Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug

MacDiarmid, J. A., Amaro-Mugridge, N. B., Madrid-Weiss, J., Sedliarou, I., Wetzel, S., Kochar, K., Brahmbhatt, V. N., Phillips, L., Pattison, S. T., Petti, C., Stillman, B., Graham, R. M., Brahmbhatt, H. (June 2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nature Biotechnology, 27 (7). pp. 643-651. ISSN 1087-0156

DOI: 10.1038/nbt.1547


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.

Item Type: Paper
Additional Information:
Uncontrolled Keywords: Animals Antineoplastic Agents administration & dosage pharmacokinetics Cell Cycle Proteins genetics Cell Line Tumor Drug Delivery Systems methods Drug Resistance Multiple Drug Resistance Neoplasm Female Gene Knockdown Techniques HCT116 Cells Humans Mice Mice Nude Microscopy Fluorescence Neoplasms drug therapy genetics metabolism therapy P-Glycoprotein biosynthesis metabolism Protein-Serine-Threonine Kinases genetics Proto-Oncogene Proteins genetics RNA, Small Interfering administration & dosage genetics Salmonella typhimurium physiology Tissue Therapy methods Xenograft Model Antitumor Assays
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > siRNA
CSHL Authors:
Communities: CSHL labs > Stillman lab
Highlight: Stillman, Bruce W.
Depositing User: CSHL Librarian
Date: 28 June 2009
Date Deposited: 06 Mar 2012 14:21
Last Modified: 20 Jun 2017 16:37
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