Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models.
Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA.
Wu
S Y
SY
Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Australia.
Singhania
A
A
Burgess
M
M
Putral
L N
LN
Kirkpatrick
C
C
Davies
N M
NM
McMillan
N A J
NA
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002584:Cervix Uteri / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D005260:Female; D020868:Gene Silencing; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000628:therapy*
D000970:Antineoplastic Agents; C068651:E6 protein, Human papillomavirus type 16; D008055:Lipids; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D002945:Cisplatin