Overcoming Akt induced therapeutic resistance in breast cancer through siRNA and Thymoquinone encapsulated multilamellar gold niosomes

Rajput, Shashi ; Puvvada, Nagaprasad ; Prashanth Kumar, B. N. ; Sarkar, Siddik ; Konar, Suraj ; Bharti, Rashmi ; Dey, Goutam ; Mazumdar, Abhijit ; Pathak, Amita ; Fisher, Paul B. ; Mandal, Mahitosh (2015) Overcoming Akt induced therapeutic resistance in breast cancer through siRNA and Thymoquinone encapsulated multilamellar gold niosomes Molecular Pharmaceutics, 12 (12). pp. 4214-4225. ISSN 1543-8384

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Official URL: https://pubs.acs.org/doi/abs/10.1021/acs.molpharma...

Related URL: http://dx.doi.org/10.1021/acs.molpharmaceut.5b00692

Abstract

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.

Item Type:Article
Source:Copyright of this article belongs to American Chemical Society.
Keywords:Akt-siRNA; Apoptosis; Breast Cancer; Cell Signaling; Gold Niosomes; Thymoquinone
ID Code:113082
Deposited On:09 May 2018 11:59
Last Modified:09 May 2018 11:59

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