Enhancing oral delivery of plant-derived vesicles for colitis

Yuan Liu¹, Adrian Lankenau Ahumada², Emine Bayraktar³, Paul Schwartz⁴, Mamur Chowdhury⁵, Sixiang Shi⁶, Manu M Sebastian⁷, Htet Khant⁸, Natalia de Val⁹, Nazende Nur Bayram¹⁰, Guodong Zhang¹¹, Thanh Chung Vu¹², Zuliang Jie¹³, Nicholas B Jennings¹⁴, Cristian Rodriguez-Aguayo¹⁵, Jody Swain¹⁶, Elaine Stur¹⁷, Lingegowda S Mangala¹⁸, Yutuan Wu⁶, Supriya Nagaraju¹⁹, Brooke Ermias²⁰, Chun Li²¹, Gabriel Lopez-Berestein²², Janet Braam²³, Anil K Sood²⁴

Affiliations

¹ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: yliu32@mdanderson.org.
² Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: ALankenau@mdanderson.org.
³ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: EBayraktar@mdanderson.org.
⁴ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: Paul.Schwartz@tufts.edu.
⁵ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: mamur@utexas.edu.
⁶ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Veterinary Medicine and Surgery, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: MMSebastian@mdanderson.org.
⁸ Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Inc., Frederick, MD 21702, USA. Electronic address: htet.khant@nih.gov.
⁹ Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Inc., Frederick, MD 21702, USA. Electronic address: natalia.deval@thermofisher.com.
¹⁰ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: NNBayram@mdanderson.org.
¹¹ Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: GZhang3@mdanderson.org.
¹² Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: TVu9@mdanderson.org.
¹³ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jiezuliang@xmu.edu.cn.
¹⁴ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: nbjennin@mdanderson.org.
¹⁵ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: CRodriguez2@mdanderson.org.
¹⁶ Department of Veterinary Medicine and Surgery, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: JSwain@mdanderson.org.
¹⁷ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: EStur@mdanderson.org.
¹⁸ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lsmangala@mdanderson.org.
¹⁹ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: SNagaraju@mdanderson.org.
²⁰ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: be13@rice.edu.
²¹ Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: CLi@mdanderson.org.
²² Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: glopez@mdanderson.org.
²³ Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: Braam@rice.edu.
²⁴ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: asood@mdanderson.org.

PMID: 37031740
PMCID: PMC10191613
DOI: 10.1016/j.jconrel.2023.03.056

Enhancing oral delivery of plant-derived vesicles for colitis

Yuan Liu et al. J Control Release. 2023 May.

. 2023 May:357:472-483.

doi: 10.1016/j.jconrel.2023.03.056. Epub 2023 Apr 20.

Authors

Affiliations

¹ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: yliu32@mdanderson.org.
² Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: ALankenau@mdanderson.org.
³ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: EBayraktar@mdanderson.org.
⁴ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: Paul.Schwartz@tufts.edu.
⁵ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: mamur@utexas.edu.
⁶ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Veterinary Medicine and Surgery, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: MMSebastian@mdanderson.org.
⁸ Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Inc., Frederick, MD 21702, USA. Electronic address: htet.khant@nih.gov.
⁹ Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Inc., Frederick, MD 21702, USA. Electronic address: natalia.deval@thermofisher.com.
¹⁰ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: NNBayram@mdanderson.org.
¹¹ Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: GZhang3@mdanderson.org.
¹² Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: TVu9@mdanderson.org.
¹³ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jiezuliang@xmu.edu.cn.
¹⁴ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: nbjennin@mdanderson.org.
¹⁵ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: CRodriguez2@mdanderson.org.
¹⁶ Department of Veterinary Medicine and Surgery, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: JSwain@mdanderson.org.
¹⁷ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: EStur@mdanderson.org.
¹⁸ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lsmangala@mdanderson.org.
¹⁹ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: SNagaraju@mdanderson.org.
²⁰ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: be13@rice.edu.
²¹ Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: CLi@mdanderson.org.
²² Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: glopez@mdanderson.org.
²³ Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: Braam@rice.edu.
²⁴ Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: asood@mdanderson.org.

PMID: 37031740
PMCID: PMC10191613
DOI: 10.1016/j.jconrel.2023.03.056

Abstract

Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs did not have an appreciable impact on PDV structure, number, or therapeutic effect. Additionally, packaging the lyophilized Eudragit S100-coated PDVs into capsules allowed them to pass through the upper gastrointestinal tract for delivery into the colon better than did suspension of PDVs in phosphate-buffered saline. Cap-cPDVs showed robust therapeutic effect in a dextran sulfate sodium-induced colitis mouse model. These findings could have broad implications for the use of PDVs as orally delivered nanocarriers of natural therapeutic plant compounds or other therapeutics.

Keywords: Eudragit S100 coat; Gastrointestinal tract; Lyophilization; Oral delivery; Plant-derived vesicles; Vesicle stability.

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Conflict of interest statement

Declaration of Competing Interest A.K.S.: scientific consulting (Kiyatec, GSK, Merck, Onxeo, ImmunoGen, Iylon); shareholder (Biopath).

Figures

**Fig.1 ∣. Plant-derived Vesicles (PDVs) exposed to conditions mimicking the gastrointestinal (GI) system.**
A, Transmission electron microscopy (TEM) imaging and quantification of PDVs exposed to different GI pH mimicconditions as indicated (red arrowheads indicate broken vesicles; n=3). B, Nanoparticle tracking analysis (NTA) showing the number of particles in samples exposed to changes in pH levels mimicking the GI tract (n=3). C, Cryo-EM comparative analysis of PDVs exposed to pH 7.5 versus pH 1.5 for 30 minutes at 37 °C. Red arrowheads show damaged PDVs. Bars=50nm, n=49. D, TEM imaging and quantification of PDVs exposed to changes in GI pH and digestive enzymes. Red arrow heads indicate broken and destroyed PDVs. Error bars indicate SD (n=3; scale bars=50nm).

**Fig. 2∣. Comparison of structure and number of PDVs suspended in phosphate-buffered saline (PBS) to PDVs subjected to lyophilization followed by resuspension in PBS.**
A, TEM, n=3. B, NTA, Error bars indicate SD (n=3; scale bars=50nm).

**Fig.3∣. Cabbage PDV in PBS and Cap-PDVs therapeutic effect to colitis.**
A, Average mouse body weight after treatment with PDVs in PBS (DSS+PDV) and Cap-PDVs (DSS+Cap-PDV) with DSS+PBS and control group, error bars indicate SEM. Mice were euthanized on day 13. B, Colon image and length after treatment. C, Hematoxylin and eosin staining (H&E) and histoscore after treatment (scale bars=100μm). D, Expression levels of cytokines in the colon relative to 36B4 after treatments (dose=1.6mg; n=5 per group). Error bars indicate SD in B-D.

**Fig.4∣. Characterization of PDVs coated with Eudragit S100 (cPDVs).**
A, TEM imaging and quantification of PDVs after Eudragit S100 coating. Error bars in SD (n=3; scale bars=100nm). B, NTA for size and particle number changes after Eudragit S100 coating. Error bars in SD (n=3).C, Cytek Aurora flow cytometry testing Eudragit S100 coating efficiency on PDVs. D, TEM imaging and quantification of cPDVs exposed to upper GI pH level and pepsin. Error bars indicate SD (n=3; scale bars=100nm).

**Fig.5∣. Tissue and organ distribution of PDV in PBS compared with Cap-PDVs and Cap-cPDVs.**
A. Blue fluorescence 4′,6-diamidino-2-phenylindole (DAPI) staining shows nuclei, Red fluorescence shows CellMask Deep Red PDVs (scale bars=5μm). B. IVIS imaging, for a does of 1.6mg (n=3).

**Fig.6∣. Cap-cPDVs therapeutic effects on DSS-induced colitis compare with PDVs suspended in PBS.**
A, Average mouse body weight after treatment with DSS+PDVs and DSS+Cap-cPDVs, error bars indicate SEM. B, Colon length comparison with control, DSS, DSS+PDVs,and DSS+ Cap-cPDVs. C, Histocore and H&E comparison between the four groups (scale bars=100μm). D, Cytokine expression levels in the colon relative to 36B4 after treatments (dose was 1.6mg; n=5 per group). B-D Error bars indicate SD.

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Enhancing oral delivery of plant-derived vesicles for colitis

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Enhancing oral delivery of plant-derived vesicles for colitis

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