Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoacti...Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune boosters.PLT-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor microenvironment.PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive environment.PLT-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold vs.control group)in mouse tumor model after intravenous or subcutaneous administration.Also,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and PD-L1.Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication.All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.展开更多
Despite the potential advantages of amorphism-induced supersaturation,the merit of new amorphiza-tion formation methods on the properties of the amorphous drug including the stability of the amor-phous state,dissoluti...Despite the potential advantages of amorphism-induced supersaturation,the merit of new amorphiza-tion formation methods on the properties of the amorphous drug including the stability of the amor-phous state,dissolution/solubility,supersaturation,and"spring-parachute"process is still poorly understood,particularly for certain amorphous supersaturating drug delivery systems(aSDDS).The present work aimed to explore the detailed merit of current attractive amorphization manufacturing methods(i.g.,hot-melt extrusion(HME)technique)on the property improvement of aSDDS in form of amorphous solid dispersion microparticles by employing a model Bcs II drug nitrendipine and a polyvinylpyrrolidone-based model polymer copovidone.Many asDDS systems were developed by various methods,and their physicochemical properties were characterized by SEM,PXRD and DSC.HME-triggered amorphization induced superior supersaturation by the observation of the highest dissolution and solubility.HME induced the optimal supersaturation duration by the observed greatest extension of"spring-parachute"process(e.g,maximum AUCspring-parachute).HME technique is comparable with other techniques for the stabilization of amorphous state during storage.All aSDDS systems by HME and other methods showed improved long-term stability of the amorphous state in comparison to the pure amorphous drug.Fourier transformation infrared spectroscopy,Noyes-Whitney equation,nucleation theory and Gibbs free energy of transfer(△G)were used to analyze the underlying mechanisms.Mo-lecular mechanism studies indicated that HME caused a stronger crystallization inhibition effect in the asDDS systems than other methods,but molecular interaction is not a dominant mechanism for property enhancement caused by HME.For the mechanism associated with the polymer itself(PVPVA64),it could inhibit the drug recrystallization,solubilize the drug spontaneously and cause the improved molecular interactions in all aSDDS systems.This study provided a deep insight into detailed advantage of HME-triggered supersaturation/amorphization and facilitated the applications of the technique both in the field of particuology and in pharmaceutical industry.展开更多
基金We would like to thank the National Natural Science Foundation of China(No.81973258)the Beijing Natural Science Foundation(Nos.L202044,7202092)for funding this work.
文摘Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune boosters.PLT-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor microenvironment.PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive environment.PLT-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold vs.control group)in mouse tumor model after intravenous or subcutaneous administration.Also,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and PD-L1.Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication.All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.
基金supported by National Natural Science Foundation of China(No.82172593 and 82204729)Science and Technology Development Program of Jjilin Province of China(No.20210101430JC,YDZJ202201ZYTS234 and YDZJ202201ZYTS223)+4 种基金China Postdoctoral Science Foundation(No.2015M571373)Science and Technology Development Program of jilin City in Jjilin Province of China(No.20200104067,201831739 and 201464053)Scientific Research Foundation of the Education Department of Jilin Province of China(No.JJKH20191072KJ and 2015-401)Doctoral Research Startup Fund Project of Jilin Medical University(No.JYBS2021002LK)the College Students'Innovation Project of Jilin Province(No.202013706026).
文摘Despite the potential advantages of amorphism-induced supersaturation,the merit of new amorphiza-tion formation methods on the properties of the amorphous drug including the stability of the amor-phous state,dissolution/solubility,supersaturation,and"spring-parachute"process is still poorly understood,particularly for certain amorphous supersaturating drug delivery systems(aSDDS).The present work aimed to explore the detailed merit of current attractive amorphization manufacturing methods(i.g.,hot-melt extrusion(HME)technique)on the property improvement of aSDDS in form of amorphous solid dispersion microparticles by employing a model Bcs II drug nitrendipine and a polyvinylpyrrolidone-based model polymer copovidone.Many asDDS systems were developed by various methods,and their physicochemical properties were characterized by SEM,PXRD and DSC.HME-triggered amorphization induced superior supersaturation by the observation of the highest dissolution and solubility.HME induced the optimal supersaturation duration by the observed greatest extension of"spring-parachute"process(e.g,maximum AUCspring-parachute).HME technique is comparable with other techniques for the stabilization of amorphous state during storage.All aSDDS systems by HME and other methods showed improved long-term stability of the amorphous state in comparison to the pure amorphous drug.Fourier transformation infrared spectroscopy,Noyes-Whitney equation,nucleation theory and Gibbs free energy of transfer(△G)were used to analyze the underlying mechanisms.Mo-lecular mechanism studies indicated that HME caused a stronger crystallization inhibition effect in the asDDS systems than other methods,but molecular interaction is not a dominant mechanism for property enhancement caused by HME.For the mechanism associated with the polymer itself(PVPVA64),it could inhibit the drug recrystallization,solubilize the drug spontaneously and cause the improved molecular interactions in all aSDDS systems.This study provided a deep insight into detailed advantage of HME-triggered supersaturation/amorphization and facilitated the applications of the technique both in the field of particuology and in pharmaceutical industry.
