Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes.
Akt overexpression in cancer causes resistance to traditional chemotherapeutics. Silencing Akt through siRNA provides new therapeutic options; however, poor in vivo siRNA pharmacokinetics impede translation. We demonstrate that acidic milieu-sensitive multilamellar gold niosomes (Nio-Au) permit targeted delivery of both Akt-siRNA and thymoquinone (TQ) in tamoxifen-resistant and Akt-overexpressing MCF7 breast cancer cells. Octadecylamine groups of functionalized gold nanoparticles impart cationic attribute to niosomes, stabilized through polyethylene glycol. TQ's aqueous insolubility renders its encapsulation within hydrophobic core, and negatively charged siRNA binds in hydrophilic region of cationic niosomes. These niosomes were exploited to effectively knockdown Akt, thereby sensitizing cells to TQ. Immunoblot studies revealed enhanced apoptosis by inducing p53 and inhibiting MDM2 expression, which was consistent with in vivo xenograft studies. This innovative strategy, using Nio-Au to simultaneously deliver siRNA (devoid of any chemical modification) and therapeutic drug, provides an efficacious approach for treating therapy-resistant cancers with significant translational potential.
Shashi
S
Rajput
Nagaprasad
N
Puvvada
B N Prashanth
BN
Kumar
Department of Human and Molecular Genetics, VCU Institute of Molecular Genetics, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine , Richmond, Virginia 23298, United States.
Siddik
S
Sarkar
Suraj
S
Konar
Rashmi
R
Bharti
Goutam
G
Dey
Department of Clinical Cancer Prevention and Systems Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas 77030, United States.
Abhijit
A
Mazumdar
Amita
A
Pathak
Department of Human and Molecular Genetics, VCU Institute of Molecular Genetics, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine , Richmond, Virginia 23298, United States.
Paul B
PB
Fisher
Mahitosh
M
Mandal
D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006046:Gold / Q000008:administration & dosage*; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology
D016227:Benzoquinones; D034741:RNA, Small Interfering; D013629:Tamoxifen; D006046:Gold; D051057:Proto-Oncogene Proteins c-akt; C003466:thymoquinone
Akt-siRNA; apoptosis; breast cancer; cell signaling; gold niosomes; thymoquinone