Single‐Component Dual‐Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase‐2 Inhibition for Lung Cancer and Spinal Metastasis

Author:

Wang Ben1,Lu Zhen‐Ni2,Song Meng‐Xiong3,He Xiao‐Wen4,Hu Zhi‐Chao1,Liang Hai‐Feng1,Lu Hong‐Wei1,Chen Qing1,Liang Bing1,Yi Tao2,Wei Peng2,Jiang Li‐Bo1ORCID,Dong Jian14

Affiliation:

1. Department of Orthopaedic Surgery Zhongshan Hospital Fudan University Shanghai 200032 China

2. State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Chemistry and Chemical Engineering Donghua University Shanghai 201620 China

3. Department of Orthopedics Surgery Minhang Hospital Fudan University Shanghai 201100 China

4. Department of Orthopaedic Surgery Shanghai Baoshan District Wusong Center Hospital Fudan University Shanghai 200940 China

Abstract

AbstractColoading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single‐component dual‐functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)‐generated HOCl. A representative prodrug (DHU‐CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU‐CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU‐CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase‐2 (COX‐2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX‐2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU‐CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single‐component dual‐functional prodrug activated by TME‐specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX‐2 inhibitor.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Shanghai Municipality

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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