Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation

[Display omitted] Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therap...

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Bibliographic Details
Published in:International journal of pharmaceutics 2023-09, Vol.644, p.123316-123316, Article 123316
Main Authors: Zhu, Wenting, Yu, Hang, Jia, Menglei, Lin, Caiyan, Yuan, Zhongwen, Tan, Xiaoxiao, Yan, Pengke
Format: Article
Language:English
Subjects:
Animals
ATF24 peptide
Cell Line, Tumor
Cisplatin
Cisplatin - pharmacology
Co-delivery
Lipopolysaccharides
Liposomes
Liver metastasis
Liver Neoplasms - drug therapy
Mice
Pancreatic cancer
Pancreatic Neoplasms
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - pathology
Peptides - therapeutic use
Rapamycin
Sirolimus - pharmacology
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Summary:[Display omitted] Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of É‘-SMA, I collagen, and fibronectin protein in vivo and in vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lps in vitro compared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2023.123316