Treatment of primary and metastatic breast and pancreatic tumors upon intravenous delivery of a PRDM14‐specific chimeric siRNA/nanocarrier complex

Abstract

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

Therapeutic siRNA targeting the cancer cell stemness regulator PRDI-BF1 and RIZ domain zinc finger protein 14

“…PEG-PLL or PEG-PLO also met this condition, and PRDM14 uPIC demonstrates antitumor effects. 12 , 46 ) A higher number of PEG-PLL molecules is required, compared with PEG-PLO molecules, to carry one molecule of siRNA; therefore, a complex of siRNA with PEG-PLL causes adverse effects, and is expensive to use for treatment, compared with PEG-PLO. A complex of siRNA with PEG-PLO as DDS has been selected and a phase I clinical trial started.…”

“…siRNAs must penetrate target cell membranes and escape from endosomes. We reported that the use of calcium phosphate (CaP) hybrid micelles, 44 ) polyethylene glycol (PEG)–poly-l-lysine (PLL) block copolymers, 45 ) and branched PEGylated poly-l-ornithine (PLO) 46 ) because DDSs for siRNA may overcome several difficulties encountered by conventional systemic delivery systems. The complex composed of these carriers with siRNA accumulates in solid tumors through enhanced permeability and retention effects because of their small particle size.…”

“…5 ). 12 , 46 ) A higher number of PEG-PLLs is required, at an N/P ratio of 10, compared with PEG-PLO molecules, at an N/P ratio of 5, to carry one siRNA molecule. Thus, a uPIC composed of PEG-PLL has a higher viscosity than one with PEG-PLO, which raises the possibility of infusion-related reactions and vein embolization.…”

“…Only a high dose of uPICs induced hepatocyte vacuolation, which was irreversible within the 14-d recovery period, without tissue damage and elevated hepatic enzyme levels. 46 )…”

“…The figures are modified from Ref. 46 . PEG: polyethylene glycol, PRDM14: PRDI-BF1 and RIZ (PR) domain zinc finger protein 14, siRNAs: small interfering RNAs.…”