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Application of Nano-Delivery Systems in Lymph Nodes for Tumor Immunotherapy

Nano-Micro Letters 2023年第9期15卷 275-309页

作者： Yiming Xia shunli fu Qingping Ma Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong University44 Wenhua Xi RoadJinan 250012ShandongPeople’s Republic of China

Immunotherapy has become a promising research“hotspot”in cancer treatment.“Soldier”immune cells are not uniform throughout the body;they accumulate mostly in the immune organs such as the spleen and lymph nodes(LNs),*** unique structure of LNs provides the microenvironment suitable for the survival,activation,and proliferation of multiple types of immune *** play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor *** taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes ***,the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy ***,LNs have become a key target for tumor ***,the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells,which leads to unsatisfactory anti-tumor *** efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune ***-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues,exhibiting powerful and promising prospects for achieving effective delivery to ***,the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed ***,developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

关键词： Cancer therapy Immunotherapy Lymph nodes Nano-delivery systems

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Nanoparticle‑Loaded Polarized‑Macrophages for Enhanced Tumor Targeting and Cell‑Chemotherapy

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Nano-Micro Letters 2021年第1期13卷 79-98页

作者： Teng Hou Tianqi Wang Weiwei Mu Rui Yang Shuang Liang Zipeng Zhang shunli fu Tong Gao Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong University44 Wenhuaxi RoadJinan 250012People’s Republic of China

Cell therapy is a promising strategy for cancer ***,its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor *** this study,the“cell-chemotherapy”strategy was presented to enhance antitumor efficacy.M1-type macrophages,which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability,carried sorafenib(SF)-loaded lipid nanoparticles(M1/SLNPs)were developed.M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously.M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide,and M1/SLNPs were obtained by incubating M1-type macrophages with *** accumulation of M1/SLNP was increased compared with SLNP(p<0.01),which proved M1/SLNP could enhance tumor targeting of *** increased ratio of M1-type macrophages to M2-type macrophages,and the CD3^+CD4^+T cells and CD3^+CD8^+T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor *** tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group(p<0.01),indicating M1/SLNP exhibited enhanced antitumor ***,M1/SLNP showed great potential as a novel cellchemotherapeutic strategy combining both cell therapy and targeting chemotherapy.

关键词： Polarized-macrophages Cell therapy Cell-mediated drug delivery Chemotherapy Lipid nanoparticles

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On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1740-1754页

作者： Xiaoqing Liu Shuang Liang Xiao Sang Lili Chang shunli fu Han Yang Huizhen Yang Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cancer immunotherapy has become a promising ***,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells ***,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"***-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive ***1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral *** addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells *** is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis ***,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

关键词： Nano-engager Cold tumors Increased DNA damage Augmented immunogenic cell death Dual immune checkpoint inhibition BRD4 inhibition Differ-targeting delivery MMP-2 sensitive

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Micro/nanomotor: A promising drug delivery system for cancer therapy

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ChemPhysMater 2023年第2期2卷 114-125页

作者： Weihan Zhang Zipeng Zhang shunli fu Qingping Ma Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Micro/nanomotors(MNMs)are small-scale devices that can effectively convert various forms of energy into mechanical *** controllable motility and good permeability have attracted the interest of researchers as promising drug carriers in cancer *** with traditional formulations,micro/nanomotor drug delivery systems can greatly improve therapeutic efficiency and reduce the side effects of antitumor *** review mainly discusses the advantages of micro/nanomotor drug delivery systems and the applications of MNMs propelled by exogenous,endogenous,and biohybrid power in cancer ***,the main challenges of the applications of micro/nanomotor drug delivery systems,as well as future development trends and opportunities are discussed.

关键词： Micro/nanomotor Cancer therapy Drug delivery systems Controllable movement

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Gas-blasting nanocapsules to accelerate carboplatin lysosome release and nucleus delivery for prostate cancer treatment

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Asian Journal of Pharmaceutical Sciences 2021年第2期16卷 192-202页

作者： shunli fu Shuang Liang Dandan Jiang Rui Yang Zipeng Zhang Lili Chang Xinke Zhang Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJinan 250012China

To improve therapeutic effect and reduce severely side effects of carboplatin(CBP),the gas-generating nanocapsules were developed to accelerate CBP lysosome release and nucleus ***/SB-NC was prepared by co-loading CBP and NaHCO 3(SB)in nanocapsules using w/o/w emulsification solvent *** exhibited vesicle-like spherical morphology,uniform particle size and negative zeta *** the tumor site with a relatively high concentration is the first step for CBP delivery and the results showed that CBP/SB-NC could effectively increase drug accumulation at tumor *** that,the drug delivery carriers need to be internalized into tumor cells and the in vitro cellular uptake ability results showed CBP/SB-NC could be internalized into RM-1 cells more efficient than CBP *** internalized by RM-1 cells,the gas-blasting release process was tested in acid *** was demonstrated that 5 mg/ml NaHCO 3 was optimal to achieve pH-responsive gas-blasting *** vitro release results showed that CBP significantly rapid release in acid environment(pH 5.0)compared to neutral pH(pH 7.4)(P<0.05).Meanwhile,TEM and the change of the concentration of H+results exhibited that the explosion of CBP/SB 5-NC was more easily happened in lysosome acid environment(pH 5.0).The blasting release can accelerate CBP lysosome release to ***,the nucleus delivery results showed CBP/SB 5-NC can promote pH-triggered rapid nucleus *** the results of Pt-DNA adduct assay showed that the binding efficiency between CBP and DNA of CBP/SB 5-NC was higher than CBP *** last,in vitro and in vivo anti-tumor efficacy proved that CBP/SB 5-NC could enhance anti-tumor activity for prostate cancer ***/SB 5-NC also showed superior safety in vitro and in vivo by hemolysis assay and histopathological *** of the results demonstrate that CBP/SB 5-NC would be an efficient gas-blasting release formulation to enhance prostate cance

关键词： Carboplatin Nanocapsule pH-responsive release Gas-blasting Prostate cancer

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Localized light-triggered release macrophage cytopharmaceuticals containing O-nitrobenzyl group for enhanced solid tumor cell-chemotherapy

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Acta Pharmaceutica Sinica B 2024年第11期14卷 5053-5068页

作者： Jinhu Liu Han Yang Xiao Sang Tong Gao Zipeng Zhang shunli fu Huizhen Yang Lili Chang Xiaoqing Liu Shuang Liang Shijun Yuan Suyun Wei Yuxin Yang Xiaoxin Yan Xinke Zhang Weiwei Mu Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug de-Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug delivery. However, it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect. Herein, a localized light-triggered release macrophage cytopharmaceutical (USIP@M) was proposed, which could utilize the tumor targeting and immunotherapy effects of macrophages to reverse the immune suppression of tumor microenvironment (TME). Amphiphilic block copolymers with ultraviolet (UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.

关键词： Cytopharmaceutical Macrophage Light-triggered release Upconverting nanoparticle O-Nitrobenzyl Exosome Solid tumor Cell-chemotherapy

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肿瘤免疫治疗中NK细胞的激活策略及研究进展

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生命的化学 2021年第3期41卷 444-451页

作者：付顺利刘永军张娜山东大学药学院天然产物化学生物学教育部重点实验室济南250012

NK细胞(natural killer cell)是机体固有免疫系统中一类重要的淋巴样细胞,在免疫调节中发挥重要作用。NK细胞MHCⅠ非限制性杀伤肿瘤细胞的特性受到人们广泛关注。然而肿瘤组织浸润难、杀伤活性弱、免疫监视功能低的缺陷极大限制了NK细... 详细信息

NK细胞(natural killer cell)是机体固有免疫系统中一类重要的淋巴样细胞,在免疫调节中发挥重要作用。NK细胞MHCⅠ非限制性杀伤肿瘤细胞的特性受到人们广泛关注。然而肿瘤组织浸润难、杀伤活性弱、免疫监视功能低的缺陷极大限制了NK细胞的活性。因此,本文总结了肿瘤免疫治疗中NK细胞激活的机制,探讨了NK细胞在肿瘤免疫治疗中的激活策略,综述了近年来激活NK细胞用于肿瘤免疫治疗的研究进展,以期为利用NK细胞提高肿瘤免疫治疗效果提供新思路。

关键词： NK细胞肿瘤免疫治疗激活策略

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沃柑皮衍生多孔碳负载钴纳米颗粒复合材料的制备及其电催化性能

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安徽科技学院学报 2024年第3期38卷 102-109页

作者：郭锐付顺利沈长辉姚悦樊晓宇安徽科技学院机械工程学院安徽凤阳233100 安徽科技学院化学与材料工程学院安徽蚌埠233030 安徽科技学院电气与电子工程学院安徽蚌埠233030

目的:研发低成本、高效耐用的生物质基氧还原催化剂来替代贵金属氧还原催化剂,以降低燃料电池商业化成本。方法:以沃柑皮和硝酸钴为原料,通过浸渍和高温热处理的方法合成负载Co纳米颗粒的生物基碳材料(Co-C)。结果:所制备的Co-C在0.1 mo... 详细信息

目的:研发低成本、高效耐用的生物质基氧还原催化剂来替代贵金属氧还原催化剂,以降低燃料电池商业化成本。方法:以沃柑皮和硝酸钴为原料,通过浸渍和高温热处理的方法合成负载Co纳米颗粒的生物基碳材料(Co-C)。结果:所制备的Co-C在0.1 mol/L KOH溶液中催化氧还原反应(ORR)的平均电子转移数为3.59,接近四电子催化途径,具有优异的催化性能;Co-C的起始电位为-0.11 V,接近商业Pt/C(Pt 20%)的起始电位-0.10 V,其稳定性及抗甲醇性均优于商业Pt/C(Pt 20%)。结论:该生物质沃柑皮衍生多孔碳负载Co纳米颗粒复合材料在电催化领域具有巨大的应用潜力。

关键词：多孔生物质碳氧还原反应电化学催化剂

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面向“互联网+”环境的毕业设计管理系统的设计与应用

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信息与电脑 2021年第1期33卷 101-103页

作者：余建国肖芳海伏顺利冯梅琳江西理工大学机电工程学院江西赣州341000

目前,高校毕业设计教学环节中存在时间跨度长、管理散漫、流程复杂、过程文档多、指导时间有限、交流互动不足等问题,无法满足本科教学评估和工程教育认证的教学需要。在此背景下,为了提高毕业设计教学环节的信息化和智慧化水平,本文基... 详细信息

目前,高校毕业设计教学环节中存在时间跨度长、管理散漫、流程复杂、过程文档多、指导时间有限、交流互动不足等问题,无法满足本科教学评估和工程教育认证的教学需要。在此背景下,为了提高毕业设计教学环节的信息化和智慧化水平,本文基于系统目标需求和模块化设计思想,采用B/S架构和J2EE框架设计了面向"互联网+"环境的毕业设计管理系统,希望能够为相关研究提供借鉴。

关键词：毕业设计管理系统 B/S结构 J2EE框架

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Sodium Alginate/Carboxyl-functionalized Graphene Composite Hydrogel Via Neodymium Ions Coordination

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Journal of Materials Science & Technology 2017年第8期33卷 821-826页

作者： Qianqian Huang shunli Liu Kewen Li Imtiaz Hussain Fang Yao Guodong fu School of Chemistry and Chemical Engineering Southeast UniversityNanjing 211189China

A facile method for the preparation of sodium alginate（SA）/carboxyl-functionalized graphene（G-COOH）composite hydrogel was developed. Based on the coordination ability of lanthanide ions to the carboxyl groups, a series of hydrogel derived from different ratios of SA and G-COOH was fabricated by neodymium（Nd3＋） ions coordination. A relatively uniform layered structure was recorded by SEM at the interior of SA/G-COOH hydrogel. Several parameters such as water content, swelling ratio（SR）, tensile test and solvent resistance were also investigated. The SA/G-COOH composite hydrogel showed excellent mechanical strength, and the tensile strength of SA/G-COOH composite hydrogel reaches 53.72 MPa at high water content. Due to the coordination ability of Nd3＋ ions, the hydrogel also exhibited an excellent solvent resistance and stability.

关键词： Carboxyl-functionalized graphene Sodium alginate Hydrogel Neodymium ions coordination Layered structure

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