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Treatment of primary and metastatic breast and pancreatic tumors upon intravenous delivery of a PRDM14 ‐specific chimeric siRNA /nanocarrier complex
Author(s) -
Taniguchi Hiroaki,
Natori Yukikazu,
Miyagi Yohei,
Hayashi Kotaro,
Nagamura Fumitaka,
Kataoka Kazunori,
Imai Kohzoh
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33579
Subject(s) - pancreatic cancer , breast cancer , metastatic breast cancer , metastasis , cancer research , cancer , in vivo , pharmacology , medicine , biology , microbiology and biotechnology
PRDM14 is highly expressed in several cancers but is not detected in normal tissues. It confers cancer stem cell‐like properties, including chemoresistance and distant metastasis, to cancer cells. Herein, we aimed to develop a highly effective therapy against advanced stage cancer based on intravenously delivered PRDM14 ‐targeted siRNA. First, we examined PRDM14 expression and gene amplification in breast and pancreatic tumors and cell lines. PRDM14 was expressed in breast cancer, including the triple‐negative subtype, and pancreatic cancer. PRDM14 was amplified in 23.8% of patients with PRDM14 + breast cancer. Next, we investigated the inoculated tumor growth and distant metastasis following PRDM14 depletion by administering mice with PRDM14 ‐specific chimeric siRNA combined with a novel branched PEGylated poly‐L‐ornithine (PLO)‐based intravenous drug delivery system, designated PRDM14 unit polyion complex (uPIC) (n = 6/group). Inhibition of PRDM14 expression with PRDM14 uPIC by systemic intravenous injection effectively reduced tumor size and metastasis in vivo, thereby improving survival. Finally, pharmacokinetic/toxicokinetic analyses were performed on PRDM14 uPIC, which was intravenously administered to rats (n = 10‐15/group) and cynomolgus monkeys (n = 3‐5/group), twice weekly for 4 weeks. This revealed that PRDM14 uPIC was relatively nontoxic and the siRNA exposure in serum was greater than that predicted by the administered dose ratio when delivered as a uPIC. Taken together, our study indicated that PRDM14 uPIC is highly effective in suppressing malignant features of solid cancers and does not cause severe toxicity, making it a promising therapeutic agent for cancer treatment.