Nanoplex delivery of siRNA and prodrug enzyme for multimodality image-guided molecular pathway targeted cancer therapy.
The ability to destroy cancer cells while sparing normal tissue is highly sought after in cancer therapy. Small interfering RNA (siRNA)-mediated silencing of cancer-cell-specific targets and the use of a prodrug enzyme delivered to the tumor to convert a nontoxic prodrug to an active drug are two promising approaches in achieving this goal. Combining both approaches into a single treatment strategy can amplify selective targeting of cancer cells while sparing normal tissue. Noninvasive imaging can assist in optimizing such a strategy by determining effective tumor delivery of the siRNA and prodrug enzyme to time prodrug administration and detecting target down-regulation by siRNA and prodrug conversion by the enzyme. In proof-of-principle studies, we synthesized a nanoplex carrying magnetic resonance imaging (MRI) reporters for in vivo detection and optical reporters for microscopy to image the delivery of siRNA and a functional prodrug enzyme in breast tumors and achieve image-guided molecular targeted cancer therapy. siRNA targeting of choline kinase-α (Chk-α), an enzyme significantly up-regulated in aggressive breast cancer cells, was combined with the prodrug enzyme bacterial cytosine deaminase (bCD) that converts the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU). In vivo MRI and optical imaging showed efficient intratumoral nanoplex delivery. siRNA-mediated down-regulation of Chk-α and the conversion of 5-FC to 5-FU by bCD were detected noninvasively with (1)H MR spectroscopic imaging and (19)F MR spectroscopy. Combined siRNA and prodrug enzyme activated treatment achieved higher growth delay than either treatment alone. The strategy can be expanded to target multiple pathways with siRNA.
Li
Cong
C
JHU ICMIC Program, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States. congli@fudan.edu.cn
Penet
Marie-France
MF
Wildes
Flonné
F
Takagi
Tomoyo
T
Chen
Zhihang
Z
Winnard
Paul T
PT
Artemov
Dmitri
D
Bhujwalla
Zaver M
ZM
D000818:Animals; D001419:Bacteria / Q000201:enzymology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D043525:Cytosine Deaminase / Q000737:chemistry / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D005437:Flucytosine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D057054:Molecular Imaging / Q000379:methods*; D049329:Nanostructures / Q000737:chemistry*; D011355:Prodrugs / Q000378:metabolism*; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D016896:Treatment Outcome
D004337:Drug Carriers; D011355:Prodrugs; D034741:RNA, Small Interfering; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil