Nanoparticles Targeted With NGR Motif Deliver c-myc siRNA and Doxorubicin for Anticancer Therapy

TLDR

A PEGylated liposome‑polycation‑DNA (LPD) nanoparticle was engineered with an NGR peptide to target CD13 on tumor cells and vasculature, enabling systemic, specific delivery of siRNA into solid tumors in mice. The LPD‑PEG‑NGR formulation efficiently delivered c‑myc siRNA to HT‑1080 cells and xenografts, downregulated c‑myc, induced apoptosis, partially inhibited tumor growth, and when co‑loaded with doxorubicin, produced an enhanced therapeutic effect.

Abstract

We have designed a PEGylated LPD (liposome-polycation-DNA) nanoparticle for systemic, specific, and efficient delivery of small interfering RNA (siRNA) into solid tumors in mice by modification with NGR (aspargine–glycine–arginine) peptide, targeting aminopeptidase N (CD13) expressed in the tumor cells or tumor vascular endothelium. LPD-PEG-NGR efficiently delivered siRNA to the cytoplasm and downregulated the target gene in the HT-1080 cells but not CD13− HT-29 cells, whereas nanoparticles containing a control peptide, LPD-PEG-ARA, showed only little siRNA uptake and gene silencing activity. LPD-PEG-NGR efficiently delivered siRNA into the cytoplasm of HT-1080 xenograft tumor 4 hours after intravenous injection. Three daily injections (1.2 mg/kg) of c-myc siRNA formulated in the LPD-PEG-NGR effectively suppressed c-myc expression and triggered cellular apoptosis in the tumor, resulting in a partial tumor growth inhibition. When doxorubicin (DOX) and siRNA were co-formulated in LPD-PEG-NGR, an enhanced therapeutic effect was observed. We have designed a PEGylated LPD (liposome-polycation-DNA) nanoparticle for systemic, specific, and efficient delivery of small interfering RNA (siRNA) into solid tumors in mice by modification with NGR (aspargine–glycine–arginine) peptide, targeting aminopeptidase N (CD13) expressed in the tumor cells or tumor vascular endothelium. LPD-PEG-NGR efficiently delivered siRNA to the cytoplasm and downregulated the target gene in the HT-1080 cells but not CD13− HT-29 cells, whereas nanoparticles containing a control peptide, LPD-PEG-ARA, showed only little siRNA uptake and gene silencing activity. LPD-PEG-NGR efficiently delivered siRNA into the cytoplasm of HT-1080 xenograft tumor 4 hours after intravenous injection. Three daily injections (1.2 mg/kg) of c-myc siRNA formulated in the LPD-PEG-NGR effectively suppressed c-myc expression and triggered cellular apoptosis in the tumor, resulting in a partial tumor growth inhibition. When doxorubicin (DOX) and siRNA were co-formulated in LPD-PEG-NGR, an enhanced therapeutic effect was observed.