Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo.

Abstract

The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target-specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects.

• Authors: Lisa A Tobin, Yili Xie, Maria Tsokos, Su I Chung, Allison A Merz, Michael A Arnold, Guang Li, Harry L Malech, King F Kwong
• Journal: Biomaterials (Biomaterials) Vol. 34 Issue 12 Pg. 2980-90 (Apr 2013) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 23369215 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ltd.

Chemical References

• Calcium Phosphates
• DNA Primers
• RNA, Small Interfering
• Reactive Oxygen Species
• Polyethylene Glycols
• Doxorubicin

Topics

• Base Sequence
• Calcium Phosphates (administration & dosage)
• Cell Line, Tumor
• Cells, Cultured
• DNA Primers
• Doxorubicin (administration & dosage)
• Endocytosis
• Humans
• Microscopy, Confocal
• Microscopy, Electron
• Nanoparticles
• Neoplasms (metabolism, pathology)
• Polyethylene Glycols (chemistry)
• RNA, Small Interfering (administration & dosage, chemistry)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction