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Actively targeted delivery of SN38 by ultrafine iron oxide nanoparticle for treating pancreatic cancer

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Abstract

Pancreatic cancer remains one of the most lethal cancers largely due to the inefficient delivery of therapeutics. Nanomaterials have been extensively investigated as drug delivery platforms, showing improved drug pharmacodynamics and pharmacokinetics. However, their applications in pancreatic cancer have not yet been successful due to limited tumor delivery caused by dense tumor stroma and distorted tumor vasculatures. Meanwhile, smaller-sized nanomaterials have shown improved tumor delivery and retention in various tumors, including pancreatic tumors, suggesting their potential in enhancing drug delivery. An ultrafine iron oxide nanoparticle (uIONP) was used to encapsulate 7-ethyl-10-hydroxyl camptothecin (SN38), the water-insoluble active metabolite of pancreatic cancer chemotherapy drug irinotecan. Insulin-like growth factor 1 (IGF-1) was conjugated to uIONP as a ligand for targeting pancreatic cancer cells overexpressing IGF-1 receptor (IGF1R). The SN38 loading and release profile were characterized. The pancreatic cancer cell targeting using IGF1-uIONP/SN38 and subsequently induced cell apoptosis were also investigated. IGF1-uIONP/SN38 demonstrated a stable drug loading in physiological pH with the loading efficiency of 68.2 ± 3.5% (SN38/Fe, wt%) and < 7% release for 24 h. In tumor-interstitial- and lysosomal-mimicking pH (6.5 and 5.5), 52.2 and 91.3% of encapsulated SN38 were released over 24 h. The IGF1-uIONP/SN38 exhibited specific receptor-mediated cell targeting and cytotoxicity Ato MiaPaCa-2 and Panc02 pancreatic cancer cells with IC50 of 11.8 ± 2.3 and 20.8 ± 3.5 nM, respectively, but not to HEK293 human embryonic kidney cells. IGF1-uIONP significantly improved the targeted SN38 delivery to pancreatic cancer cells, holding the potential for in vivo theranostic applications.

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All data and materials in current study are available from the corresponding authors on reasonable request.

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Acknowledgements

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Funding

This work was funded by Guangdong Basic and Applied Basic Research Foundation [2020A1515010535], Shenzhen Fundamental Research Program [JCYJ20190808095413252], and Department of Innovation of Science and Technology of Longhua, Shenzhen.

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  1. Ting Xue and Peijia Xu these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, Affiliated Longhua People’s Hospital, the Third School of Clinical Medicine, Southern Medical University, Shenzhen, 518109, China

    Ting Xue, Peijia Xu, Xingkui Xue & Liya Wang

  2. LLC, 5M Biomed, Atlanta, GA, 30333, USA

    Jonathan Padelford & Yuancheng Li

  3. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, 30322, USA

    Alyssa Y. Wu & Yuancheng Li

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  1. Ting Xue
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Contributions

Liya Wang and Yuancheng Li contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ting Xue, Peijia Xu, Jonathan Padelford, Alyssa Y Wu, and Xingkui Xue. The first draft of the manuscript was written by Ting Xue and Peijia Xu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yuancheng Li or Liya Wang.

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Xue, T., Xu, P., Padelford, J. et al. Actively targeted delivery of SN38 by ultrafine iron oxide nanoparticle for treating pancreatic cancer. Invest New Drugs 40, 546–555 (2022). https://doi.org/10.1007/s10637-022-01231-9

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