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

• Published in: Nature biotechnology Vol. 27; no. 7; pp. 643 - 651
• Main Authors: Brahmbhatt, Himanshu, MacDiarmid, Jennifer A, Amaro-Mugridge, Nancy B, Madrid-Weiss, Jocelyn, Sedliarou, Ilya, Wetzel, Stefanie, Kochar, Kartini, Brahmbhatt, Vatsala N, Phillips, Leo, Pattison, Scott T, Petti, Carlotta, Stillman, Bruce, Graham, Robert M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2009; Nature Publishing Group
• Subjects: Agriculture; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - biosynthesis; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cancer; Care and treatment; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell- and Tissue-Based Therapy - methods; Cellular biology; Chemotherapy; Drug Delivery Systems - methods; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug therapy; Female; Fundamental and applied biological sciences. Psychology; Gene Knockdown Techniques; Genetic aspects; HCT116 Cells; Health. Pharmaceutical industry; Heterogeneity; Humans; Industrial applications and implications. Economical aspects; Life Sciences; Mice; Mice, Nude; Microscopy, Fluorescence; Miscellaneous; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - therapy; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins - genetics; Ribonucleic acid; RNA; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Salmonella typhimurium - physiology; Toxicity; Tumors; Xenograft Model Antitumor Assays; Australia; United States; Antineoplastic agent; Drug; Resistance; Delivery system; Gene silencing; RNA interference; Treatment; Targeting; Tumor; siRNA; Minicell; Cancer
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.1547

Drug resistance remains a major hurdle to effective cancer chemotherapy. MacDiarmid et al . show that bacterially derived minicells packaged with siRNAs reverse tumor drug resistance and that subsequent treatment with minicells loaded with cytotoxic drugs causes tumor stabilization or regression. 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.