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

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.

• Authors: Shashi Rajput, Nagaprasad Puvvada, B N Prashanth Kumar, Siddik Sarkar, Suraj Konar, Rashmi Bharti, Goutam Dey, Abhijit Mazumdar, Amita Pathak, Paul B Fisher, Mahitosh Mandal
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 12 Issue 12 Pg. 4214-25 (Dec 07 2015) ISSN: 1543-8392 [Electronic] United States
• PMID: 26505213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzoquinones
• RNA, Small Interfering
• Tamoxifen
• Gold
• Proto-Oncogene Proteins c-akt
• thymoquinone

Topics

• Apoptosis (drug effects)
• Benzoquinones (pharmacology)
• Breast Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gold (administration & dosage)
• Humans
• MCF-7 Cells
• Nanoparticles (administration & dosage)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Tamoxifen (pharmacology)