Design of Cationic Multi-Walled Carbon Nanotubes as Efficient siRNA Vectors for Lung Cancer Xenograft Eradication

TY - JOUR

T1 - Design of Cationic Multi-Walled Carbon Nanotubes as Efficient siRNA Vectors for Lung Cancer Xenograft Eradication

AU - Guo, Chang

AU - Al-Jamal, Wafa T

AU - Toma, Francesca M

AU - Bianco, Alberto

AU - Prato, Maurizio

AU - Al-Jamal, Khuloud T

AU - Kostarelos, Kostas

PY - 2015/6/3

Y1 - 2015/6/3

N2 - Polo-Like Kinase (PLK1) has been identified as a potential target in cancer gene therapy via chemical or genetic inhibitory approaches. The biomedical applications of chemically functionalized carbon nanotubes (f-CNTs) in cancer therapy have been studied due to their ability to efficiently deliver siRNA intracellularly. In this study, we established the capacity of cationic MWNT-NH3+ to deliver the apoptotic siRNA against PLK1 (siPLK1) in Calu6 tumor xenografts by direct intratumoural injections. A direct comparison with cationic liposomes was made. This study validates the PLK1 gene as a potential target in cancer gene therapy including lung cancer, as demonstrated by the therapeutic efficacy of siPLK1:MWNT-NH3+ complexes and their ability to significantly improve animal survival. Biological analysis of the siPLK1:MWNT-NH3+ treated tumors by RT-PCR and Western blot, in addition to TUNEL staining confirmed the biological functionality of the siRNA intratumourally, suggesting that tumor eradication was due to PLK1 knockdown. Furthermore, by using a fluorescently labelled, non-coding siRNA sequence complexed with MWNT-NH3+, we established for the first time that the improved therapeutic efficacy observed in f-CNT-based siRNA delivery is directly proportional to the enhanced siRNA retention in the solid tumor and subsequent uptake by tumor cells after local administration in vivo.

AB - Polo-Like Kinase (PLK1) has been identified as a potential target in cancer gene therapy via chemical or genetic inhibitory approaches. The biomedical applications of chemically functionalized carbon nanotubes (f-CNTs) in cancer therapy have been studied due to their ability to efficiently deliver siRNA intracellularly. In this study, we established the capacity of cationic MWNT-NH3+ to deliver the apoptotic siRNA against PLK1 (siPLK1) in Calu6 tumor xenografts by direct intratumoural injections. A direct comparison with cationic liposomes was made. This study validates the PLK1 gene as a potential target in cancer gene therapy including lung cancer, as demonstrated by the therapeutic efficacy of siPLK1:MWNT-NH3+ complexes and their ability to significantly improve animal survival. Biological analysis of the siPLK1:MWNT-NH3+ treated tumors by RT-PCR and Western blot, in addition to TUNEL staining confirmed the biological functionality of the siRNA intratumourally, suggesting that tumor eradication was due to PLK1 knockdown. Furthermore, by using a fluorescently labelled, non-coding siRNA sequence complexed with MWNT-NH3+, we established for the first time that the improved therapeutic efficacy observed in f-CNT-based siRNA delivery is directly proportional to the enhanced siRNA retention in the solid tumor and subsequent uptake by tumor cells after local administration in vivo.

U2 - 10.1021/acs.bioconjchem.5b00249

DO - 10.1021/acs.bioconjchem.5b00249

M3 - Article

C2 - 26036843

SN - 1043-1802

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

ER -