Microalgae－carrying nanomedicine for bioadhesive drug delivery for treating chemotherapy－induced intestinal injury

Abstract

Gastrointestinal tract toxicity represents a serious adverse effect of chemotherapy, leading to reduced quality of life and survival. For instance, irinotecan (CPT-11) usually causes severe gastrointestinal toxicity, with a lack of effective therapeutic interventions, making treatment often unsustainable. Therefore, development of an effective and safe therapy is crucial for improving chemotherapy efficacy and the patients’ quality of life. In this work, we developed a novel approach involving the helical-shaped cyanobacterium microalgae, Spirulina platensis (SP), to carry the bornyl acetate (BA)-loaded chitosan nanoparticles to enhance drug retention in the small intestine. We demonstrated the protection effect of BA against chemotherapy-induced intestinal injury using an epithelial cell model. In a mouse model, orally administered BA-ChNPs@SP accumulated in the small intestine and attenuated inflammation by reducing dsDNA release and oxidative stress. This was concomitant with the restoration of the intestinal barrier and modulation of the immune microenvironment. This work suggests the promise of the microalgae-carrying nanomedicine strategy for treatment of intestinal diseases, emphasizing its potential in addressing chemotherapy-induced gastrointestinal complications.

Keywords

Microalgae / Bioadhesive delivery / Chemotherapy-induced intestinal injury / Bornyl acetate / Macrophages

Conflicts of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

We are thankful to the National Key Research and Development Program of China (2022YFE0203600, China), NFSC (81925035, 82341232), Program of Shanghai Committee of Science and Technology (21ZR1475200, China), Department of Science and Technology of Guangdong Province (High-Level R&D and Innovative Research Institute 2021B0909050003), and SciTech Projects of Zhongshan (CXTD2022011, LJ2021001). We are thankful for the support from the Molecular Imaging Center, TEM, and Flow Cytometry Facility at SIMM, CAS. In addition, we thank the staff members of the Large-scale Protein Preparation System at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Science, China for providing the Electron Microscopy System and Flow cytometry technical support and assistance in data collection and analysis.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101024. The figures and tables with " S " before the serial number are included in the Supplementary data.

References

[1] Sougiannis AT, VanderVeen BN, Davis JM, Fan D, Murphy EA. Understanding chemotherapy-induced intestinal mucositis and strategies to improve gut resilience. Am J Physiol Gastrointest Liver Physiol 2021; 320(5):G712-9.

[2] Keefe DM, Elting LS, Nguyen HT, Grunberg SM, Aprile G, Bonaventura A, et al. Risk and outcomes of chemotherapy-induced diarrhea (CID) among patients with colorectal cancer receiving multi-cycle chemotherapy. Cancer Chemother Pharmacol 2014; 74(4):675-80.

[3] Pizzolato JF, Saltz LB. The camptothecins. Lancet 2003; 361(9376):2235-42.

[4] Elad S, Cheng KKF, Lalla RV, Yarom N, Hong C, Logan RM, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2020; 126(19):4423-31.

[5] Carlotto A, Hogsett VL, Maiorini EM, Razulis JG, Sonis ST. The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. PharmacoEcon 2013; 31(9):753-66.

[6] Mego M, Chovanec J, Vochyanova-Andrezalova I, Konkolovsky P, Mikulova M, Reckova M, et al. Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo controlled pilot study. Complement Ther Med 2015; 23(3):356-62.

[7] Abigerges D, Armand JP, Chabot GG, Da Costa L, Fadel E, Cote C, et al. Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 1994; 86(6):446-9.

[8] Zidan J, Haim N, Beny A, Stein M, Gez E, Kuten A. Octreotide in the treatment of severe chemotherapy-induced diarrhea. Ann Oncol 2001; 12(2):227-9.

[9] Zhang T, Lu SH, Bi Q, Liang L, Wang YF, Yang XX, et al. Volatile oil from amomi fuctus attenuates 5-fluorouracil-induced intestinal mucositis. Front Pharmacol 2017; 8:786.

[10] Begum A, Sandhya S, Shaffath Ali S, Vinod KR, Reddy S, Banji D. An in-depth review on the medicinal flora rosmarinus officinalis (Lamiaceae). Acta Sci Pol Technol Aliment 2013; 12(1):61-73.

[11] Lee JI, Choi JH, Kwon TW, Jo HS, Kim DG, Ko SG, et al. Neuroprotective effects of bornyl acetate on experimental autoimmune encephalomyelitis via anti-inflammatory effects and maintaining blood-brain-barrier integrity. Phytomedicine 2023; 112:154569.

[12] Zhao ZJ, Sun YL, Ruan XF. Bornyl acetate: a promising agent in phytomedicine for inflammation and immune modulation. Phytomedicine 2023; 114:154781.

[13] Yang L, Liu J, Li Y, Qi G. Bornyl acetate suppresses ox-LDL-induced attachment of THP-1 monocytes to endothelial cells. Biomed Pharmacother 2018; 103:234-9.

[14] Chen N, Sun G, Yuan X, Hou J, Wu Q, Soromou LW, et al. Inhibition of lung inflammatory responses by bornyl acetate is correlated with regulation of myeloperoxidase activity. J Surg Res 2014; 186(1):436-45.

[15] Rosales-Mendoza S, Angulo C, Meza B. Food-grade organisms as vaccine biofactories and oral delivery vehicles. Trends Biotechnol 2016; 34(2):124-36.

[16] Wu Q Liu L, Miron A, Klímová B, Wan D, Kuča K. The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: an overview. Arch Toxicol 2016; 90(8):1817-40.

[17] Zhong D, Zhang D, Chen W, He J, Ren C, Zhang X, et al. Orally deliverable strategy based on microalgal biomass for intestinal disease treatment. Sci Adv 2021; 7(48):eabi9265.

[18] Park JH, Yang SH, Lee J, Ko EH, Hong D, Choi IS. Nanocoating of single cells: from maintenance of cell viability to manipulation of cellular activities. Adv Mater 2014; 26(13):2001-10.

[19] Akolpoglu MB, Dogan NO, Bozuyuk U, Ceylan H, Kizilel S, Sitti M. High-yield production of biohybrid microalgae for on-demand cargo delivery. Adv Sci 2020; 7(16):2001256.

[20] Park BW, Zhuang J, Yasa O, Sitti M. Multifunctional bacteria-driven microswimmers for targeted active drug delivery. ACS Nano 2017; 11(9):8910-23.

[21] Zhong D, Zhang D, Xie T, Zhou M. Biodegradable microalgae-based carriers for targeted delivery and imaging-guided therapy toward lung metastasis of breast cancer. Small 2020; 16(20):e2000819.

[22] Wang X, Cai J, Sun L, Zhang S, Gong D, Li X, et al. Facile fabrication of magnetic microrobots based on spirulina templates for targeted delivery and synergistic Chemo-photothermal therapy. ACS Appl Mater Interfaces 2019; 11(5):4745-56.

[23] Zhao P, Zhang J, Wu A, Zhang M, Zhao Y, Tang Y, et al. Biomimetic codelivery overcomes osimertinibresistant NSCLC and brain metastasis via macrophage-mediated innate immunity. J Control Release 2021; 329:1249-61.

[24] Zhou J, Li M, Chen Q, Li X, Chen L, Dong Z, et al. Programmable probiotics modulate inflammation and gut microbiota for inflammatory bowel disease treatment after effective oral delivery. Nat Commun 2022; 13(1):3432.

[25] Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, et al. Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP 3 inflammasome. J Exp Med 2017; 214(6):1737-52.

[26] Xue H, Field CJ, Sawyer MB, Dieleman LA, Baracos VE. Prophylactic ciprofloxacin treatment prevented high mortality, and modified systemic and intestinal immune function in tumour-bearing rats receiving dose-intensive CPT-11 chemotherapy. Br J Cancer 2009; 100(10):1581-8.

[27] Wang D, Li D, Zhang Y, Chen J, Zhang Y, Liao C, et al. Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage. Acta Pharm Sin B 2021; 11(3):763-80.

[28] Lian Q, Xu J, Yan S, Huang M, Ding H, Sun X, et al. Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation. Cell Res 2017; 27(6):784-800.

[29] Karas S, Etheridge AS, Tsakalozou E, Ramírez J, Cecchin E, van Schaik RHN, et al. Optimal sampling strategies for irinotecan (CPT-11) and its active metabolite (SN-38) in cancer patients. Aaps j 2020; 22(3):59.

[30] Lavelle F, Bissery MC, André S, Roquet F, Riou JF.Preclinical evaluation of CPT-11 and its active metabolite SN-38. Semin Oncol 1996; 23(1Suppl 3): 11-20.

[31] Sun R, Zhu L, Li L, Song W, Gong X, Qi X, et al. Irinotecan-mediated diarrhea is mainly correlated with intestinal exposure to SN-38: critical role of gut ugt. Toxicol Appl Pharmacol 2020; 398:115032.

[32] Zhang Q, Zhang F, Li S, Liu R, Jin T, Dou Y, et al. A multifunctional nanotherapy for targeted treatment of colon cancer by simultaneously regulating tumor microenvironment. Theranostics 2019; 9(13):3732-53.

[33] Gençosman S, Ceylanlı D, Şehirli A, Teralı K, Bölükbaşı F, Çetinel Ş, et al. Investigation of the possible protective effect of N-acetylcysteine (NAC) against irinotecan (CPT-11)-induced toxicity in rats. Antioxidants (Basel) 2022; 11(11):2219.

[34] Wu D, Zhu L, Li Y, Wang H, Xu S, Zhang X, et al. Superparamagnetic chitosan nanocomplexes for colorectal tumor-targeted delivery of irinotecan. Int J Pharm 2020; 584:119394.

[35] Garg AD, Krysko DV, Vandenabeele P, Agostinis P. DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown. Photochem Photobiol Sci 2011; 10(5):670-80.

[36] Ahn J, Gutman D, Saijo S, Barber GN. STING manifests self DNA-dependent inflammatory disease. Proc Natl Acad Sci USA 2012; 109(47):19386-91.

[37] Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13(3):159-75.

[38] Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504(7480):451-5.

[39] Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, et al. Extrathymically generated regulatory T cells control mucosal TH 2 inflammation. Nature 2012; 482(7385):395-9.

[40] Shinohara H, Killion JJ, Kuniyasu H, Kumar R, Fidler IJ.Prevention of intestinal toxic effects and intensification of irinotecan's therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002. Clin Cancer Res 1998; 4(9):2053-63.

[41] Juang V, Chang CH, Wang CS, Wang HE, Lo YL. pH-responsive PEG-shedding and targeting peptide-modified nanoparticles for dual-delivery of irinotecan and microRNA to enhance tumor-specific therapy. Small 2019; 15(49):e1903296.

[42] Keefe DM, Brealey J, Goland GJ, Cummins AG. Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 2000; 47(5):632-7.

[43] Alagoz M, Gilbert DC, El-Khamisy S, Chalmers AJ. DNA repair and resistance to topoisomerase I inhibitors: mechanisms, biomarkers and therapeutic targets. Curr Med Chem 2012; 19(23):3874-85.

[44] Ikuno N, Soda H, Watanabe M, Irinotecan Oka M. CPT-11) and characteristic mucosal changes in the mouse ileum and cecum. J Natl Cancer Inst 1995; 87(24):1876-83.

[45] Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12(12):860-75.

[46] Wang Y, Wei B, Wang D, Wu J, Gao J, Zhong H, et al. DNA damage repair promotion in colonic epithelial cells by andrographolide downregulated cGAS-STING pathway activation and contributed to the relief of CPT-11-induced intestinal mucositis. Acta Pharm Sin B 2022; 12(1):262-73.

[47] Ahn J, Barber GN. Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Curr Opin Immunol 2014; 31:121-6.

[48] Yasa O, Erkoc P, Alapan Y, Sitti M. Microalga-powered microswimmers toward active cargo delivery. Adv Mater 2018; 30(45):e1804130.

[49] Zhang D, Zhong D, Ouyang J, He J, Qi Y, Chen W, et al. Microalgae-based oral microcarriers for gut microbiota homeostasis and intestinal protection in cancer radiotherapy. Nat Commun 2022; 13(1):1413.

[50] Seyidoğlu N, Köşeli E, Gurbanlı R, Aydın C. The preventive role of spirulina platensis (arthrospira platensis) in immune and oxidative insults in a stress-induced rat model. J Vet Res 2021; 65(2):193-200.