Nanoplex Delivery of siRNA and Prodrug Enzyme for Multimodality Image-Guided Molecular Pathway Targeted Cancer Therapy

Abstract

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, or the use of a prodrug enzyme delivered to the tumor to convert a non-toxic 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 downregulation 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 non-toxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU). In vivo MRI and optical imaging showed efficient intratumoral nanoplex delivery. siRNA-mediated downregulation of Chk-α and the conversion of 5-FC to 5-FU by bCD were detected noninvasively with 1H MR spectroscopic imaging and 19F 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.

Therapeutic effects of adenovirus‑mediated CD and NIS expression combined with Na131I/5‑FC on human thyroid cancer

“…The uracil phosphoribosyl transferase (UPRT) gene from Escherichia coli encodes uracil phosphoribosyltransferase, which converts uracil and 5-phosphoribosyl-1-R-diphosphate to uridine monophosphate (UMP). This protein is a potential target in cancer therapy, but not present in mammalian genomes when combining with UPRT (33,34).…”

Delayed Progression of Lung Metastases Following Delivery of a Prodrug-activating Enzyme

“…Breton and colleagues performed a study using a modified Ankara virus to express yeast CD in situ, reducing tumor growth in a glioblastoma mouse model (10). After introducing a viral vector for in vitro transformation of several cancer cell lines (12,31) and evaluation in preclinical models (32) not detected significant immunogenicity of bCD in animals (33,34). We do not anticipate that bCD 1525 would have immunogenic properties different from those of the regular protein, but this should be evaluated before translation to human use.…”

Oligonucleotide-Based Theranostic Nanoparticles in Cancer Therapy

“…future science group Review Shahbazi, Ozpolat & Ulubayram ously reported that tumor doubling time was reduced threefold with bCD only and sixfold with siRNA-and bCD-containing nanoplexes together with a single dose of 5-fluorocytosine [186].…”