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Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)
Journal article   Peer reviewed

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

Devaraja Rajasekaran, Jyoti Srivastava, Kareem Ebeid, Rachel Gredler, Maaged Akiel, Nidhi Jariwala, Chadia L Robertson, Xue-Ning Shen, Ayesha Siddiq, Paul B Fisher, …
Bioconjugate chemistry, Vol.26(8), pp.1651-1661
08/19/2015
DOI: 10.1021/acs.bioconjchem.5b00254
PMCID: PMC4783168
PMID: 26079152
url
https://www.ncbi.nlm.nih.gov/pmc/articles/4783168View
Open Access

Abstract

Hepatocellular carcinoma (HCC) is a fatal cancer with no effective therapy. Astrocyte elevated gene-1 (AEG-1) plays a pivotal role in hepatocarcinogenesis and inhibits retinoic acid-induced gene expression and cell death. The combination of a lentivirus expressing AEG-1 shRNA and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We have now developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (Gal) (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). The polymer conjugate was characterized by (1)H-NMR, MALDI, and mass spectrometry; and optimal nanoplex formulations were characterized for surface charge, size, and morphology. Orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) were established in the livers of athymic nude mice and tumor development was monitored by bioluminescence imaging (BLI). Tumor-bearing mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si, and PAMAM-AEG-1si+ATRA. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth, and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. A marked decrease in AEG-1 level was observed in tumor samples treated with PAMAM-AEG-1si. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation, and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anticancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC.
 Genetic Therapy RNA, Small Interfering - genetics Cell Adhesion Molecules - genetics Nanoparticles - chemistry Apoptosis - drug effects Humans Cell Adhesion Molecules - antagonists & inhibitors Liver Neoplasms - therapy Liver - drug effects Carcinoma, Hepatocellular - genetics Liver Neoplasms - pathology Antineoplastic Agents - pharmacology Tumor Cells, Cultured Tretinoin - pharmacology Liver Neoplasms - genetics Liver - metabolism Mice, Inbred C57BL Combined Modality Therapy Xenograft Model Antitumor Assays Animals Mice, Nude Carcinoma, Hepatocellular - pathology Carcinoma, Hepatocellular - therapy Cell Proliferation - drug effects Mice Nanoparticles - administration & dosage

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