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Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4224-4234页

作者： Zekun Li Yongchun Pan Shiyu Du Yayao Li Chao Chen Hongxiu Song Yueyao Wu Xiaowei Luan Qin Xu Xiaoxiang Guan Yujun Song Xin Han Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of Medicine&Holistic Integrative MedicineJiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative MedicineNanjing University of Chinese MedicineNanjing 210023China College of Engineering and Applied Sciences Jiangsu Key Laboratory of Artificial Functional MaterialsState Key Laboratory of Analytical Chemistry for Life ScienceNanjing UniversityNajing 210023China Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China

Near-infrared(NIR)-light-triggered nanomedicine, including photodynamic therapy(PDT)and photothermal therapy(PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania(TiO_(2-x)) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase(HAase) and glutathione(GSH) can readily destroy hyaluronic acid(HA) and disulfide bond and releases the Cas9/sgRNA from TiO_(2-x) to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2(NRF2) and heat shock protein 90a(HSP90a), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO_(2-x) demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

关键词： Near infrared phototherapy Gene editing Nuclear factor E2-related factor 2 .Heat shock protein 90c TiO_(2-x) Sensitized phototherapy nanoprodrug Tumor microenvironment

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Deep tumor-penetrating nano-delivery strategy to improve diagnosis and therapy in patient-derived xenograft(PDX)oral cancer model and patient tissue

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Nano Research 2023年第2期16卷 2927-2937页

作者： Longmeng Li Aaron R.Lindstrom Andrew C.Birkeland Menghuan Tang Tzu-Yin Lin Yikai Zhou Bai Xiang Xiangdong Xue Yuanpei Li State Key Laboratory of Environment Health(Incubation) Key Laboratory of Environment and HealthMinistry of EducationKey Laboratory of Environment and Health(Wuhan)Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Biochemistry and Molecular Medicine UC Davis Comprehensive Cancer CenterUniversity of California Davis2700 Stockton BlvdSacramentoCalifornia 95817USA Department of Otolaryngology-Head and Neck Surgery University of California Davis2521 Stockton BlvdSacramentoCalifornia 95817USA Division of Hematology and Oncology Department of Internal MedicineSchool of MedicineUniversity of California Davis2700 Stockton BlvdSacramentoCalifornia 95817USA Key Laboratory of Hebei Province for Innovative drug research and evaluation School of Pharmaceutical SciencesHebei Medical UniversityShijiazhuang 050017China School of Pharmacy Pharm-X CenterShanghai Jiao Tong UniversityShanghai 200240China

nanoprodrugs that are directly assembled by prodrugs attract considerable attention with high anticancer ***,their stability and efficiency of tumor-targeted delivery remain a major challenge in practical biomedical ***,we report a new deep tumor-penetrating nano-delivery strategy to achieve enhanced anti-cancer performance by systematic optimization of a porphyrin-doxorubicin-based nanoprodrug using various PEGylations/crosslinks and co-administration of targeting peptide *** glycols(PEGs)with different molecular weights and grafts are employed to crosslink the nanoprodrug and optimize size,charge,tumor accumulation and penetration,and anti-cancer efficiency,*** tumor penetration was validated in syngeneic oral cancer mouse models,patient-derived xenograft(PDX)models,and oral cancer tissue from *** optimized nanoprodrug co-administrated with iRGD remarkably enhances the accumulation and penetration both in tumor vascular and PDX tumor *** is effective and safe to improve in vivo therapeutic efficacy via the passive tumor targeting dependent and independent *** tumor-penetrating nano-delivery strategy is promising to strengthen the nanoprodrugs in clinical implementation.

关键词： nanoprodrug tumor-penetrating tumor-targerting multilevel delivery optimization drug delivery

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