Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo.
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.
Thoracic Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
Lisa A
LA
Tobin
Yili
Y
Xie
Maria
M
Tsokos
Su I
SI
Chung
Allison A
AA
Merz
Michael A
MA
Arnold
Guang
G
Li
Harry L
HL
Malech
King F
KF
Kwong
D001483:Base Sequence; D002130:Calcium Phosphates / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017931:DNA Primers; D004317:Doxorubicin / Q000008:administration & dosage; D004705:Endocytosis; D006801:Humans; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D053758:Nanoparticles; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D002130:Calcium Phosphates; D017931:DNA Primers; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D004317:Doxorubicin