Camptothecin(CPT)exhibits potent antitumor activity;however,its clinical application is limited by significant gastrointestinal adverse effects(GAEs).Although the severity of GAEs associated with CPT derivatives has d...Camptothecin(CPT)exhibits potent antitumor activity;however,its clinical application is limited by significant gastrointestinal adverse effects(GAEs).Although the severity of GAEs associated with CPT derivatives has decreased,the incidence rate of these adverse effects has remained high.CPT multifunctional nanoparticles(PCRHNs)have the potential to increase the efficacy of CPT while reducing side effects in major target organs;however,the impact of PCRHNs on the GAEs from CPT remains uncertain.Here,we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota.We found that the therapeutic efficacy of PCRHNs+Laser treatment was superior to that of high-dose CPT,and PCRHNs+Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity,intestinal microbiota diversity,and intestinal microbiota abundance.In summary,compared to high-dose CPT treatment,PCRHNs+Laser treatment can effectively balance therapeutic effects and GAEs.A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella,which may be attributed to diarrhea caused by CPT,thus leading to a reduction in microbial burden;additionally,Escherichia-Shigella rapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea.PCRHNs+Laser treatment increased the abundance of Lactobacillus(probiotics),possibly due to the photothermal effect of the PCRHNs.This effect increased catalase activity,thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body,which is conducive to the growth of facultative anaerobic bacteria.展开更多
Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens,including prolonged circulation in the bloodstream,specific cell recognition and targeting...Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens,including prolonged circulation in the bloodstream,specific cell recognition and targeting capabilities,and potential for immunotherapy.Herein,we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs.Comprising microporous Prussian blue nanoparticles(MPB NPs)serving as both a photothermal sensitizer and carrier for 3-bromopyruvate(3BP),these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory proteinα(SIRPα)with enhanced affinity to CD47.As a result,MPB-3BP@CM NPs inherit the characteristics of the original cell membrane,exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer(CRC)cells.Notably,blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages.Additionally,3BP,an inhibitor of hexokinase II(HK2),suppresses glycolysis,leading to a reduction in adenosine triphosphate(ATP)levels and lactate production.Besides,it promotes the polarization of tumor-associated macrophages(TAMs)towards an anti-tumor M1 phenotype.Furthermore,integration with MPB NPs-mediated photothermal therapy(PTT)enhances the therapeutic efficacy against tumors.These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC.Concurrently,it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.展开更多
The production of CaC2 from coke/lime powders and compressed powder pellets are low cost and fast processes. A number of studies have reported the reaction kinetics of these reactions but they are still not well under...The production of CaC2 from coke/lime powders and compressed powder pellets are low cost and fast processes. A number of studies have reported the reaction kinetics of these reactions but they are still not well understood and the proposed kinetic models are not comparable due to differences in the reaction conditions. Therefore the reaction behavior of CaO/C powders （0.074 mm） and cubes （5 mm × 5 mm × （4.6-5.1） mm） compressed from a mixture of powders have been studied using thermal gravimetric analysis （TGA） at 1700- 1850 ℃. Kinetic models were obtained from the TGA data using isoconversional and model-fitting methods. The reaction rates for the compressed feeds were lower than those for the powder feeds. This is due to the reduced surface area of the compressed samples which inhibits heat transfer from the surrounding environment （or the heating source） to the sample. The compression pressure had little influence on the reaction rate. The reaction kinetics of both the powder and the compressed feeds can be described by the contracting volume modelf（α） = 3（1 -α）^2/3, where a is the conversion rate of reactant. The apparent activation energy and pre-exponential factor of the powder feed were estimated to 346-354 kJ·mol^-1 and 5.9 x 10^7 min^-1, respectively, whereas those of the compressed feed were 305-327 kJ·mol^-1 and 3.6 ×10^6 min^-1, respectively.展开更多
Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity,their development is hindered by the limitations of ...Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity,their development is hindered by the limitations of neoantigens identification,low immunogenicity,and weak immune response.Cyclophosphamide(CTX)not only directly kills tumors but also causes immunogenic cell death,providing a promising source of antigens for cancer vaccines.Herein,a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is designed.First,CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity,and then 3 days later,PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune responses.The results confirm that this combined strategy reduces the toxicity of CTX,and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth,prolong survival,and significantly improve the tumor cure rate.Moreover,a long-lasting immune memory response is observed in the mice.About 90%of the cured mice survive for at least 60 days after being re-inoculated with tumors,and the distant tumor growth is also well inhibited.Hence,this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines.展开更多
The intracellular retention of nanotherapeutics is essential for their therapeutic activity.The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors.However,strategies for th...The intracellular retention of nanotherapeutics is essential for their therapeutic activity.The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors.However,strategies for the intracellular immobilization of nanoparticles are limited.Herein,a cisplatin prodrug was synthesized and utilized as a glutathione(GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly.The nanoassembly has been reprogrammed with peptidecontaining moieties for tumor-targeting and PD-1/PD-L1 blockade.The aggregation of the nanoassemblies is dependent on GSH concentration.Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species(ROS)generation and immunogenic cell death.Moreover,the nanoassemblies reinvigorate the immunocytes,especially the systemic immunocytes,and thereby alleviate pulmonary metastasis,even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics.This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo.展开更多
基金National Natural Science Foundation of China Regional Innovation and Development Joint Fund(NSFCU21A20417)National Natural Science Foundation of China(NSFC31930067,NSFC32001003,NSFC82202320)+5 种基金Natural Science Foundation of Sichuan Province(2022NSFSC1282)135 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD18002)We also thank the support by Post-Doctor Research Project,West China Hospital,Sichuan University(2023HXBH011,19HXBH099)Postdoctoral Interdisciplinary Innovation Foundation Project of Sichuan University(1082204112G23)China Postdoctoral Science Foundation(2023M742476)Natural Science Foundation of Sichuan Province(2023NSFSC1585).
文摘Camptothecin(CPT)exhibits potent antitumor activity;however,its clinical application is limited by significant gastrointestinal adverse effects(GAEs).Although the severity of GAEs associated with CPT derivatives has decreased,the incidence rate of these adverse effects has remained high.CPT multifunctional nanoparticles(PCRHNs)have the potential to increase the efficacy of CPT while reducing side effects in major target organs;however,the impact of PCRHNs on the GAEs from CPT remains uncertain.Here,we investigated the therapeutic effects of PCRHNs and different doses of CPT and examined their impacts on the intestinal barrier and the intestinal microbiota.We found that the therapeutic efficacy of PCRHNs+Laser treatment was superior to that of high-dose CPT,and PCRHNs+Laser treatment also provided greater benefits by helping maintain intestinal barrier integrity,intestinal microbiota diversity,and intestinal microbiota abundance.In summary,compared to high-dose CPT treatment,PCRHNs+Laser treatment can effectively balance therapeutic effects and GAEs.A high dose of CPT promotes the enrichment of the pathogenic bacteria Escherichia-Shigella,which may be attributed to diarrhea caused by CPT,thus leading to a reduction in microbial burden;additionally,Escherichia-Shigella rapidly grows and occupies niches previously occupied by other bacteria that are lost due to diarrhea.PCRHNs+Laser treatment increased the abundance of Lactobacillus(probiotics),possibly due to the photothermal effect of the PCRHNs.This effect increased catalase activity,thus facilitating the conversion of hydrogen peroxide into oxygen within tumors and increasing oxygen levels in the body,which is conducive to the growth of facultative anaerobic bacteria.
基金supported by the National Natural Science Foundation of China(NSFC82202320,NSFC31930067,and NSFC U21A2041)the Natural Science Foundation of Sichuan Province(2023NSFSC1585)+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Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens,including prolonged circulation in the bloodstream,specific cell recognition and targeting capabilities,and potential for immunotherapy.Herein,we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs.Comprising microporous Prussian blue nanoparticles(MPB NPs)serving as both a photothermal sensitizer and carrier for 3-bromopyruvate(3BP),these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory proteinα(SIRPα)with enhanced affinity to CD47.As a result,MPB-3BP@CM NPs inherit the characteristics of the original cell membrane,exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer(CRC)cells.Notably,blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages.Additionally,3BP,an inhibitor of hexokinase II(HK2),suppresses glycolysis,leading to a reduction in adenosine triphosphate(ATP)levels and lactate production.Besides,it promotes the polarization of tumor-associated macrophages(TAMs)towards an anti-tumor M1 phenotype.Furthermore,integration with MPB NPs-mediated photothermal therapy(PTT)enhances the therapeutic efficacy against tumors.These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC.Concurrently,it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.
基金Acknowledgements Financial support from the National Basic Research Program of China （2011CB201306） and the National Natural Science Foundation of China （Grant No. 20976011） are acknowledged.
文摘The production of CaC2 from coke/lime powders and compressed powder pellets are low cost and fast processes. A number of studies have reported the reaction kinetics of these reactions but they are still not well understood and the proposed kinetic models are not comparable due to differences in the reaction conditions. Therefore the reaction behavior of CaO/C powders （0.074 mm） and cubes （5 mm × 5 mm × （4.6-5.1） mm） compressed from a mixture of powders have been studied using thermal gravimetric analysis （TGA） at 1700- 1850 ℃. Kinetic models were obtained from the TGA data using isoconversional and model-fitting methods. The reaction rates for the compressed feeds were lower than those for the powder feeds. This is due to the reduced surface area of the compressed samples which inhibits heat transfer from the surrounding environment （or the heating source） to the sample. The compression pressure had little influence on the reaction rate. The reaction kinetics of both the powder and the compressed feeds can be described by the contracting volume modelf（α） = 3（1 -α）^2/3, where a is the conversion rate of reactant. The apparent activation energy and pre-exponential factor of the powder feed were estimated to 346-354 kJ·mol^-1 and 5.9 x 10^7 min^-1, respectively, whereas those of the compressed feed were 305-327 kJ·mol^-1 and 3.6 ×10^6 min^-1, respectively.
基金This work was financially supported by the National Natural Science Foundation of China(31930067,31525009,31800797 and 31771096)the National Key Research and Development Program of China(2017YFC1103502)+1 种基金China Postdoctoral Science Foundation(2018M631094 and 2019M653410)1⋅3⋅5project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18002).
文摘Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity,their development is hindered by the limitations of neoantigens identification,low immunogenicity,and weak immune response.Cyclophosphamide(CTX)not only directly kills tumors but also causes immunogenic cell death,providing a promising source of antigens for cancer vaccines.Herein,a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is designed.First,CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity,and then 3 days later,PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune responses.The results confirm that this combined strategy reduces the toxicity of CTX,and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth,prolong survival,and significantly improve the tumor cure rate.Moreover,a long-lasting immune memory response is observed in the mice.About 90%of the cured mice survive for at least 60 days after being re-inoculated with tumors,and the distant tumor growth is also well inhibited.Hence,this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines.
基金financially supported by the State Key Program of National Natural Science Foundation of China(31930067)the National Natural Science Fund for Distinguished Young Scholar(NSFC31525009,China)+3 种基金National Natural Science Funds(NSFC31771096,NSFC31871008,and NSFC31500809,China)the China Postdoctoral Science Foundation(2018M643484)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18002,China)the Post-Doctor Research Project,West China Hospital,Sichuan University(18HXBH038,China)。
文摘The intracellular retention of nanotherapeutics is essential for their therapeutic activity.The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors.However,strategies for the intracellular immobilization of nanoparticles are limited.Herein,a cisplatin prodrug was synthesized and utilized as a glutathione(GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly.The nanoassembly has been reprogrammed with peptidecontaining moieties for tumor-targeting and PD-1/PD-L1 blockade.The aggregation of the nanoassemblies is dependent on GSH concentration.Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species(ROS)generation and immunogenic cell death.Moreover,the nanoassemblies reinvigorate the immunocytes,especially the systemic immunocytes,and thereby alleviate pulmonary metastasis,even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics.This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo.
