1. Research Projects
National Natural Science Foundation of China (No.81803457), China Postdoctoral Science Foundation Project (NO.2020T130724 and NO.2018M642378), Post-doctoral support of Jiangsu Province (NO.2018Z063).
2. Representative Research Achievements
(1) It was difficult for nanodrugs to simultaneously meet the contradictory requirements of prolonged circulation time, augmented cellular uptake, rapid lysosome escape, precise drug release, and tumor penetration in tumor drug delivery. We prepared a nanotransformer (DTIG) through assembling doxorubicin, tannic acid, and indocyanine green to overcome this dilemma. Hydrophilic DTIG showed prolonged blood circulation time. Besides, DTIG could be efficiently internalized by tumor cells through transforming into hydrophobic particles in an acidic tumor microenvironment. Subsequently, oversized hydrophobic particles were further formed in acidic lysosomes to escape from it through rupturing the lysosome. These hydrophobic DTIGs could rapidly revert to a smaller hydrophilic nanoassembly and release the payloads in cytoplasm. Similar to denaturation and renaturation of protein, these high-efficiency instantaneous transformations were activated by proton. Besides, photothermal therapy of DTIG promoted drug penetration efficiency in tumor. This optimized drug delivery process of DTIG finally offered potent antitumor efficacy and an obvious advantage on prognosis.
(2) Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Mobius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/ VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4+ and CD8+T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.
(3) Ferroptosis had shown huge potential for antitumor treatment due to its capacity of improving the limited ef-ficiency of traditional antitumor strategies. On the other hand, low confidence in clinical application prospects impeded their development as a result of use of toxic-dose iron. Herein, we prepared a nano-activator (DAR) which was assembled by doxorubicin (DOX), tannic-acid (TA) and IR820 as a photosensitizer to make full use of endogenous iron stored in endo-lysosome, realizing ferroptosis and its related oxidative stress through artificially intracellular positive feedback loop. Interestingly, this process could also promote immunogenic cell death (ICD)- associated immunotherapy through endoplasmic reticulum (ER) stress. After DAR + laser treatment, the intra-cellular oxidative stress response was intensified. The produced ROS could be effectively distributed in intra-cellular lysosomes and ERs to facilitate ferroptosis and immunotherapy respectively. The pharmacodynamics study revealed that DAR + laser had excellent antitumor combination therapy efficiency even under the adverse combined drug ratio of DOX and IR820 due to the unique synergism activation effect of DAR mediated ferroptosis-immunotherapy. In summary, our study provided an innovative solution for the development of antitumor treatment based on ferroptosis-immunotherapy.
Intelligent targeting nanodrug delivery systems and their druggability study.
1. Research Projects
National Natural Science Foundation of China (No.81803457), China Postdoctoral Science Foundation Project (NO.2020T130724 and NO.2018M642378), Post-doctoral support of Jiangsu Province (NO.2018Z063).
2. Representative Research Achievements
(1) It was difficult for nanodrugs to simultaneously meet the contradictory requirements of prolonged circulation time, augmented cellular uptake, rapid lysosome escape, precise drug release, and tumor penetration in tumor drug delivery. We prepared a nanotransformer (DTIG) through assembling doxorubicin, tannic acid, and indocyanine green to overcome this dilemma. Hydrophilic DTIG showed prolonged blood circulation time. Besides, DTIG could be efficiently internalized by tumor cells through transforming into hydrophobic particles in an acidic tumor microenvironment. Subsequently, oversized hydrophobic particles were further formed in acidic lysosomes to escape from it through rupturing the lysosome. These hydrophobic DTIGs could rapidly revert to a smaller hydrophilic nanoassembly and release the payloads in cytoplasm. Similar to denaturation and renaturation of protein, these high-efficiency instantaneous transformations were activated by proton. Besides, photothermal therapy of DTIG promoted drug penetration efficiency in tumor. This optimized drug delivery process of DTIG finally offered potent antitumor efficacy and an obvious advantage on prognosis.
(2) Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Mobius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/ VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4+ and CD8+T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.
(3) Ferroptosis had shown huge potential for antitumor treatment due to its capacity of improving the limited ef-ficiency of traditional antitumor strategies. On the other hand, low confidence in clinical application prospects impeded their development as a result of use of toxic-dose iron. Herein, we prepared a nano-activator (DAR) which was assembled by doxorubicin (DOX), tannic-acid (TA) and IR820 as a photosensitizer to make full use of endogenous iron stored in endo-lysosome, realizing ferroptosis and its related oxidative stress through artificially intracellular positive feedback loop. Interestingly, this process could also promote immunogenic cell death (ICD)- associated immunotherapy through endoplasmic reticulum (ER) stress. After DAR + laser treatment, the intra-cellular oxidative stress response was intensified. The produced ROS could be effectively distributed in intra-cellular lysosomes and ERs to facilitate ferroptosis and immunotherapy respectively. The pharmacodynamics study revealed that DAR + laser had excellent antitumor combination therapy efficiency even under the adverse combined drug ratio of DOX and IR820 due to the unique synergism activation effect of DAR mediated ferroptosis-immunotherapy. In summary, our study provided an innovative solution for the development of antitumor treatment based on ferroptosis-immunotherapy.
1. Xiong, H.; Liu, X.; Xie, Z.; Zhu, L.; Lu, H.; Wang, C.; Yao, J. Metabolic Symbiosis‐Blocking Nano‐Combination for Tumor Vascular Normalization Treatment. Adv. Funct. Mater. 2022, 11(17), 2102724-2102724. (IF: 11.1)
2. Deng, Y.; Jiang, Z.; Jin, Y.; Qiao, J.; Yang, S.; Xiong, H.; Yao, J. Reinforcing vascular normalization therapy with a bi-directional nano-system to achieve therapeutic-friendly tumor microenvironment. J Control Release. 2021, 340, 87-101.（IF:9.776）
3. Xiong, H.; Wang, C.; Wang, Z.; Lu, H.; Yao, J. Self-assembled nano-activator constructed ferroptosis-immunotherapy through hijacking endogenous iron to intracellular positive feedback loop. J Control Release. 2021, 332, 539-552. (IF: 11.1)
4. Xiong, H.; Wang, Z.; Wang, C.; Yao, J. Transforming Complexity to Simplicity: Protein-Like Nanotransformer for Improving Tumor Drug Delivery Programmatically. Nano Lett. 2020, 20, 1781-1790. (IF: 12.272)
5. Xiong, H.; Wang, C.; Wang, Z.; Jiang, Z.; Zhou, J.; Yao, J. Intracellular cascade activated nanosystem for improving ER+ breast cancer therapy through attacking GSH-mediated metabolic vulnerability. J Control Release. 2019, 309, 145-157. (IF: 7.901)
