe aggressiveness and inac...Brain metastasis is a major cause of death in patients with solid cancers. Breast cancer cells have high tendency to migrate towards brain. Cancer cells within brain are characterized by severe aggressiveness and inaccessibility. Currently, breast cancer and its metastasis are the second leading cause of death among women. Tumor microenvironment and blood brain barrier (BBB) represent great obstacles in targeting breast cancer and its metastasis. Chemotherapy is a safer treatment modality for brain metastasis compared with risky surgical resection and brain radiotherapy. Unfortunately, conventional chemotherapy lack penetration of BBB and suffer from multiple resistance mechanisms. Current treatment technologies for brain metastases of breast cancer have limited long-term success and numerous side effects, illustrating the urgent need for novel smart strategies. Various novel drug entities and nanosystems have been employed to improve diagnosis and targeted treatment of breast cancer and its metastasis. Immunotherapy agents and small tyrosine kinase inhibitors have been shown to reduce tumor size and increase survival in patients with breast cancer, but still poorly penetrate BBB. Tailored sized nanoparticles to some extent crossed brain tumor barrier and enhanced drug accumulation in tumors by taking advantage of enhanced permeability and retention. Furthermore, various active targeting strategies have been adopted to improve accessibility to brain malignancies. Therefore, to achieve enhanced antitumor therapy against ;breast cancer and its brain metastasis, multi-talented delivery systems are urgently needed for optimal treatment. This review focuses on the various active and passive targeting technologies for the treatment of breast cancer brain metastases in the past decade. A comprehensive summary and examples along with pros and cons of each system will be discussed. Different treatment modalities and nanotechnology facilities will be demonstrated to aid in designing the optimal smart, safe, targeted and effective systems to combat brain metastases of breast cancer.展开更多
Nowadays,although functionalized pillararenes have been widely designed to be used in drug delivery system,targeted group modified pillararenes have been seldom reported and used in tumor multimodal therapy.Herein,a f...Nowadays,although functionalized pillararenes have been widely designed to be used in drug delivery system,targeted group modified pillararenes have been seldom reported and used in tumor multimodal therapy.Herein,a functionalized pillararene with a polyethylene glycol chain and triphenylphosphonium cation WP5-PEG-TPP was designed and synthesized.Subsequently,an active targeted drug delivery system was constructed based on its host-vip interactions with a newly designed porphyrin derivative,Py-Por.The experimental results demonstrated that this drug delivery system has exhibited excellent targeting ability against tumor cells,but interestingly it could not enter normal cells.After loading the hypoxia-activated prodrug tirapazamine,the prepared nanodrugs displayed high lethality to tumor cells due to their chemo/photodynamic synergistic therapy capability,but negligible toxicity to normal cells.Preliminary therapeutic mechanism study elucidated the synergistic therapy process.展开更多
Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains c...Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.展开更多
It was reported that a 5-amino acid peptide Ala-Pro-Arg-Pro-Gly （APRPG） could specifically bind to the tumor angiogenic site. We investigated the antitumor efficacy of doxorubicin （DOX） encapsulated in APRPG modif...It was reported that a 5-amino acid peptide Ala-Pro-Arg-Pro-Gly （APRPG） could specifically bind to the tumor angiogenic site. We investigated the antitumor efficacy of doxorubicin （DOX） encapsulated in APRPG modified liposome （APRPG-LP） compared with DOX encapsulated in non-APRPG modified liposomes （LP） and DOX solution （flee DOX） on Lewis lung carcinoma （LLC） bearing mice. APRPG-LP could efficiently suppress the tumor growth of the experimental mice, compared with LP （P〈0.001）, free DOX （P〈0.001） and saline of negative control （P〈0.001）. The present results demonstrated that the APRPG modified liposomes exhibited a much better therapeutic efficacy over the non-modified liposomes and the DOX solution, because of the effect of targeted tumor angiogenesis disruption. Thus, APRPG-LP could be a promising active-targeting drug carrier to tumor angiogenic site.展开更多
Hyperbranched polysulfonamine （HPSA） is a promising biomaterial due to its highly branched spherical architecture and efficient intracellular translocation. To realize the fianctionalization of HPSA, both N-succinim...Hyperbranched polysulfonamine （HPSA） is a promising biomaterial due to its highly branched spherical architecture and efficient intracellular translocation. To realize the fianctionalization of HPSA, both N-succinimidyl 3-（2- pyridyldithio） propionate （SPDP） for tethering the human-mouse chimeric monoclonal antibody CH12 and N-hydroxy succinimidyl S-acetylmercaptoacetyltriglycinate （NHS-MAG3） for labeling 188Re were sequentially grafted onto the primary amine terminals of HPSA via covalent linkages, attaining the SPDP-HPSA-MAG3 intermediate. In order to reserve the structural integrity of CH12, the fragment crystallizable （Fc） region was also processed by oxidation of oligosaccharide moieties with sodium periodate and then reacted with N-（κ-maleimidoundecanoic acid） hydrazide （KMUH）. After chelating 188Re with MAG3 group, the SPDP was reduced to PDP and connected onto the maleinimide group at the Fc region. As a result, both the epidermal growth factor receptor viii （EGFRvIII） targeted monoclonal antibody CH12 and the radionuclide 188Re were conjugated to the HPSA-based vehicles, forming the 188Re-labeled and CH12-tethered HPSA （CH12-HPSA- 188Re）. The molecular weight and in vitro stability of CH12-HPSA-188Re were evaluated by gel electrophoresis and paper chromatography. On one hand, the CH12-HPSA-188Re could specifically bind to the EGFRvlII-positive human hepatocarcinoma cells in vitro. On the other hand, it could also target at the tumor tissue of nude mice in vivo. Hence, the CH12-HPSA-188Re could effectively target at the human hepatocarcinoma and facilitate the tumor detection and targeted radioimmunotherapy.展开更多
Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma si...Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma site after SCI.This intrinsic targeting,coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI.Worth mentioning,macrophages have multiple polarization states,which may not be ignored when designing macrophage-based delivery systems.Herein,we fabricated macrophage membrane-camouflaged liposomes(RM-LIPs)and evaluated their abilities to extend drug circulation time and target the injured spinal cord.Specially,we detected the expression levels of the two main targeted receptors Mac-1 and integrinα4 in three macrophage subtypes,including unactivated(M0)macrophages,classically activated(M1)macrophages and alternatively activated(M2)macrophages,and compared targeting of these macrophage membrane-coated nanoparticles for SCI.The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro.RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo.Besides,RM-LIPs loaded with minocycline(RM-LIP/MC)showed a comprehensive therapeutic effect on SCI mice,and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI.Moreover,the levels of Mac-1 and integrinα4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states.Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.展开更多
Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation ...Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop.The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate(MTX)self-assembles into nanoparticles(VSeM);decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time.Upon reaching tumor sites,acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake.Afterward,the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release;then the released VES could produce extra ROS to accelerate the collapse of VSeM.Finally,the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy.Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.展开更多
Waxy maize is a specialty maize that produces mainly amylopectin starch with special food or industrial values. The objective of this study was to overcome the limitations of wx mutant allele acquisition and breeding ...Waxy maize is a specialty maize that produces mainly amylopectin starch with special food or industrial values. The objective of this study was to overcome the limitations of wx mutant allele acquisition and breeding efficiency by conversion of parental lines from normal to waxy maize. The intended mutation activity was achieved by in vivo CRISPR/Cas9 machinery involving desired-target mutation of the Wx locus in the ZC01 background,abbreviated as ZC01-DTM^(wx). Triple selection was applied to segregants to obtain high genome background recovery with transgene-free wx mutations. The targeted mutation was identified, yielding six types of mutations among progeny crossed with ZC01-DTM^(wx).The amylopectin contents of the endosperm starch in mutant lines and hybrids averaged94.9%, while those of the wild-type controls were significantly(P < 0.01) lower, with an average of 76.9%. Double selection in transgene-free lines was applied using the Bar strip test and Cas9 PCR screening. The genome background recovery ratios of the lines were determined using genome-wide SNP data. That of lines used as male parents was as high as98.19% and that of lines used as female parents was as high as 86.78%. Conversion hybrids and both parental lines showed agronomic performance similar to that of their wild-type counterparts. This study provides a practical example of the efficient extension of CRISPR/Cas9 targeted mutation to industrial hybrids for transformation of a recalcitrant species.展开更多
Although the benefits of China’s trade expansion have been distributed much more broadly than those of some early industrialized nations,China has become the primary target of anti-dumping activities.Being a new and ...Although the benefits of China’s trade expansion have been distributed much more broadly than those of some early industrialized nations,China has become the primary target of anti-dumping activities.Being a new and relatively efficient new rival in the global market may be an important reason for this.On the other hand,China’s development stage and her trade structure also place her in a disadvantageous position when it comes to anti-dumping activities.展开更多
Microbubbles can enhance the detection in noninvasive ultrasound imaging.Recently,targeted microbubbles have been developed to selectively adhere to specific and overexpressed p molecules in endothelial cells in some ...Microbubbles can enhance the detection in noninvasive ultrasound imaging.Recently,targeted microbubbles have been developed to selectively adhere to specific and overexpressed p molecules in endothelial cells in some pathologic conditions.However,the law of展开更多
Objective:To improve the efficiency of drug delivery,a mannose vinyl stearate mannose ligand(Man ligand)with active liver-targeting properties was synthesized.Methods:Non-aqueous enzymatic synthesis was used to modify...Objective:To improve the efficiency of drug delivery,a mannose vinyl stearate mannose ligand(Man ligand)with active liver-targeting properties was synthesized.Methods:Non-aqueous enzymatic synthesis was used to modify the structure of mannose.Glycyrrhetinic acid-tanshinone lipid nanoparticles(GT-LN)and liver-targeted glycyrrhetinic acid-tanshinone mannose-modified lipid nanoparticles(GT-MLN)were prepared.The physicochemical properties and release profiles of both formulations were evaluated,and their pharmacokinetic behavior and tissue distribution were investigated.Results:The average particle sizes of GT-LN and GT-MLN were 190.20±1.35 and 204.83±3.86 nm,respectively,with corresponding surface Zeta potentials of-28.0±1.68 and-30.24±2.10 mV.The drug release profile of GT-LN conformed to the Higuchi equation,whereas that of GT-MLN followed both the first-order kinetic and RitgerePeppas equations.Both formulations significantly enhanced the gastrointestinal stability of the drug.In vivo studies in mice demonstrated that hepatic GA and TSN concentrations in both groups were significantly higher than those in the original drug suspension group(P=.01).Notably,the concentrations in the GT-MLN group were significantly higher compared to the GTLN group(P=.01).Conclusion:Man ligand was formed via the linkage of vinyl stearate with the hydroxyl group at C-6 in mannose.The Manligand endowed these lipid nanoparticles with obvious active liver-targeting properties.Our results provide an efficient and stable route of drug delivery to the liver with improved drug availability.展开更多
Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpre...Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin(DDP)for bladder cancer treatment.Methods:The liposomes were prepared by ethanol injection and high-pressure microjet homogenization.The liposomes were characterized,and the drug content,entrapment efficiency,andin vitro release were studied.The targeting efficiency was investigated using confocal microscopy,ultra-fast liquid chromatography,and an orthotopic bladder cancer model.The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8(CCK-8)assay,a colony formation assay,and cell apoptosis and cell cycle analyses.The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model.Results:ATF24-PEG-Lipo-β-E had small and uniform sizes(~79 nm),high drug loading capacity(~5.24 mg/mL),high entrapment efficiency(98.37±0.95%),and exhibited sustained drug release behavior.ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol(PEG)ylatedβ-elemene liposomes(PEG-Lipo-β-E).DDP,combined with ATF24-PEG-Lipo-β-E,exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase,and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways.Furthermore,thein vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors,using the combined strategy.Conclusions:The present study provided an effective strategy for the targeted delivery ofβ-elemene(β-E)to bladder cancer,and a combined strategy for bladder cancer treatment.展开更多
Objective:To compare the targeting effects of lactosarninated alginate(AlgNP)、polyethylene glycol - coated hydroxyapatite- poly- L- lysine nanoparticles (PLL- PCHNP)and relative nonlactosaminated ones load ed with ex...Objective:To compare the targeting effects of lactosarninated alginate(AlgNP)、polyethylene glycol - coated hydroxyapatite- poly- L- lysine nanoparticles (PLL- PCHNP)and relative nonlactosaminated ones load ed with exogenous gene on liver via peripheral intravenous route. Methods:Preparation of AlgNP based on control of gelification phenomenon of algiante by calcium ions and HA- PLLNP with collosol - gel method, both further modified with lactosaminated - poly- L - lysine synthesized by reductive lactosamination . We used pEGFPCl as the reporter gene to establish receptor- mediated and positive liver targeting nanoparticles- gene model. The potential of adsorbing DNA on nanoparticles was analysed by electrophoresis and spectrophotometer. Then different complexes were transferred into the rat's body by peripheral intravenous route and their targeting characteristics in liver were investigated by using radioisotope tracing assay. Results: PCHNP presented as needle - like particles with a diameter of 20nm by TEM and could be effectively combined with PLL. The diameter of AlgNP was 280nm. Agarpse gel electrophoresis showed both nanoparticles could effectively combine with DNA and the optimal proportion of PLLPCHNP and DNA was 30:1 (w/w); DNA mixed ratio of AlgPLL was 68.3 % by spectrophotometer. The radioactivities in liver for the two lactosaminated nanoparticles were higher than the nonlactosaminated ones. No statistic difference between AlgNP and AlgLacNP could be found . Conclusions: Lactosaminated naroparticles can target to liver more effectively by peripheral intravenous route than nonlactosaminated ones, which is closely concerned with the characteritics of the nanopartide complex.展开更多
The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At...The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At the same time,SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modifi-cation can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs,proteins and carriers in drug delivery systems.展开更多
Extensive research has been performed on cell membrane camouflaged-based drug delivery systems in recent years.Herein,we provide an overview of the challenges in system preparation,functional design,continuous industr...Extensive research has been performed on cell membrane camouflaged-based drug delivery systems in recent years.Herein,we provide an overview of the challenges in system preparation,functional design,continuous industrial production of these systems,and solution strategies for these challenges.Further,we analyze and discuss the frontier medical applications of cell membrane-camouflaged drug delivery systems in anti-inflammatory,anti-pathogenic microorganisms,and biological detoxification.This review takes a challenge-oriented perspective and seeks innovative strategies,provides a literature review of research into cell membrane-camouflaged drug delivery systems,and promotes the development of personalized clinical treatments.展开更多
基金supported by the National Key R&D Program of China(Nos.2022YFA1602402,2020YFE0202001,2023YFA1606900)the National Natural Science Foundation of China(NSFC)(Nos.12235003,11835002,11925502,11705031,12275053,12147101).
文摘Active target time projection chambers are state-of-the-art tools in the field of low-energy nuclear physics and are particularly suitable for experiments using low-intensity radioactive ion beams or gamma rays.The Fudan multi-purpose active target time projection chamber(fMeta-TPC)with 2048 channels was developed to studyα-clustering nuclei.This study focused on the photonuclear reaction with a laser Compton scattering gamma source,particularly for the decay of the highly excitedαcluster state.The design of fMeta-TPC is described in this paper.A comprehensive evaluation of its offline performance was conducted using an ultraviolet laser and ^(241)Amαsource.The results showed that the intrinsic angular resolution of the detector was within 0.30°,and the detector had an energy resolution of 6.85%for 3.0 MeVαparticles.The gain uniformity of the detector was approximately 10%(RMS/Mean),as tested by the ^(55)Fe X-ray source.
基金supported by the Science and Technology Innovation Plan Laboratory Animal Research Project of Shanghai(23141900400)the National Natural Science Foundation of China(82172746 and 82473342)International Cooperation Project of Shanghai Science and Technology Innovation Plan(24410741500).
文摘Targeting drug delivery systems mediated by nanoparticles has shown great potential in the diagnosis and treatment of cancer.However,influences of different tumor progressions on the accumulation of nanoparticles,especially the ligand-modified active targeting nanoparticles are seldom exploited.In this work,the accumulation and penetration of RGD-modified gold nanoparticles(active AuNPs)with different sizes were investigated in orthotopic breast cancer with different tumor progressions.The results showed that the smallest active AuNPs had better accumulation and permeation effects in early tumor tissues with the relatively looser extracellular matrix,larger gaps,lower interstitial fluid pressure,and less receptor expression,which was due to size effects.However,the larger active AuNPs had better accumulation and penetration effects in late tumor tissues with highly expressed target receptors integrinαvβ3 because of the multivalent interactions between larger active nanoparticles and integrinαvβ3.In the midterm,tumor accumulation of active AuNPs was equally influenced by size effects and multivalent interactions.Therefore,RGD-modified nanoparticles with sizes of 7 and 90 nm accumulated more in tumors.This study will guide a rational design of active targeting nanoparticles for enhancing the diagnosis and treatment of tumors based on their progressions.
文摘This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.
基金Supported in part by the Strategic Priority Research Program of Chinese Academy of Sciences(XDB34020200)the National Key Research and Development program(MOST 2016YFA0400501)from the Ministry of Science and Technology of China+2 种基金the State Key Laboratory of Nuclear Physics and Technology,PKU(NPT2020KFY06)the National Natural Science Foundation of China(U1632142,12175156),the National Natural Science Foundation of China(11905260)the Western Light Project of Chinese Academy of Sciences。
文摘The ^(12)C+^(12)C fusion reaction was studied in the range of E_(c.m.)=8.9 to 21 MeV using the active-target Time Projection Chamber.With full information on all tracks of the reaction products,cross sections of the^(12)C(^(12)C,^(8)Be)^(16)O_(g.s.)channel and the ^(12)C(^(12)C,3a)^(12)C channel could be measured down to the level of a few milibarns.The ^(12)C(^(12)C,^(8)Be)^(16)O_(g.s.)reaction channel was determined to be 10_(-8)^(+24) mb at E_(c.m.)=11.1 MeV,supporting the direct a transfer reaction mechanism.The ^(12)C(^(12)C,3α)^(12)C reaction channel was studied for the first time using an exclusive measurement.Our result does not confirm the anomaly behavior reported in the previous inclusive measurement by Kolata et al.[Phys.Rev.C 21,579(1980)].Our comparisons with statistical model calculations suggest that the 3 a channel is dominated by the fusion evaporation process at E_(c.m.)>19 MeV.The additional contribution of the 3 a channel increases the fusion reaction cross section by 10% at energies above 20 MeV.We also find that an additional reaction mechanism is needed to explain the measured cross section at E_(c.m.)<15 MeV at which point the statistical model prediction vanishes.
文摘This article mainly introduced novel carrier-modified methods for active targeting antitumor preparation as well as their evaluation methodology in recent years. By reviewing related domestic and overseas literatures, the up-to-date scientific researches concerning active targeting antitumor preparation were elaborated and the problems existing in present studies were discussed. Numerous valid vector- embellished methods had been discovered with excellent targeting effects, and the significant progress was acquired for the evaluation tools in vitroand in vivo. The active targeting agent would be a major direction in prospective tumor or cancer therapeutic regimen.
文摘Brain metastasis is a major cause of death in patients with solid cancers. Breast cancer cells have high tendency to migrate towards brain. Cancer cells within brain are characterized by severe aggressiveness and inaccessibility. Currently, breast cancer and its metastasis are the second leading cause of death among women. Tumor microenvironment and blood brain barrier (BBB) represent great obstacles in targeting breast cancer and its metastasis. Chemotherapy is a safer treatment modality for brain metastasis compared with risky surgical resection and brain radiotherapy. Unfortunately, conventional chemotherapy lack penetration of BBB and suffer from multiple resistance mechanisms. Current treatment technologies for brain metastases of breast cancer have limited long-term success and numerous side effects, illustrating the urgent need for novel smart strategies. Various novel drug entities and nanosystems have been employed to improve diagnosis and targeted treatment of breast cancer and its metastasis. Immunotherapy agents and small tyrosine kinase inhibitors have been shown to reduce tumor size and increase survival in patients with breast cancer, but still poorly penetrate BBB. Tailored sized nanoparticles to some extent crossed brain tumor barrier and enhanced drug accumulation in tumors by taking advantage of enhanced permeability and retention. Furthermore, various active targeting strategies have been adopted to improve accessibility to brain malignancies. Therefore, to achieve enhanced antitumor therapy against ;breast cancer and its brain metastasis, multi-talented delivery systems are urgently needed for optimal treatment. This review focuses on the various active and passive targeting technologies for the treatment of breast cancer brain metastases in the past decade. A comprehensive summary and examples along with pros and cons of each system will be discussed. Different treatment modalities and nanotechnology facilities will be demonstrated to aid in designing the optimal smart, safe, targeted and effective systems to combat brain metastases of breast cancer.
基金National Natural Science Foundation of China(Grant No.32301184)Universities Natural Science Research Project of Jiangsu Province(Grant No.23KJB150027).
文摘Nowadays,although functionalized pillararenes have been widely designed to be used in drug delivery system,targeted group modified pillararenes have been seldom reported and used in tumor multimodal therapy.Herein,a functionalized pillararene with a polyethylene glycol chain and triphenylphosphonium cation WP5-PEG-TPP was designed and synthesized.Subsequently,an active targeted drug delivery system was constructed based on its host-vip interactions with a newly designed porphyrin derivative,Py-Por.The experimental results demonstrated that this drug delivery system has exhibited excellent targeting ability against tumor cells,but interestingly it could not enter normal cells.After loading the hypoxia-activated prodrug tirapazamine,the prepared nanodrugs displayed high lethality to tumor cells due to their chemo/photodynamic synergistic therapy capability,but negligible toxicity to normal cells.Preliminary therapeutic mechanism study elucidated the synergistic therapy process.
基金support from the National Natural Science Foundation of China(Grant Nos.:U21A20407 and 81973467).
文摘Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.
基金National Natural Science Foundation of China (Grant No.30772665)Beijing Nature Science Foundation(Grant No.7083111).
文摘It was reported that a 5-amino acid peptide Ala-Pro-Arg-Pro-Gly （APRPG） could specifically bind to the tumor angiogenic site. We investigated the antitumor efficacy of doxorubicin （DOX） encapsulated in APRPG modified liposome （APRPG-LP） compared with DOX encapsulated in non-APRPG modified liposomes （LP） and DOX solution （flee DOX） on Lewis lung carcinoma （LLC） bearing mice. APRPG-LP could efficiently suppress the tumor growth of the experimental mice, compared with LP （P〈0.001）, free DOX （P〈0.001） and saline of negative control （P〈0.001）. The present results demonstrated that the APRPG modified liposomes exhibited a much better therapeutic efficacy over the non-modified liposomes and the DOX solution, because of the effect of targeted tumor angiogenesis disruption. Thus, APRPG-LP could be a promising active-targeting drug carrier to tumor angiogenic site.
基金financially supported by the National Natural Science Foundation of China (Nos.20974062,30700175)National Basic Research Program (Nos.2009CB930400,2012CB821500)China National Funds for Distinguished Young Scientists (No.21025417)
文摘Hyperbranched polysulfonamine （HPSA） is a promising biomaterial due to its highly branched spherical architecture and efficient intracellular translocation. To realize the fianctionalization of HPSA, both N-succinimidyl 3-（2- pyridyldithio） propionate （SPDP） for tethering the human-mouse chimeric monoclonal antibody CH12 and N-hydroxy succinimidyl S-acetylmercaptoacetyltriglycinate （NHS-MAG3） for labeling 188Re were sequentially grafted onto the primary amine terminals of HPSA via covalent linkages, attaining the SPDP-HPSA-MAG3 intermediate. In order to reserve the structural integrity of CH12, the fragment crystallizable （Fc） region was also processed by oxidation of oligosaccharide moieties with sodium periodate and then reacted with N-（κ-maleimidoundecanoic acid） hydrazide （KMUH）. After chelating 188Re with MAG3 group, the SPDP was reduced to PDP and connected onto the maleinimide group at the Fc region. As a result, both the epidermal growth factor receptor viii （EGFRvIII） targeted monoclonal antibody CH12 and the radionuclide 188Re were conjugated to the HPSA-based vehicles, forming the 188Re-labeled and CH12-tethered HPSA （CH12-HPSA- 188Re）. The molecular weight and in vitro stability of CH12-HPSA-188Re were evaluated by gel electrophoresis and paper chromatography. On one hand, the CH12-HPSA-188Re could specifically bind to the EGFRvlII-positive human hepatocarcinoma cells in vitro. On the other hand, it could also target at the tumor tissue of nude mice in vivo. Hence, the CH12-HPSA-188Re could effectively target at the human hepatocarcinoma and facilitate the tumor detection and targeted radioimmunotherapy.
基金supported by the National Natural Science Foundation of China(No.81673376)the National Natural Science Foundation of Chongqing(cstc2015jcyj BX0100)the project for innovative Research Group at Higher Educational Institutions in Chongqing(CXQT20006)。
文摘Targeted delivery of therapeutics for spinal cord injury(SCI)has been a long-term challenge due to the complexity of the pathological procession.Macrophage,as an immune cell,can selectively accumulate at the trauma site after SCI.This intrinsic targeting,coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI.Worth mentioning,macrophages have multiple polarization states,which may not be ignored when designing macrophage-based delivery systems.Herein,we fabricated macrophage membrane-camouflaged liposomes(RM-LIPs)and evaluated their abilities to extend drug circulation time and target the injured spinal cord.Specially,we detected the expression levels of the two main targeted receptors Mac-1 and integrinα4 in three macrophage subtypes,including unactivated(M0)macrophages,classically activated(M1)macrophages and alternatively activated(M2)macrophages,and compared targeting of these macrophage membrane-coated nanoparticles for SCI.The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro.RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo.Besides,RM-LIPs loaded with minocycline(RM-LIP/MC)showed a comprehensive therapeutic effect on SCI mice,and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI.Moreover,the levels of Mac-1 and integrinα4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states.Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.
基金This work was partially supported by the National Natural Science Foundation of China(Grant Nos.81871483,81671813 and 61727823)the open project funding of The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province(Grant No.2018ZDSY2001).
文摘Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop.The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate(MTX)self-assembles into nanoparticles(VSeM);decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time.Upon reaching tumor sites,acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake.Afterward,the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release;then the released VES could produce extra ROS to accelerate the collapse of VSeM.Finally,the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy.Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.
基金supported the National Transgenic Science and Technology Program(2019ZX08010-003)the National Natural Science Foundation of China(31771808)+3 种基金the National Key Research and Development Program of China(2016YFD0101803)the Key Area Research and Development Program of Guangdong Province(2018B020202008)Beijing Municipal Science and Technology Commission(D171100007717001)National Engineering Laboratory for Crop Molecular Breeding。
文摘Waxy maize is a specialty maize that produces mainly amylopectin starch with special food or industrial values. The objective of this study was to overcome the limitations of wx mutant allele acquisition and breeding efficiency by conversion of parental lines from normal to waxy maize. The intended mutation activity was achieved by in vivo CRISPR/Cas9 machinery involving desired-target mutation of the Wx locus in the ZC01 background,abbreviated as ZC01-DTM^(wx). Triple selection was applied to segregants to obtain high genome background recovery with transgene-free wx mutations. The targeted mutation was identified, yielding six types of mutations among progeny crossed with ZC01-DTM^(wx).The amylopectin contents of the endosperm starch in mutant lines and hybrids averaged94.9%, while those of the wild-type controls were significantly(P < 0.01) lower, with an average of 76.9%. Double selection in transgene-free lines was applied using the Bar strip test and Cas9 PCR screening. The genome background recovery ratios of the lines were determined using genome-wide SNP data. That of lines used as male parents was as high as98.19% and that of lines used as female parents was as high as 86.78%. Conversion hybrids and both parental lines showed agronomic performance similar to that of their wild-type counterparts. This study provides a practical example of the efficient extension of CRISPR/Cas9 targeted mutation to industrial hybrids for transformation of a recalcitrant species.
文摘Although the benefits of China’s trade expansion have been distributed much more broadly than those of some early industrialized nations,China has become the primary target of anti-dumping activities.Being a new and relatively efficient new rival in the global market may be an important reason for this.On the other hand,China’s development stage and her trade structure also place her in a disadvantageous position when it comes to anti-dumping activities.
基金supported by National Natural Science Foundation of China,No.30700151
文摘Microbubbles can enhance the detection in noninvasive ultrasound imaging.Recently,targeted microbubbles have been developed to selectively adhere to specific and overexpressed p molecules in endothelial cells in some pathologic conditions.However,the law of
基金the High-level construction discipline of the National Administration of Traditional Chinese Medicine(zyyzdxk-2023272).
文摘Objective:To improve the efficiency of drug delivery,a mannose vinyl stearate mannose ligand(Man ligand)with active liver-targeting properties was synthesized.Methods:Non-aqueous enzymatic synthesis was used to modify the structure of mannose.Glycyrrhetinic acid-tanshinone lipid nanoparticles(GT-LN)and liver-targeted glycyrrhetinic acid-tanshinone mannose-modified lipid nanoparticles(GT-MLN)were prepared.The physicochemical properties and release profiles of both formulations were evaluated,and their pharmacokinetic behavior and tissue distribution were investigated.Results:The average particle sizes of GT-LN and GT-MLN were 190.20±1.35 and 204.83±3.86 nm,respectively,with corresponding surface Zeta potentials of-28.0±1.68 and-30.24±2.10 mV.The drug release profile of GT-LN conformed to the Higuchi equation,whereas that of GT-MLN followed both the first-order kinetic and RitgerePeppas equations.Both formulations significantly enhanced the gastrointestinal stability of the drug.In vivo studies in mice demonstrated that hepatic GA and TSN concentrations in both groups were significantly higher than those in the original drug suspension group(P=.01).Notably,the concentrations in the GT-MLN group were significantly higher compared to the GTLN group(P=.01).Conclusion:Man ligand was formed via the linkage of vinyl stearate with the hydroxyl group at C-6 in mannose.The Manligand endowed these lipid nanoparticles with obvious active liver-targeting properties.Our results provide an efficient and stable route of drug delivery to the liver with improved drug availability.
基金This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.81672932,81730108,81874380,and 81973635)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.LR18H160001)the Zhejiang Province Science and Technology Project of TCM(Grant No.2019ZZ016).
文摘Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin(DDP)for bladder cancer treatment.Methods:The liposomes were prepared by ethanol injection and high-pressure microjet homogenization.The liposomes were characterized,and the drug content,entrapment efficiency,andin vitro release were studied.The targeting efficiency was investigated using confocal microscopy,ultra-fast liquid chromatography,and an orthotopic bladder cancer model.The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8(CCK-8)assay,a colony formation assay,and cell apoptosis and cell cycle analyses.The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model.Results:ATF24-PEG-Lipo-β-E had small and uniform sizes(~79 nm),high drug loading capacity(~5.24 mg/mL),high entrapment efficiency(98.37±0.95%),and exhibited sustained drug release behavior.ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol(PEG)ylatedβ-elemene liposomes(PEG-Lipo-β-E).DDP,combined with ATF24-PEG-Lipo-β-E,exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase,and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways.Furthermore,thein vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors,using the combined strategy.Conclusions:The present study provided an effective strategy for the targeted delivery ofβ-elemene(β-E)to bladder cancer,and a combined strategy for bladder cancer treatment.
文摘Objective:To compare the targeting effects of lactosarninated alginate(AlgNP)、polyethylene glycol - coated hydroxyapatite- poly- L- lysine nanoparticles (PLL- PCHNP)and relative nonlactosaminated ones load ed with exogenous gene on liver via peripheral intravenous route. Methods:Preparation of AlgNP based on control of gelification phenomenon of algiante by calcium ions and HA- PLLNP with collosol - gel method, both further modified with lactosaminated - poly- L - lysine synthesized by reductive lactosamination . We used pEGFPCl as the reporter gene to establish receptor- mediated and positive liver targeting nanoparticles- gene model. The potential of adsorbing DNA on nanoparticles was analysed by electrophoresis and spectrophotometer. Then different complexes were transferred into the rat's body by peripheral intravenous route and their targeting characteristics in liver were investigated by using radioisotope tracing assay. Results: PCHNP presented as needle - like particles with a diameter of 20nm by TEM and could be effectively combined with PLL. The diameter of AlgNP was 280nm. Agarpse gel electrophoresis showed both nanoparticles could effectively combine with DNA and the optimal proportion of PLLPCHNP and DNA was 30:1 (w/w); DNA mixed ratio of AlgPLL was 68.3 % by spectrophotometer. The radioactivities in liver for the two lactosaminated nanoparticles were higher than the nonlactosaminated ones. No statistic difference between AlgNP and AlgLacNP could be found . Conclusions: Lactosaminated naroparticles can target to liver more effectively by peripheral intravenous route than nonlactosaminated ones, which is closely concerned with the characteritics of the nanopartide complex.
基金the National Natural Science Foundation of China(Grant No.81373334).
文摘The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At the same time,SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modifi-cation can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs,proteins and carriers in drug delivery systems.
基金supported by the National Natural Science Foundation of China (No.82073789)Innovative Research Group at Higher Educational Institutions in Chongqing (No.CXQT20006)。
文摘Extensive research has been performed on cell membrane camouflaged-based drug delivery systems in recent years.Herein,we provide an overview of the challenges in system preparation,functional design,continuous industrial production of these systems,and solution strategies for these challenges.Further,we analyze and discuss the frontier medical applications of cell membrane-camouflaged drug delivery systems in anti-inflammatory,anti-pathogenic microorganisms,and biological detoxification.This review takes a challenge-oriented perspective and seeks innovative strategies,provides a literature review of research into cell membrane-camouflaged drug delivery systems,and promotes the development of personalized clinical treatments.
