A multistage drug delivery approach for colorectal primary tumors and lymph node metastases
Abstract The presence of lymph node (LN) metastases guides cancer staging and worsens prognoses. Incomplete lymphadenectomy of metastatic LNs may end up with disease recurrence, while excessive resection can result in increased postoperative complications with even no survival benefit. Thus, effecti...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56768-z |
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| author | Yihang Yuan Quanjun Lin Hai-Yi Feng Yunpeng Zhang Xing Lai Mao-Hua Zhu Jue Wang Jiangpei Shi Yanhu Huang Lele Zhang Qin Lu Zeli Yuan Jonathan F. Lovell Hong-Zhuan Chen Peng Sun Chao Fang |
| author_facet | Yihang Yuan Quanjun Lin Hai-Yi Feng Yunpeng Zhang Xing Lai Mao-Hua Zhu Jue Wang Jiangpei Shi Yanhu Huang Lele Zhang Qin Lu Zeli Yuan Jonathan F. Lovell Hong-Zhuan Chen Peng Sun Chao Fang |
| author_sort | Yihang Yuan |
| collection | DOAJ |
| description | Abstract The presence of lymph node (LN) metastases guides cancer staging and worsens prognoses. Incomplete lymphadenectomy of metastatic LNs may end up with disease recurrence, while excessive resection can result in increased postoperative complications with even no survival benefit. Thus, effective non-invasive methods to treat metastatic LNs would be highly desirable. Here, we develop an enzyme-responsive formulation of small-sized doxorubicin-loaded mesoporous silica nanoparticles (DMSN, 40 nm) encapsulated in nanoliposomes (DMSN@Pla-Lipo, 160 nm). The liposomal membrane contains 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), two phospholipids sensitive to secreted phospholipase A2 in human colorectal tumors. In an orthotopic colorectal murine tumor model, phospholipase-induced membrane permeabilization triggers the liberation of DMSN from liposomes for enhanced tumor penetration, conferring an enhanced suppression for the primary tumor. Furthermore, through translocation into metastatic LNs via tumor lymphatics, metastatic tumor cells in LNs are eradicated. Metastases to other major organs are also suppressed, which can be ascribed to the inhibition of colorectal cancer metastasis-associated TGF-β, Wnt, and Hippo signaling pathways in metastatic LNs. The treatment confers an 80% 90-day survival rate in this aggressive tumor model. Taken together, this study demonstrates a deliberate treatment approach for management of both primary tumors and metastatic LNs through multistage drug delivery. |
| format | Article |
| id | doaj-art-8b634516d9ce40938a0662be3eed99dc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8b634516d9ce40938a0662be3eed99dc2025-02-09T12:45:33ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56768-zA multistage drug delivery approach for colorectal primary tumors and lymph node metastasesYihang Yuan0Quanjun Lin1Hai-Yi Feng2Yunpeng Zhang3Xing Lai4Mao-Hua Zhu5Jue Wang6Jiangpei Shi7Yanhu Huang8Lele Zhang9Qin Lu10Zeli Yuan11Jonathan F. Lovell12Hong-Zhuan Chen13Peng Sun14Chao Fang15Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Department of General Surgery, Tongren Hospital, SJTU-SMHongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Department of General Surgery, Tongren Hospital, SJTU-SMHongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Department of General Surgery, Tongren Hospital, SJTU-SMHongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Hongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Key Laboratory of Basic Pharmacology of Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical UniversityDepartment of Biomedical Engineering, University at Buffalo, State University of New YorkShanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Tongren Hospital, SJTU-SMHongqiao International Institute of Medicine, Tongren Hospital and State Key Laboratory of Systems Medicine for Cancer, Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)Abstract The presence of lymph node (LN) metastases guides cancer staging and worsens prognoses. Incomplete lymphadenectomy of metastatic LNs may end up with disease recurrence, while excessive resection can result in increased postoperative complications with even no survival benefit. Thus, effective non-invasive methods to treat metastatic LNs would be highly desirable. Here, we develop an enzyme-responsive formulation of small-sized doxorubicin-loaded mesoporous silica nanoparticles (DMSN, 40 nm) encapsulated in nanoliposomes (DMSN@Pla-Lipo, 160 nm). The liposomal membrane contains 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), two phospholipids sensitive to secreted phospholipase A2 in human colorectal tumors. In an orthotopic colorectal murine tumor model, phospholipase-induced membrane permeabilization triggers the liberation of DMSN from liposomes for enhanced tumor penetration, conferring an enhanced suppression for the primary tumor. Furthermore, through translocation into metastatic LNs via tumor lymphatics, metastatic tumor cells in LNs are eradicated. Metastases to other major organs are also suppressed, which can be ascribed to the inhibition of colorectal cancer metastasis-associated TGF-β, Wnt, and Hippo signaling pathways in metastatic LNs. The treatment confers an 80% 90-day survival rate in this aggressive tumor model. Taken together, this study demonstrates a deliberate treatment approach for management of both primary tumors and metastatic LNs through multistage drug delivery.https://doi.org/10.1038/s41467-025-56768-z |
| spellingShingle | Yihang Yuan Quanjun Lin Hai-Yi Feng Yunpeng Zhang Xing Lai Mao-Hua Zhu Jue Wang Jiangpei Shi Yanhu Huang Lele Zhang Qin Lu Zeli Yuan Jonathan F. Lovell Hong-Zhuan Chen Peng Sun Chao Fang A multistage drug delivery approach for colorectal primary tumors and lymph node metastases Nature Communications |
| title | A multistage drug delivery approach for colorectal primary tumors and lymph node metastases |
| title_full | A multistage drug delivery approach for colorectal primary tumors and lymph node metastases |
| title_fullStr | A multistage drug delivery approach for colorectal primary tumors and lymph node metastases |
| title_full_unstemmed | A multistage drug delivery approach for colorectal primary tumors and lymph node metastases |
| title_short | A multistage drug delivery approach for colorectal primary tumors and lymph node metastases |
| title_sort | multistage drug delivery approach for colorectal primary tumors and lymph node metastases |
| url | https://doi.org/10.1038/s41467-025-56768-z |
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