Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes

Shashi Rajput, Nagaprasad Puvvada, Prashanth Kumar Bhusetty Nagesh, Siddik Sarkar, Suraj Konar, Rashmi Bharti, Goutam Dey, Abhijit Mazumdar, Amita Pathak, Paul B. Fisher, Mahitosh Mandal

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4214-4225
Number of pages12
JournalMolecular Pharmaceutics
Volume12
Issue number12
DOIs
StatePublished - Oct 27 2015

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Liposomes
Gold
Small Interfering RNA
Breast Neoplasms
Therapeutics
Tamoxifen
Heterografts
Nanoparticles
Neoplasms
Pharmacokinetics
thymoquinone
Apoptosis
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes. / Rajput, Shashi; Puvvada, Nagaprasad; Bhusetty Nagesh, Prashanth Kumar; Sarkar, Siddik; Konar, Suraj; Bharti, Rashmi; Dey, Goutam; Mazumdar, Abhijit; Pathak, Amita; Fisher, Paul B.; Mandal, Mahitosh.

In: Molecular Pharmaceutics, Vol. 12, No. 12, 27.10.2015, p. 4214-4225.

Research output: Contribution to journalArticle

Rajput, S, Puvvada, N, Bhusetty Nagesh, PK, Sarkar, S, Konar, S, Bharti, R, Dey, G, Mazumdar, A, Pathak, A, Fisher, PB & Mandal, M 2015, 'Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes', Molecular Pharmaceutics, vol. 12, no. 12, pp. 4214-4225. https://doi.org/10.1021/acs.molpharmaceut.5b00692
Rajput, Shashi ; Puvvada, Nagaprasad ; Bhusetty Nagesh, Prashanth Kumar ; Sarkar, Siddik ; Konar, Suraj ; Bharti, Rashmi ; Dey, Goutam ; Mazumdar, Abhijit ; Pathak, Amita ; Fisher, Paul B. ; Mandal, Mahitosh. / Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes. In: Molecular Pharmaceutics. 2015 ; Vol. 12, No. 12. pp. 4214-4225.
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