Research abstract
Article abstract
Nature Biotechnology 27, 643 - 651 (2009)
Published online: 28 June 2009 | doi:10.1038/nbt.1547
Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug
Jennifer A MacDiarmid1, Nancy B Amaro-Mugridge1, Jocelyn Madrid-Weiss1, Ilya Sedliarou1, Stefanie Wetzel1, Kartini Kochar1, Vatsala N Brahmbhatt1, Leo Phillips1, Scott T Pattison1, Carlotta Petti1, Bruce Stillman2, Robert M Graham3,4 & Himanshu Brahmbhatt1
Abstract
The dose-limiting toxicity of chemotherapeutics, heterogeneity and drug resistance of cancer cells, and difficulties of targeted delivery to tumors all pose daunting challenges to effective cancer therapy. We report that small interfering RNA (siRNA) duplexes readily penetrate intact bacterially derived minicells previously shown to cause tumor stabilization and regression when packaged with chemotherapeutics. When targeted via antibodies to tumor-cell-surface receptors, minicells can specifically and sequentially deliver to tumor xenografts first siRNAs or short hairpin RNA (shRNA)–encoding plasmids to compromise drug resistance by knocking down a multidrug resistance protein. Subsequent administration of targeted minicells containing cytotoxic drugs eliminate formerly drug-resistant tumors. The two waves of treatment, involving minicells loaded with both types of payload, enable complete survival without toxicity in mice with tumor xenografts, while involving several thousandfold less drug, siRNA and antibody than needed for conventional systemic administration of cancer therapies.
- EnGeneIC Pty Ltd., Sydney, New South Wales, Australia.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
- University of New South Wales, Kensington, New South Wales, Australia.
Correspondence to: Himanshu Brahmbhatt1 e-mail: hbrahmbhatt@engeneic.com
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