Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/12/2651 |
| _version_ | 1797379748646617088 |
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| author | Vidhi M. Shah Syed Rizvi Alexander Smith Motoyuki Tsuda Madeline Krieger Carl Pelz Kevin MacPherson Jenny Eng Koei Chin Michael W. Munks Colin J. Daniel Adel Al-Fatease Galip Gürkan Yardimci Ellen M. Langer Jonathan R. Brody Brett C. Sheppard Adam WG. Alani Rosalie C. Sears |
| author_facet | Vidhi M. Shah Syed Rizvi Alexander Smith Motoyuki Tsuda Madeline Krieger Carl Pelz Kevin MacPherson Jenny Eng Koei Chin Michael W. Munks Colin J. Daniel Adel Al-Fatease Galip Gürkan Yardimci Ellen M. Langer Jonathan R. Brody Brett C. Sheppard Adam WG. Alani Rosalie C. Sears |
| author_sort | Vidhi M. Shah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T20:27:32Z |
| format | Article |
| id | doaj.art-e9a791e9964242ceae9c1bd09d990aef |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-08T20:27:32Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e9a791e9964242ceae9c1bd09d990aef2023-12-22T14:31:48ZengMDPI AGPharmaceutics1999-49232023-11-011512265110.3390/pharmaceutics15122651Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor MicroenvironmentVidhi M. Shah0Syed Rizvi1Alexander Smith2Motoyuki Tsuda3Madeline Krieger4Carl Pelz5Kevin MacPherson6Jenny Eng7Koei Chin8Michael W. Munks9Colin J. Daniel10Adel Al-Fatease11Galip Gürkan Yardimci12Ellen M. Langer13Jonathan R. Brody14Brett C. Sheppard15Adam WG. Alani16Rosalie C. Sears17Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USACancer Early Detection Advanced Research Center, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USACancer Early Detection Advanced Research Center, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Molecular and Medical Genetics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Pharmaceutics, College of Pharmacy, King Khalid University, Guraiger, Abha 62529, Saudi ArabiaCancer Early Detection Advanced Research Center, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USACancer Early Detection Advanced Research Center, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USADepartment of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 South Moody Avenue, Portland, OR 97201, USABrenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USAPancreatic 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.https://www.mdpi.com/1999-4923/15/12/2651juglonedrug deliverypancreatic cancermicellesnanotechnology |
| spellingShingle | Vidhi M. Shah Syed Rizvi Alexander Smith Motoyuki Tsuda Madeline Krieger Carl Pelz Kevin MacPherson Jenny Eng Koei Chin Michael W. Munks Colin J. Daniel Adel Al-Fatease Galip Gürkan Yardimci Ellen M. Langer Jonathan R. Brody Brett C. Sheppard Adam WG. Alani Rosalie C. Sears Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment Pharmaceutics juglone drug delivery pancreatic cancer micelles nanotechnology |
| title | Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment |
| title_full | Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment |
| title_fullStr | Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment |
| title_full_unstemmed | Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment |
| title_short | Micelle-Formulated Juglone Effectively Targets Pancreatic Cancer and Remodels the Tumor Microenvironment |
| title_sort | micelle formulated juglone effectively targets pancreatic cancer and remodels the tumor microenvironment |
| topic | juglone drug delivery pancreatic cancer micelles nanotechnology |
| url | https://www.mdpi.com/1999-4923/15/12/2651 |
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