Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment
-
Published:2023-11-21
Issue:12
Volume:15
Page:2651
-
ISSN:1999-4923
-
Container-title:Pharmaceutics
-
language:en
-
Short-container-title:Pharmaceutics
Author:
Shah Vidhi M.1ORCID, Rizvi Syed2ORCID, Smith Alexander1, Tsuda Motoyuki3, Krieger Madeline4, Pelz Carl13, MacPherson Kevin3, Eng Jenny3, Chin Koei456, Munks Michael W.1, Daniel Colin J.3, Al-Fatease Adel7ORCID, Yardimci Galip Gürkan4, Langer Ellen M.45, Brody Jonathan R.158, Sheppard Brett C.158, Alani Adam WG.25ORCID, Sears Rosalie C.135ORCID
Affiliation:
1. Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA 2. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USA 3. Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA 4. Cancer Early Detection Advanced Research Center, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA 5. Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA 6. Department of Biomedical Engineering, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA 7. Department of Pharmaceutics, College of Pharmacy, King Khalid University, Guraiger, Abha 62529, Saudi Arabia 8. Department of Surgery, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
Abstract
Pancreatic cancer remains a formidable challenge due to limited treatment options and its aggressive nature. In recent years, the naturally occurring anticancer compound juglone has emerged as a potential therapeutic candidate, showing promising results in inhibiting tumor growth and inducing cancer cell apoptosis. However, concerns over its toxicity have hampered juglone’s clinical application. To address this issue, we have explored the use of polymeric micelles as a delivery system for juglone in pancreatic cancer treatment. These micelles, formulated using Poloxamer 407 and D-α-Tocopherol polyethylene glycol 1000 succinate, offer an innovative solution to enhance juglone’s therapeutic potential while minimizing toxicity. In-vitro studies have demonstrated that micelle-formulated juglone (JM) effectively decreases proliferation and migration and increases apoptosis in pancreatic cancer cell lines. Importantly, in-vivo, JM exhibited no toxicity, allowing for increased dosing frequency compared to free drug administration. In mice, JM significantly reduced tumor growth in subcutaneous xenograft and orthotopic pancreatic cancer models. Beyond its direct antitumor effects, JM treatment also influenced the tumor microenvironment. In immunocompetent mice, JM increased immune cell infiltration and decreased stromal deposition and activation markers, suggesting an immunomodulatory role. To understand JM’s mechanism of action, we conducted RNA sequencing and subsequent differential expression analysis on tumors that were treated with JM. The administration of JM treatment reduced the expression levels of the oncogenic protein MYC, thereby emphasizing its potential as a focused, therapeutic intervention. In conclusion, the polymeric micelles-mediated delivery of juglone holds excellent promise in pancreatic cancer therapy. This approach offers improved drug delivery, reduced toxicity, and enhanced therapeutic efficacy.
Funder
Brenden-Colson Center for Pancreatic Care Brenden-Colson Center Foundation and Oregon State University College of Pharmacy
Subject
Pharmaceutical Science
Reference56 articles.
1. A phase II study of gemcitabine plus nab-paclitaxel as first-line therapy for locally advanced pancreatic cancer;Fukahori;Medicine,2021 2. Yang, J., Zhang, Q., Wang, J., Lou, Y., Hong, Z., Wei, S., Sun, K., Wang, J., Chen, Y., and Sheng, J. (2022). Dynamic profiling of immune microenvironment during pancreatic cancer development suggests early intervention and combination strategy of immunotherapy. EBioMedicine, 78. 3. Muller, M., Haghnejad, V., Schaefer, M., Gauchotte, G., Caron, B., Peyrin-Biroulet, L., Bronowicki, J.P., Neuzillet, C., and Lopez, A. (2022). The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers, 14. 4. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors;Hong;N. Engl. J. Med.,2020 5. Increased frequency of CpG island methylator phenotype and CDH1 methylation in a gastric cancer high-risk region of china;Zhang;Transl. Oncol.,2008
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|