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Bioengineered let‐7c is Effective at Reducing Orthotopic Hepatocellular Carcinoma Tumor Burden and is Well Tolerated in Mouse Models
Author(s) -
Jilek Joseph Lionel,
Zhang Qianyu,
Ho Pui Yan,
Tu Meijuan,
Duan Zhijian,
Yu Aiming
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.565.2
Subject(s) - in vivo , luciferase , hepatocellular carcinoma , microrna , in vitro , endogeny , cancer research , pharmacology , chemistry , medicine , gene , biology , biochemistry , microbiology and biotechnology , transfection
Given pleiotropic molecular targeting mechanisms, restoration or inhibition of endogenous microRNAs (miRNA) is a promising pharmacological strategy. Recently, our group has bioengineered a collection of miRNA agents in live cells using a n on‐coding ca rrier R NA (nCAR) based technology. In vitro screening identified nCAR/let‐7c as the most potent at inhibiting hepatocellular carcinoma (HCC) viability; this was found to be processed to the mature let‐7c molecule and suppressed target gene expression. As such, in vivo efficacy and safety of this agent was characterized in the present study using polyethyleneimine (PEI) and liposomal‐polyplex (LPP) RNA formulations. Huh7 cells stably expressing luciferase and green fluorescent protein were orthotopically engrafted into immunocompromised mice. To evaluate efficacy, 40 μg of nCAR/let‐7c or a truncated control agent was administered systemically every‐other day for two weeks, followed immediately by necropsy. Live animal bioluminescent and ex vivo fluorescent imaging suggested that LPP‐formulated nCAR/let‐7c reduced tumor burden to a greater degree than all controls and PEI‐formulated nCAR/let‐7c. Additionally, both nCAR/let‐7c and truncated control agents were well‐tolerated compared to untreated mice, as evidenced by gross evaluation and similar bodyweights throughout the study; however, further studies are warranted in immunocompetent animal models to elucidate the complete toxicological profile and immunogenic potential of nCAR/let‐7c. These data are the first to demonstrate that let‐7c restoration using a biologically‐derived agent can serve as a potent antineoplastic agent, presenting a new, clinically‐relevant strategy for HCC therapy. Support or Funding Information This work was supported by National Institutes of Health grants [R01GM113888 and U01CA175315 to A.‐M.Y.] and an institutional Pharmacology Training Program grant [T32GM099608 to J.L.J.]. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .