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Tumor microenvironment-sensitive polymeric nanoparticles for synergetic chemo-photo therapy

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Chinese Chemical Letters 2024年第11期35卷 44-56页

作者： Tingting Hu Chao Shen Xueyan Wang Fengbo Wu Zhiyao He Department of Pharmacy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry West China School of PharmacySichuan UniversityChengdu 610041China

nanoparticles that employ stimuli-responsive polymeric delivery carriers have emerged as intelligent nanoplatforms with great potential in cancer theranostics,mainly including cancer diagnosis,controlled/triggered drug delivery,and real-time monitoring of therapeutic ***,tumor microenvironment(TME)-responsive polymeric nanocarriers in response to weak acidity,hypoxia,reactive oxygen species(ROS),glutathione(GSH),or tumor enzymes in the TME show great promise in facilitating tumor accumulation,enhancing tumor penetration,prolonging tumor retention,and achieving controlled drug release,thereby improving the efficiency of tumor ***,the combination of chemotherapy and phototherapy presents a promising endeavor for the treatment of tumors,which allows for the integration of the advantages of each treatment modality,addressing the shortcomings of the two methods,and amplifying the efficacy of tumor treatment while reducing adverse *** review focuses on the latest progress in the development of TME-responsive polymeric nanoparticles for synergetic chemo-photo therapy,and discusses the critical challenges and future considerations involved in the fabrication of TME-responsive nanocarriers.

关键词： polymeric nanoparticles Tumor microenvironment-sensitive Chemotherapy Photothermal therapy photodynamic therapy Combination therapy

On-demand assembly of polymeric nanoparticles for longer-blood-circulation and disassembly in tumor for boosting sonodynamic therapy

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Bioactive Materials 2022年第12期7卷 242-253页

作者： Mei Wen Nuo Yu Shiwen Wu Mengmeng Huang Pu Qiu Qian Ren Meifang Zhu Zhigang Chen State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Materials Science and EngineeringDonghua UniversityShanghai201620China

Sonodynamic therapy (SDT) is one of the promising strategies for tumor therapy, but its application is usually hindered by fast clearance in blood-circulation, abnormal tumor microenvironment, and inefficient generation of reactive oxygen species. To solve these problems, we proposed an on-demand assembly-disassembly strategy, where the assembly is favorable for longer-blood-circulation and then the disassembly in tumor is favorable for boosting SDT. Hematoporphyrin monomethyl ether (HMME) as the model of organic sonosensitizers were conjugated with hyaluronic acid (HA). Then HA-HMME was mixed with catalase (CAT) and assembled into polymeric nanoparticles (CAT@HA-HMME NPs) with size of ~80 nm. CAT@HA-HMME NPs exhibit good biocompatibility and a longer blood half-time (t1/2 = 4.17 h) which is obviously longer than that (~0.82 h) of HMME molecules. After HA receptor-mediated endocytosis of cancer cells, CAT@HA-HMME NPs can be cleaved by endogenous hyaluronidase, resulting in the on-demand disassembly in tumor to release HA-HMME molecules and CAT. The CAT catalyzes the endogenous H_(2)O_(2) into O_(2) to relieve the hypoxic microenvironment, and the released HA-HMME exhibits a higher ROS generation ability, greatly boosting SDT for the inhibition of tumor growth. Therefore, the on-demand assembly-disassembly strategy may provide some insight in the design and development of nanoagents for tumor therapy.

关键词： polymeric nanoparticles On-demand assembly Longer-blood-circulation On-demand disassembly Sonodynamic therapy

Co-delivery of paclitaxel and gemcitabine via folic acid-conjugated polymeric multi-drug nanoparticles (FA-PMDNPs) for the treatment of breast cancer

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Journal of Chinese Pharmaceutical Sciences 2020年第10期29卷 701-710页

作者： Meng Lei Xueyuan Wang Hang Miao Jia Wang Sijia Sha Jiang Zhu Yongqiang Zhu College of Science Nanjing Forestry UniversityNanjing 210037China College of Life Science Nanjing Normal UniversityNanjing 210046China Jiangsu Chia Tai Fenghai Pharmaceutical Co.Ltd. Nanjing 210046China

Multi-drug delivery focuses on different signaling pathways in cancer cells and has synergistic antiproliferative *** this manuscript,we developed folic acid(FA)-conjugated polymeric multi-drug nanoparticles(FA-PMDNPs)consisting of poly-L-lysine(PLL)and poly glutamic-conjugated PTX/GEM(PGA-PTX and PGA-GEM)for FA receptor-targeted synergistic breast cancer *** carboxyl-rich structure of PGA provided plenty reaction sites and negative charge for drug *** electron microscopy(TEM)results showed that FA-PMDNPs had uniform particle size and spherical *** hemolysis study proved that FA-PMDNPs had good *** vitro cell viability and in vivo studies showed that FA-PMDNPs more effectively inhibited the proliferation of FA receptor(FR)-overexpressing breast cancer cells(4T1)than the pure ***,these results demonstrated that FA-PMDNPs could be effectively targeted at cancer cells compared with free drugs,indicating their strong potential as efficient multi-drug-carrying nano-platforms for cancer treatment.

关键词： FA-receptor targeted polymeric nanoparticles Combined chemotherapy Breast cancer Drug targeted delivery

On the origin and regulation of ultrasound responsiveness of block copolymer nanoparticles

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Science China Chemistry 2020年第2期63卷 272-281页

作者： Bo Yang Jianzhong Du Department of Orthopedics Shanghai Tenth People's HospitalTongji University School of MedicineShanghai 200072China Department of polymeric Materials School of Materials Science and EngineeringTongji UniversityShanghai 201804China

Noninvasive ultrasound is more convenient and easily accessible for controlled drug delivery of polymeric nanoparticles than many other ***,controlled ultrasound responsiveness is rather challenging as the mechanism is still *** this article,we disclose the origin and the key regulating factors of ultrasound responsiveness of block copolymer nanoparticles such as simple vesicles,framboidal vesicles,lamellae,beads-like micelles and complex micelles that are self-assembled from a range of poly(ethylene oxide)-b-polymethacrylates based model *** discover that the intrinsic ultrasound responsiveness of block copolymer nanoparticles thermodynamically originates from their metastable states,and its expression kinetically relates to the mobility of the hydrophobic segments of block ***,the self-assembly temperature(Ts) that has been usually considered as a less important factor in most of macromolecular self-assembly systems,and the solvents for the selfassembly are two dominant regulating factors of the ultrasound responsiveness because they determine the thermodynamic state(metastable or stable) of *** example,simple vesicles with good or excellent ultrasound responsiveness can be prepared in THF/water when the Tsis around or slightly below the glass transition temperature(Tg) of the hydrophobic segment of the block copolymer because the combination of this solvent with this Tsfacilitates the formation of metastable *** contrast,thermodynamically stable solid nanoparticles such as spherical micelles and lamellae(mainly formed in DMF/water)are not sensitive to ultrasound at all,neither are the vesicles in THF/water at stable states when the Tsis highly above *** addition,we unravel that the responsive rate is highly dependent on the sonication temperature(Tu),i.e.,the higher the Tu,the faster the ***,the above important findings provide us with a fresh insight into how to design ultrasound-r

关键词： ultrasound responsiveness polymeric nanoparticles polymer vesicles self-assembly metastable states

Paclitaxel Prodrug Nanomedicine for Potential CT-imaging Guided Breast Cancer Therapy

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Chinese Journal of Polymer Science 2023年第11期41卷 1747-1759,I0008页

作者： Jia-Wei Chen Yi Shen Qing-Song Yu Zhi-Hua Gan State Key Laboratory of Organic-Inorganic Composite Materials Beijing Laboratory of Biomedical MaterialsBeijing Advanced Innovation Center for Soft Matter Science and EngineeringCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing 100029China

Nanotheranostics,which combine the therapeutic and diagnostic functions in one integrated system,have received extensive attentions in cancer treatments because they enable non-invasive diagnosis,tumor-targeted drug delivery,and real-time monitoring of therapeutic ***,due to the high systemic toxicity of commonly used chemotherapeutics,current treatment still has ***,to simultaneously achieve safe cancer therapy and therapeutic response monitoring,an iodinated prodrug strategy was proposed.2,3,5-Triiodobenzoic acid(TIBA)was used to modify both paclitaxel(PTX)and the polymeric vehicle,so that the encapsulation efficiency of PTX could be increased and the systemic toxicity could be ***-prepared prodrug nanoparticles could accumulate passively in the tumor site and promptly release loaded drugs in response to the overexpressed GSH in cancer cells,which then caused efficient cell cycle arrest and apoptosis like that of the parent *** this rational design,safe and efficient antitumor therapy and real-time computer tomography(CT)imaging could be simultaneously realized,facilitating potential CT imaging-guided therapy of metastatic breast cancer.

关键词： CT imaging Paclitaxel Prodrug GSH responsiveness polymeric nanoparticles

The enhanced permeability and retention effect based nanomedicine at the site of injury

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Nano Research 2020年第2期13卷 564-569页

作者： Yingjun Liu Dongdong Sun Qin Fan Qingle Ma Ziliang Dong Weiwei Tao Huiquan Tao Zhuang Liu Chao Wang Institute of Functional Nano&Soft Materials(FUNSOM) Jiangsu Key Laboratory for Carbon-based Functional Materials and DevicesSoochow UniversitySuzhou 215123China Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine School of Integrated Chinese and Western MedicineNanjing University of Chinese MedicineNanjing 210023China

The enhanced permeability retention(EPR)effect based nanomedicine has been widely used for tumor targeting during the past *** we unexpectedly observed the similar"EPR effect"at the site of *** found that the temporary dilated and leaky blood vessels caused by the potent vasodilator histamine in response to injury allowed the injected nanoparticles to pass through the vasculature and reached the injured *** finding shows the potential underline mechanism of"EPR effect"at the injured *** loading with antibiotics,we further demonstrated a new strategy for prevention of infection at the site of injury.

关键词： enhanced permeability retention(EPR)effect injured tissue polymeric nanoparticles histamine immune response

mRNA delivery in cancer immunotherapy

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1348-1357页

作者： Yichen Zhong Shi Du Yizhou Dong Division of Pharmaceutics&Pharmacology College of PharmacyThe Ohio State UniversityColumbusOH 43210USA Department of Radiation Oncology Department of Biomedical EngineeringCenter for Clinical and Translational ScienceComprehensive Cancer CenterDorothy M.Davis Heart&Lung Research InstituteCenter for Cancer EngineeringCenter for Cancer MetabolismPelotonia Institute for Immune-OncologyThe Ohio State UniversityColumbusOH 43210USA Icahn Genomics Institute Precision Immunology InstituteDepartment of Oncological SciencesTisch Cancer InstituteFriedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA

Messenger RNA(mRNA)has drawn much attention in the medical *** various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for ***,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular ***,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA *** this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer *** also highlight promising treatment regimens and their clinical translation.

关键词： Cancer immunotherapy Lipid nanoparticles Lipid—polymer hybrid nanoparticles Messenger RNA mRNA delivery polymeric nanoparticles Protein/peptide-mediated nanoparticles

Surface charge tunable nanoparticles for TNF-α siRNA oral delivery for treating ulcerative colitis

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Nano Research 2018年第5期11卷 2872-2884页

作者： Shoaib Iqbal Xiaojiao Du Jilong Wang Hongjun Li Youyong Yuan Jun Wang School of Life Sciences University of Science and Technology of China Hefei 230027 China School of Medicine South China University of Technology Guangzhou 510006 China Institutes for Life Sciences South China University of Technology Guangzhou 510006 China Key Laboratory of Biomedical Materials of Ministry of Education South China University of Technology Guangzhou 510641 Chino National Engineering Research Center for Tissue Restoration and Reconstruction Guangzhou 510006 China Research Institute for Food Nutrition and Human Health Guangzhou 510641 China

Nanopartide （NP） drug delivery systems have been successfully designed and implemented to orally deliver small interfering RNAs （siRNAs） for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly（ethylene glycol）-block-poly（lactic-co-glycolic acid）（PEG5K-b-PLGA10K） NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs （ANPs）, plain NPs （PNPs）, or carboxylated NPs （CNPs） based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis （UC）. This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.

关键词： surface charge tumor necrosis factor alpha(TNF-α) small interferingRNA (siRNA) drug delivery polymeric nanoparticles ulcerative colitis

Ionizable polymeric nanocarriers for the codelivery of bi-adjuvant and neoantigens in combination tumor immunotherapy

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Bioactive Materials 2023年第8期26卷 169-180页

作者： Ting Su Xiang Liu Shuibin Lin Furong Cheng Guizhi Zhu Center for Translational Medicine Precision Medicine InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou510080China Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences Institute for Structural Biology and Drug DiscoverySchool of PharmacyThe Developmental Therapeutics ProgramMassey Cancer CenterVirginia Commonwealth UniversityRichmondVA23298USA

Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA ***,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor *** vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor *** defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic ***,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC *** NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor *** a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.

关键词： polymeric nanoparticles Combination adjuvants Cancer neoantigen Nanovaccine codelivery Cancer immunotherapy