Journal
JOURNAL OF BIOMATERIALS APPLICATIONS
Volume 36, Issue 7, Pages 1317-1331Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/08853282211060252
Keywords
Autophagy; si-Beclin1; chemotherapy; nanotechnology; prostate cancer
Funding
- National Natural Science Foundation of China [81672516, 81672545]
- Science and Technology Project of Jiaxing, Zhejiang, China [2019AY32013, 199331309]
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Resistance to apoptosis in cancer cells can be overcome by inhibiting autophagy, as demonstrated in this study through the delivery of DOX-EMCH and si-Beclin1 using Co-PMs. The Co-PMs not only enhanced the cytotoxicity and proapoptotic ability in prostate cancer cells, but also showed passive targeting to tumor tissues, resulting in a significant antiproliferative effect in vivo. This suggests that the developed Co-PMs have the potential to combine autophagy inhibition and chemotherapy for effective cancer treatment, particularly in prostate cancer.
Resistance to apoptosis is a key mechanism underlying how cancer cells evade tumor therapy. Autophagy can prevent anticancer drug-induced apoptosis and promote tumor resistance. The purpose of this study was to improve the sensitivity and efficacy of chemotherapeutic drugs through the inhibition of autophagy. Hydrophobic doxorubicin-hydrazone-caproyl-maleimide (DOX-EMCH) and autophagy-inhibiting si-Beclin1 were simultaneously delivered via the amphiphilic peptide micelle system (Co-PMs) using poly(L-arginine)-poly(L-histidine)-DOX-EMCH as the copolymer building unit. The constructed micelle system promoted the escape of si-Beclin1 from endosomes and the release of DOX into the nucleus. The Co-PMs exhibited 2.7-fold higher cytotoxicity and proapoptotic ability in PC3 cells than DOX treatment alone, demonstrating that si-Beclin1 could inhibit the autophagic activity of prostate cancer (PCa) cells by targeting the type III PI3K pathway and enhance the sensitivity of the cells to the chemotherapeutic drug DOX. In addition, the peptide micelles successfully passively targeted DOX and si-Beclin1 to the tumor tissue. Compared with DOX or si-Beclin1 treatment alone, the Co-PMs showed a 3.4-fold greater tumor inhibitory potential in vivo, indicative of a significant antiproliferative effect. Our results suggested that the Co-PMs developed in this study have the potential to combine autophagy inhibition and chemotherapy in cancer treatment, especially for PCa.
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