Layered double hydroxides (LDHs) exhibit characteristic anion-exchange chemistry making them ideal carriers of negatively charged molecules like deoxyribonucleic acid (DNA). In this study, hydrotalcite (Mg−Al) and hydrotalcite-like compounds (Mg−Fe, Zn−Al, and Zn−Fe), also known as LDHs, were evaluated for their potential application as a carrier of DNA. LDHs were prepared by coprecipitation at low supersaturation and characterized by Powder X-ray diffraction (XRD), infrared (IR), Raman, and inductively coupled plasma—optical emission spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). XRD patterns showed strong and sharp diffraction peaks for the (003) and (006) planes indicating well-ordered crystalline materials. TEM images yielded irregular circular to hexagonal-shaped particles of 50–250 nm in size. Varying degrees of DNA binding was observed for all the compounds, and nuclease digestion studies revealed that the LDHs afford some degree of protection to the bound DNA. Minimal toxicity was observed in human embryonic kidney (HEK293), cervical cancer (HeLa) and hepatocellular carcinoma (HepG2) cell lines with most showing a cell viability in excess of 80 %. All LDH complexes promoted significant levels of luciferase gene expression, with the DNA:Mg−Al LDHs proving to be the most efficient in all cell lines.
Cancer stem cells (CSCs) are a subpopulation of tumorigenic cells capable of self-renewal and differentiation. These cells are highly resistant to chemo/radiation therapy and may be responsible for tumor recurrence and metastasis. MicroRNAs (miRNAs) are involved in cancer initiation and progression by regulating genes responsible for cell proliferation and/or death. The tumor suppressor miRNA miR-34a is directly regulated by p53. miR-34a targets Notch and Bcl-2, both of which are involved in the self-renewal and survival of CSCs. We recently showed that miR-34a potently inhibits tumorsphere growth and tumor-initiation of p53-mutant pancreatic cancer, accompanied by reduction of CSCs and inhibition of Bcl-2/Notch signaling pathways. However, like other gene therapeutics, tumor-targeted delivery of miRNA, especially targeting to CSCs, remains a great challenge. We have established a self-assembled nanovector system that shows promising tumor specificity and efficiency for tumor-targeted gene/siRNA delivery (US Patent No. 6,749,863 and 7,479,276 with modification). The nanovectors show promising specificity and efficacy for systemic p53 tumor suppressor gene therapy in human cancer models. The first-in-human Phase I clinical trial of nano-p53 (NCT00470613, ClinicalTrails.gov) by Chang EH group shows a promising safety profile, efficient therapeutic gene expression in tumors and early tumor response. We have modified this nanotechnology and established a nanovector delivery system to deliver miR-34a, which resulted in a high transfection efficiency and significant Bcl-2/Notch downregulation in pancreatic, breast and prostate cancer cell lines, accompanied with reduced tumorsphere growth in vitro and tumor formation in vivo. More importantly, systemic injection of nano-miR-34a can delivermiR-34a to the established pancreatic, breast and prostate cancer xenograft tumors and reduce Bcl-2/Notch expression in these tumors. CSC population was also reduced in the treated tumors. Our studies demonstrate that our nano-miR-34a may provide a novel and effective molecular therapy for human cancers with high Bcl-2 and p53 loss of function, potentially by modulating cancer stem cells. Molecularly targeted miRNA therapy delivered by nanovectors could be a powerful tool to correct the cancer stem cell dysregulation. Supported in part by NIH grant CA121830(S1). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5692. doi:1538-7445.AM2012-5692
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