Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug.
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.
MacDiarmid
Jennifer A
JA
EnGeneIC Pty Ltd., Sydney, New South Wales, Australia.
Amaro-Mugridge
Nancy B
NB
Madrid-Weiss
Jocelyn
J
Sedliarou
Ilya
I
Wetzel
Stefanie
S
Kochar
Kartini
K
Brahmbhatt
Vatsala N
VN
Phillips
Leo
L
Pattison
Scott T
ST
Petti
Carlotta
C
Stillman
Bruce
B
Graham
Robert M
RM
Brahmbhatt
Himanshu
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D012486:Salmonella typhimurium / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1