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Cathepsin B-responsive and gadolinium-labeled branched glycopolymer-PTX conjugate-derived nanotheranostics for cancer treatment

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Acta Pharmaceutica Sinica B 2021年第2期11卷 544-559页

作者： Hao Cai Yufan Xiang Yujun Zeng Zhiqian Li Xiuli Zheng Qiang Luo Hongyan Zhu Qiyong Gong Zhongwei Gu Yanhui Liu Hu Zhang Kui Luo Huaxi MR Research Center(HMRRC) Department of Neurosurgeryand Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China HospitalSichuan UniversityChengdu 610041China Laboratory of Stem Cell Biology West China HospitalSichuan UniversityChengdu 610041China amgen bioprocessing centre Keck Graduate InstituteClaremontCA 91711USA

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of *** carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched *** branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic *** theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h *** imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic *** branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

关键词： Stimuli-responsive Drug delivery Branched glycopolymers Biodegradability Nanomedicine Theranostics

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GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine

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Acta Pharmaceutica Sinica B 2022年第1期12卷 424-436页

作者： Lei Luo Yiming Qi Hong Zhong Shinan Jiang Hu Zhang Hao Cai Yahui Wu Zhongwei Gu Qiyong Gong Kui Luo Huaxi MR Research Center(HMRRC) Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China College of Pharmaceutical Sciences Southwest UniversityChongqing 400716China Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengdu 610041China amgen bioprocessing centre Keck Graduate InstituteClaremontCA 91711USA

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

关键词： Stimuli responsiveness Polymeric prodrug Photodynamic therapy Combinational therapy Nanomedicine

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Polymeric dual-modal imaging nanoprobe with two-photon aggregation-induced emission for fluorescence imaging and gadolinium-chelation for magnetic resonance imaging

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Bioactive Materials 2023年第1期19卷 538-549页

作者： Xueyang Xiao Hao Cai Qiaorong Huang Bing Wang Xiaoming Wang Qiang Luo Yinggang Li Hu Zhang Qiyong Gong Xuelei Ma Zhongwei Gu Kui Luo Department of Radiology Department of BiotherapyHuaxi MR Research Center(HMRRC)Laboratory of Stem Cell BiologyCancer CenterDepartment of UltrasoundNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Functional and Molecular Imaging Key Laboratory of Sichuan Province Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China amgen bioprocessing centre Keck Graduate InstituteCA91711USA

Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic ***,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains *** this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,*** of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging *** contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR ***,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous ***-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than *** high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.

关键词： RAFT polymerization Amphiphilic block polymers Magnetic resonance/fluorescence dual-modal imaging Tumor/vascular imaging Two-photon AIE fluorescent contrast agent

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A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody

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Bioactive Materials 2023年第3期21卷 299-312页

作者： Zhilin Li Hao Cai Zhiqian Li Long Ren Xuelei Ma Hongyan Zhu Qiyong Gong Hu Zhang Zhongwei Gu Kui Luo Laboratory of Stem Cell Biology Department of RadiologyHuaxi MR Research Centner(HMRRC)Department of BiotherapyCancer CenterNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China amgen bioprocessing centre Keck Graduate InstituteClaremontCA91711USA Functional and Molecular Imaging Key Laboratory of Sichuan Province And Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint ***,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell *** acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity *** biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)*** induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive *** with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 *** self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

关键词： Cell membrane Biomimetic nanosystem Immunogenic cell death Immunotherapy anti-PD-L1 antibody

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Polysaccharide-based nanomedicines for cancer immunotherapy:A review

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Bioactive Materials 2021年第10期6卷 3358-3382页

作者： Yujun Zeng Yufan Xiang Ruilong Sheng Helena Tomás João Rodrigues Zhongwei Gu Hu Zhang Qiyong Gong Kui Luo Huaxi MR Research Center(HMRRC) Department of RadiologyDepartment of NeurosurgeryFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu610041China Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengdu610041China CQM-Centro de Quimica da Madeira MMRGUniversidade da MadeiraCampus da Penteada9000-390FunchalMadeiraPortugal amgen bioprocessing centre Keck Graduate InstituteClaremontCA91711USA

Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by ***,direct administration of“naked”immunotherapeutic agents(such as nucleic acids,cytokines,adjuvants or antigens without delivery vehicles)often results in:(1)an unsatisfactory efficacy due to suboptimal pharmacokinetics;(2)strong toxic and side effects due to low targeting(or off-target)*** overcome these shortcomings,a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side *** are a family of natural polymers that hold unique physicochemical and biological properties,as they could interact with immune system to stimulate an enhanced immune *** structures offer versatility in synthesizing multifunctional nanocomposites,which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor *** review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.

关键词： Polysaccharides Drug delivery systems Nanomedicines Cancer immunotherapy Anticancer efficacy

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Enzyme-triggered deep tumor penetration of a dual-drug nanomedicine enables an enhanced cancer combination therapy

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Bioactive Materials 2023年第8期26卷 102-115页

作者： Lei Gu Zhenyu Duan Xue Li Xin Li Yinggang Li Xiaoling Li Gang Xu Peng Gao Hu Zhang Zhongwei Gu Jie Chen Qiyong Gong Kui Luo Huaxi MR Research Center(HMRRC) Department of RadiologyFrontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Liver Transplant Center Organ Transplant CenterBreast CenterLaboratory of Stem Cell BiologyLaboratory of Clinical Proteomics and MetabolomicsInstitutes for Systems GeneticsNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuanChina amgen bioprocessing centre Keck Graduate InstituteClaremontCA91711USA Functional and Molecular Imaging Key Laboratory of Sichuan Province Key Laboratory of Transplant Engineering and ImmunologyNHCResearch Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamen361000FujianChina

Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species(ROS)via emerging ***,tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site,and ROS at a low level promote tumor cell growth,thus diminishing the therapeutic effect of these ***,we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine(Lap@pOEGMA-b-p(GFLG-Dendron-Ppa),GFLG-DP/Lap NPs)that incorporates a photosensitizer,Pyropheophorbide a(Ppa),for ROS therapy and Lapatinib(Lap)for molecular targeted ***,an epidermal growth factor receptor(EGFR)inhibitor that plays a role in inhibiting cell growth and proliferation,is hypothesized to synergize with ROS therapy for effectively killing cancer *** results suggest that the enzyme-sensitive polymeric conjugate,pOEGMA-b-p(GFLG-Dendron-Ppa)(GFLG-DP),releases in response to cathepsin B(CTSB)after entering the tumor ***-Ppa has a strong adsorption capacity to tumor cell membranes,which promotes efficient penetration and long-term *** can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle *** irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell ***,Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions,thus generating a significant synergistic anti-tumor therapeutic *** novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.

关键词： Proliferation inhibition Apoptosis Amphiphilic and block polymer-dendron conjugate Enhanced penetration Membrane flow Combination therapy

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Corrigendum to “A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody” [Bioact. Mater. 21 299-312]

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Bioactive Materials 2023年第4期22卷 74-74页

作者： Zhilin Li Hao Cai Zhiqian Li Long Ren Xuelei Ma Hongyan Zhu Qiyong Gong Hu Zhang Zhongwei Gu Kui Luo Laboratory of Stem Cell Biology Department of RadiologyHuaxi MR Research Centner(HMRRC)Department of BiotherapyCancer CenterNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China amgen bioprocessing centre Keck Graduate InstituteClaremontCA91711USA Functional and Molecular Imaging Key Laboratory of Sichuan Province Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China

The authors regret the incorrect publication of corresponding authors for the *** corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@***)and Kui Luo(luokui@***),and the same should be updated in the su... 详细信息

关键词： boost updated Cor

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