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药物递送与疼痛管理实验室

Laboratory for Drug Delivery and Pain Management

国家纳米科学中心

National Center for Nanoscience

and Technology (NCNST)

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研究方向

研究方向一：药物递送体系用于疼痛管理

延长局部麻醉药物的作用时效、降低其组织毒性和系统毒性，可减轻病人痛苦、降低用药风险。开发长效、低毒的局部麻醉制剂一直是疼痛管理领域重要课题。另一方面，对于癌痛等剧烈慢性疼痛，会造成中枢神经系统敏化，亟需开发非阿片类强效镇痛药物制剂，避免成瘾性、耐药性及副作用。本课题组致力于设计药物控释体系，实现长效麻醉或镇痛，并探究疼痛管理的机制。

1. 多肽纳米结构对河豚毒素的特异性装载

图1. 仿生型纳米药物载体设计及其对新型局麻药物（河豚毒素）的特异性装载。A）河豚毒素（TTX）及其与钠离子通道结合位点；B）不同疏水基团修饰的多肽组装体TEM形貌及其与TTX结合的示意图；C）优选组多肽序列及其与TTX的亲和力；D）载体对TTX的缓释；E）荧光标记载体在注射部位滞留时间；F）游离TTX与纳米剂型的麻醉剂量及时长。此仿生型药物载体的设计灵感源于河豚毒素与离子通道的特异性相互作用，实现了河豚毒素的特异性装载，显著提高了TTX的包载效率，为神经毒素类新型麻醉制剂的设计提供了新思路。

研究方向二：重塑肿瘤微环境的纳米药物

抗肿瘤纳米药物功效受限的原因之一是恶性实体肿瘤组织具有致密的间质，其塑造利于肿瘤生长的微环境，并阻碍药物在肿瘤组织中的渗透。另一方面，实体肿瘤具有极高的异质性，靶向治疗对于受体缺失的肿瘤细胞类型束手无策。针对肿瘤治疗面临的这两方面瓶颈问题，课题组以肿瘤间质成分为靶点，并利用微环境理化性质来设计纳米药物，重塑肿瘤微环境，改善肿瘤异质性，提升化疗及免疫治疗的效力。

2. 布比卡因胶束用于静脉给药的局部麻醉

图2. 布比卡因纳米胶束及其静脉给药的局部麻醉（IVRA）。A）布比卡因的胶束（15 nm）及脂质体（100 nm）剂型的透射电镜形貌；B, C）布比卡因剂型在生物界面的吸附；D）荧光标记胶束及脂质体剂型，用于局部滞留的延长；E）麻醉时效评价；F）血药浓度测试。此工作是纳米技术首次在IVRA的应用，利用纳米材料的小尺寸效应，实现了生物界面滞留的功效，并最终实现了长效、低毒的麻醉效果，有望解决IVRA技术镇痛时效短、有潜在心脏毒性的临床难题。

相关论文：

1. T. Ji#, Y. Li#, X. Deng, A. Y. Rwei, A. Offen, S. Hall, W. Zhang, C. Zhao, M. Mehta, D. S. Kohane*. Delivery of local anaesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel. Nat. Biomed. Eng. 2021, 5, 1099-1109.

2. W. Zhang, T. Ji, Y. Li, Y. Zheng, M. Mehta, C. Zhao, A. Liu, D.S. Kohane*. Light-triggered release of conventional local anesthetics from a macromolecular prodrug for on-demand local anesthesia. Nat. Commun. 2020, 11, 2323.

3. J. Miao, X. Zhou, T. Ji, G. Chen*. NF-κB p65-dependent transcriptional regulation of histone deacetylase 2 contributes to the chronic constriction injury-induced neuropathic pain via the microRNA-183/TXNIP/NLRP3 axis. J. Neuroinflammation 2020, 17, 225.

4. A. Y. Rwei, B. Wang, T. Ji, D. S. Kohane*. Predicting the tissue depth for remote triggering of drug delivery systems. J. Control Release 2018, 286, 55-63.

5. A. Y. Rwei, B. Y. Wang, T. Ji, C. Zhan, D. S. Kohane*. Enhanced triggering of local anesthetic particles by photosensitization and photothermal effect using a common wavelength. Nano Lett. 2017, 11, 7138-7145.

6. J. Miao, Z. Chen, Y. Wu, Q. Hu, T. Ji. Sp1 Inhibits PGC-1α via HDAC2-catalyzed histone deacetylation in chronic constriction injury-induced neuropathic pain. ACS Chem. Neurosci. 2022, doi.org/10.1021/acschemneuro.2c00440.

7. C. Zhao, A. Liu, C. M. Santamaria, A. Shomorony, T. Ji, T. Wei, A. Gordon, H. Elofsson, M. Mehta, R.Yang, D. S. Kohane*. Polymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity. Nat. Commun. 2019, 10, 2566.

8. Y. Wang, A. Barhoumi, R. Tong, W. Wang, T. Ji, X. Deng, L. Li, S. A. Lyon, G. Reznor, D. Zurakowski, D. S. Kohane*. BaTiO₃-core Au-shell nanoparticles for photothermal therapy and bimodal imaging. Acta Biomater. 2018, 72, 287-294.

9. Q. Liu, C. Santamaria, T. Wei, C. Zhao, T. Ji, T. Yang, A. Shomorony, B. Wang, D. S. Kohane*. Hollow silica nanoparticles penetrate the peripheral nerve and enhance the nerve blockade from tetrodotoxin. Nano Lett. 2018, 18, 32–37.

研究方向二：重塑肿瘤微环境的纳米药物

1. 精准靶向及调控肿瘤相关成纤维细胞的纳米药物体系

图1. 肿瘤相关成纤维细胞（CAFs）内CXCL12靶点的纳米药物及肿瘤微环境重塑。A）CXCL12为靶点的纳米基因药物设计；B）重塑肿瘤微环境的策略.

2. pH响应穿膜肽（pHLIP）偶联抗体对缺少受体的肿瘤细胞靶向及免疫治疗策略

图2. pHLIP偶联抗体重塑肿瘤受体异质微环境。A）pHLIP与抗体的偶联；B）pHLIP偶联抗体在肿瘤细胞膜表面的组装；C）NK细胞对标记后的肿瘤细胞的识别和杀伤示意图；D）pHLIP偶联抗体对抗原阴性肿瘤细胞的标记；E）pHLIP偶联Fc分子对肿瘤的抑制效果。

相关论文：

1. L. Zhang#, Z. Li#, F. Wang#, Q. Chen, M. Zu, X. Li, J. Wan, X. Yao, X. Lou, Y. Shi, Y. Sheng, M. Wang, J. Yang,X. Wang, Z. Qin*, T. Ji*. Integrin-enriched membrane nanocarrier for the specific delivery of RGD‐modified relaxin analog to inhibit pancreatic cancer liver metastasis through reversing hepatic stellate cell activation. Adv. Funct. Mater. 2022, 32, 2208404.

2. T. T. Wheeler#, P. Cao#, M. D. Ghouri, T. Ji*, G. Nie, YL. Zhao*. Nanotechnological strategies for prostate cancer imaging and diagnosis. Sci. China Chem. 2022, 65, 1498-1514.

3. T. Ji#, J. Lang#, B. Ning#, F. Qi#, H. Wang, Y. Zhang, R. Zhao, X. Yang, L. Zhang, W. Li, X. Shi, Z. Qin*, Y. Zhao*, G. Nie*. Enhanced natural killer cell immunotherapy by rationally assembling Fc dragments of antibodies onto tumor membranes. Adv. Mater. 2019, 31, 1804395.

4. J. Lang, X. Zhao, Y. Qi, Y. Zhang, X. Han, Y. Ding, J. Guan, T. Ji*, Y. Zhao*, G. Nie*. Reshaping prostate tumor microenvironment to suppress metastasis via cancer-associated fibroblast inactivation with peptide-assembly-based nanosystem. ACS Nano 2019,13, 12357-12371.

5. T. Ji#, J. Lang#, J. Wang, R. Cai, Y. Zhang, F. Qi, L. Zhang, X. Zhao, W. Wu, J. Hao, Z. Qin*, Y. Zhao*, G.Nie*. Designing liposomes to suppress extracellular matrix expression to enhance drug penetration and pancreatic tumor therapy. ACS Nano 2017, 11, 8668-8678.

6. T. Ji#, Y. Zhao#, Y. Ding#, J. Wang, R. Zhao, J. Lang, H. Qin, X. Liu, J. Shi, N. Tao, Z. Qin, G. Nie, YL. Zhao*. Transformable peptide nanocarriers for expeditious drug release and effective cancer therapy via cancer-associated fibroblasts activation. Angew. Chem. Int. Ed. 2016, 55, 1050-1055.

7. T. Ji, S. Li, Y. Zhang, J. Lang, Y. Ding, et al. An MMP-2 responsive liposome integrating anti-fibrosis and chemotherapeutic drugs for enhanced drug perfusion and efficacy in pancreatic cancer. ACS Appl. Mater. Interfaces 2016, 8, 3438-3445.

8. T. Ji, Y. Zhao, Y. Ding, G. Nie*. Using nanomaterials to target and regulate the tumor microenvironment: diagnostic and therapeutic applications. Adv. Mater. 2013, 25, 3508-3525.

9. T. Ji, Y. Zhao, J. Wang, X. Zheng, Y. Tian, et al. Tumor fibroblast specific activation of hybrid ferritin nanocage-based optical probe for tumor microenvironment imaging. Small 2013, 9, 2427-2431.

研究方向三：超分子组装体系设计与构筑

利用超分子组装技术构建药物递送体系，有利于实现药物高效、便捷的装载。同时，将功能型基元引入组装体设计，可赋予组装体靶向、环境响应等功能。本课题组致力于超分子组装基元（分子）及组装体系的设计及构筑，为药物递送体系的设计提供新思路。

1. 离子通道仿生型多肽组装体系构筑及其用于生物毒素类局麻制剂的特异性装载

封面文章：

Nat. Biomed. Eng.

2021, 5, 1099-1109

2. 酶响应型两亲性药物载体的设计及其与疏水化疗药物的可形变共组装

图2. 具有酶切位点的两亲性多肽设计及组装行为。A）多肽分子设计；B）多肽自组装、药物诱导重组装进程；C）酶响应释药行为示意图及释药前后形貌变化。

1. L. Zhang#, Z. Li#, F. Wang#, Q. Chen, M. Zu, X. Li, J. Wan, X. Yao, X. Lou, Y. Shi, Y. Sheng, M. Wang, J. Yang, X. Wang, Z. Qin*, T. Ji*. Integrin-enriched membrane nanocarrier for the specific delivery of RGD‐modified relaxin analog to inhibit pancreatic cancer liver metastasis through reversing hepatic stellate cell activation. Adv. Funct. Mater. 2022, 32, 2208404.

2. T. Ji#, Y. Li#, X. Deng, A. Y. Rwei, A. Offen, S. Hall, W. Zhang, C. Zhao, M. Mehta, D. S. Kohane*. Delivery of local anaesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel. Nat. Biomed. Eng. 2021, 5, 1099-1109.

3. D. Liu, B. Deng, Z. Liu, B. Ma, X. Leng, D. Kong, T. Ji*, L. Liu*. Enhanced antitumor immune responses via a self-assembled carrier-free nanovaccine. Nano Lett. 2021, 21, 3965-3973.

4. Z. Lian, T. Ji*. Functional peptide-based drug delivery systems. J. Mater. Chem. B 2020, 8, 6517-6529. (“Emerging Investigators2020” invited).

7. T. Ji#, Y. Ding#, Y. Zhao*, J. Wang, H. Qin, X. Liu, et al. Peptide assemblies integration of fibroblast targeting and cell penetration features for enhanced antitumor drugs delivery. Adv. Mater. 2015, 27, 1865-1873.

8.Y. Ding#, T. Ji#, Y. Zhao, X. Zhao, R. Zhao, et al. A tumor microenvironment activable peptide self-assembly as tumor angiogenesis and metastasis antagonist. Mol. Cancer Ther. 2015, 14, 2390-2400.

9. Y. Zhao#, T. Ji#, H. Wang, S. Li, et al. Self-assembled peptide nanoparticles as tumor microenvironment activatable probes for tumor targeting and imaging. J. Control Release 2014, 177, 11-19.

10. Y. Wang, C.H. Liu, T. Ji, M. Mehta, W. Wang, E. Marino, J. Chen, D. S. Kohane*. Intravenous treatment of choroidal neovascularization by photo-targeted nanoparticles. Nat. Commun. 2019, 10, 804.