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Somatostatin receptor 2 targeting peptide modifications for peptide-drug conjugate treatment of small cell lung cancer

Acta Pharmacologica Sinica volume 46, pages 3291–3301 (2025)Cite this article

Abstract

Peptide-drug conjugate (PDC) represents a special therapeutic strategy to enhance drug delivery by targeting tumor cell receptors while minimizing off-target effects. Comparing the antibody-drug conjugate (ADC), the targeting peptide constitutes the pivotal component of PDC, especially with easy optimization of peptides to promote their in vivo stability, and with the agonist stimulated GPCR internalization to facilitate drug distribution into tumor cell plasma. Herein, we have optimized a highly stable peptide molecule LanTC targeting somatostatin receptor 2 (SSTR2), through amino acid substitution and disulfide bond modification from an FDA proved peptide drug Lanreotide. The LanTC based PDC was constructed through conjugation of the cytotoxic drug emtansine (DM1). The LanTC-DM1 PDC exhibited high stability and high agonist affinity to SSTR2. Subsequent in vitro and in vivo pharmacological data revealed that LanTC-DM1 PDC exhibited antitumor activity in small cell lung cancers (SCLC) which was known to have over-expressing SSTR2. The LanTC-DM1 PDC with specific targeting and antitumor activity provides a solid basis not only for advancing SSTR2-targeted PDCs as a promising therapy for SCLC, but also for other PDC developments targeting GPCRs in plasma membrane of tumor cells.

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Scheme 1
Fig. 1: The peptide LanTC was designed based on the modification of Lanreotide.
Fig. 2: Chemical synthesis of LanTC peptide and LanTC-DM1 PDC.
Fig. 3: Structural analysis of LanTC peptide and LanTC-DM1 PDC.
Fig. 4: The in vitro pharmacodynamic and pharmacokinetic analysis of the LanTC-DM1 PDC.
Fig. 5: In vivo efficacy analysis of LanTC-DM1 PDC in xenografted NCI-H524 and NCI-H69 mice.

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Data availability

The cryo-EM density maps and corresponding atomic coordinates of the SSTR2-DNGi complex bound with LanTC-DM1 have been deposited in the Electron Microscopy Data Bank and the Protein Data Bank under accession codes EMD-xxxx and PDB xxxx, respectively. All data analysed in this study are included in this paper and the Supplementary Information. Animal experiments were conducted in accordance with the guidelines and protocols approved by the Science and Technology Ethics Committee of the Hefei Institutes of Physical Science, Chinese Academy of Sciences, and the Experimental Animal Management Committee of the Suzhou Institutes of Materia Medica, Chinese Academy of Sciences.

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Acknowledgements

This research was supported by the National Key Research & Development Project, Ministry of Science and Technology of the People’s Republic of China (2022YFC3400500 to CLT), the National Natural Science Foundation of China (22277114 to PS, 22437005 to CLT, 22207100 to FY, 22477116 to FY), the Foundation of National Facility for Translational Medicine (Shanghai) to PS, the Strategic Priority Research Program of Chinese Academy of Sciences (XDB37000000 to CLT), Anhui Provincial Natural Science Foundation (2108085J16 to PS), the “USTC Research Funds of the Double First-Class Initiative” (YD9100002021 to PS, YD9990002027 to FY). The cryo-EM data were collected at the Center for Integrative Imaging of University of Science and Technology of China (Hefei). We also thank the staff members of the Superconducting Magnet 4 and MRI system (https://cstr.cn/31125.02.SHMFF.SM4.MRI) at the Steady High Magnetic Field Facility, CAS (https://cstr.cn/31125.02.SHMFF), for providing technical support and assistance in data collection and analysis.

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Author notes

  1. These authors contributed equally: Qing Bo, Meng-ge Zhang, Fan Yang

Authors and Affiliations

  1. Department of Chemistry and the First Affiliated Hospital of USTC,School of Life Sciences and School of Biomedical Engineering, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of China, Hefei, 230026, China

    Qing Bo, Meng-ge Zhang, Fan Yang, Yong Zheng, Ze-lin Li, Jun Liang, Li Zhou, Chang-lin Tian, Pei Lv & Pan Shi

  2. Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, 215123, China

    Qing Bo, Meng-ge Zhang, Chang-lin Tian & Pei Lv

  3. Anhui Engineering Laboratory of Peptide Drug, University of Science and Technology of China, Hefei, 230026, China

    Meng-ge Zhang, Fan Yang, Yong Zheng, Ze-lin Li, Jun Liang, Li Zhou, Chang-lin Tian, Pei Lv & Pan Shi

  4. Anhui Provincial Key Laboratory of High Magnetic Resonance Image, High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Anhui, 230030, China

    Yan-min Zheng, Fang-ming Wu, Dong-sheng Li, Yun Wu & Chang-lin Tian

  5. School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Studies, Shanghai Jiao Tong University, Shanghai, 201203, China

    Chang-lin Tian

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Contributions

CLT, PS and PL conceived and supervised the whole project; QB, MGZ, LZ and YZ designed and synthesize drugs; QB, FY designed the expression constructs, expressed, optimized and purified the receptor; FY and QB prepared the cryo-EM grids, collected the cryo-EM data, performed cryo-EM map calculation, model building and analyzed the structures; PS and FMW performed the NMR experiments; YW performed the MRI experiments; QB, MGZ, PL and PS designed experiments related to drug characterization both in vitro and in vivo. QB, MGZ and ZLL performed in vitro experiments; QB, MGZ, YMZ and DSL performed in vivo experiments; QB, PL, PS, FY and JL prepared the figures and participated manuscript writing; CLT and PS wrote the manuscript with inputs from the authors.

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Correspondence to Chang-lin Tian, Pei Lv or Pan Shi.

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Bo, Q., Zhang, Mg., Yang, F. et al. Somatostatin receptor 2 targeting peptide modifications for peptide-drug conjugate treatment of small cell lung cancer. Acta Pharmacol Sin 46, 3291–3301 (2025). https://doi.org/10.1038/s41401-025-01584-w

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