2. Academic Validation
  3. Co-delivering irinotecan and imiquimod by pH-responsive micelle amplifies anti-tumor immunity against colorectal cancer

Co-delivering irinotecan and imiquimod by pH-responsive micelle amplifies anti-tumor immunity against colorectal cancer

  • Int J Pharm. 2023 Nov 7:648:123583. doi: 10.1016/j.ijpharm.2023.123583.
Wenlu Yan 1,  Yu Li 2,  Yiting Zou 3,  Runqi Zhu 4,  Ting Wu 5,  Wenhui Yuan 4,  Tianqun Lang 6,  Yaping Li 7,  Qi Yin 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 211116, China.
  • 6 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China. Electronic address: langtq@lglab.ac.cn.
  • 7 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China; Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264000, China. Electronic address: ypli@simm.ac.cn.
  • 8 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: qyin@simm.ac.cn.
PMID: 37940081 DOI: 10.1016/j.ijpharm.2023.123583
Abstract

Irinotecan (IRT), a classic clinical chemotherapeutic agent for treating colorectal Cancer, has been found to induce immunogenic cell death (ICD) while exerting cytotoxicity in tumor cells. This effect is likely to be amplified in combination with immune modulators. Unfortunately, free drugs without targeting capacity would receive poor outcomes and strong side effects. To address these issues, in this work, an acid-sensitive micelle based on an amphiphilic poly(β-amino ester) derivative was constructed to co-deliver IRT and the immune Adjuvant imiquimod (IMQ), termed PII. PII kept stable under normal physiological conditions. After internalization by tumor cells, PII dissociated in acidic lysosomes and released IRT and IMQ rapidly. In the CT26 tumor mouse model, PII increased the intra-tumoral SN38 (the active metabolite of IRT) and IMQ concentrations by up to 9.39 and 3.44 times compared with the free drug solution. The tumor inhibition rate of PII achieved 87.29%. This might profit from that IRT induced ICD, which promoted dendritic cells (DCs) maturation and intra-tumoral infiltration of CD8+ T cells. In addition, IMQ enhanced the antigen presenting ability of DCs and stimulated tumor associated macrophages to secrete tumor-killing cytokines. PII provided an effective strategy to combat colorectal Cancer by synergy of chemotherapy and immunoregulation.

Keywords

Colorectal cancer; Imiquimod; Immune response; Irinotecan; Micelle.

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