Abstract
The largest obstacle to the effective use of short interfering RNA (siRNA) in an animal body is the ability to deliver it to the target tissue. Here we showed a systemic delivery method of siRNA specific to pregrown solid tumors via atelocollagen. Atelocollagen facilitated the selective uptake of siRNA into the tumors when an siRNA/atelocollagen complex was administered intravenously to mice. We chose a Bcl-xL protein as a model target to prove the therapeutic efficacy of the atelocollagen-mediated method. Bcl-xL acts as an anti-apoptotic factor, which is overexpressed in many cancers, including prostate cancer. One of the four designed siRNAs to human Bcl-xL potently inhibited the expression of Bcl-xL by the PC-3 human prostate cancer cell line in vitro, leading to cell apoptosis. Intravenous injections for3 consecutive days (siRNA, 100 microg/injection per day as a complex with atelocollagen) effectively downregulated Bcl-xL expression in the PC-3 xenograft. We administered four series of 3 consecutive days of intravenous injections each, for a total of 12 injections, which significantly inhibited tumor growth when the treatment was combined with cisplatin (2 mg/kg). Local injection of Bcl-xL siRNA also potently inhibited tumor growth. All of the tumors treated with Bcl-xL siRNA/atelocollagen complex via both intravenous and intratumoral injection showed terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptosis. There were no severe side effects such as interferon-alpha induction and liver or renal damage in mice. Our results indicate that systemic delivery of siRNA via atelocollagen, which specifically targets tumors, is safe and feasible for cancer therapy.