Abstract
AS1411 (previously known as AGRO100) is a 26 nucleotide guanine-rich DNA aptamer which forms a guanine quadruplex structure. AS1411 has shown promising utility as a treatment for cancers in Phase I and Phase II clinical trials without causing major side-effects. AS1411 inhibits tumor cell growth by binding to nucleolin which is aberrantly expressed on the cell membrane of many tumors. In this study, we utilized a simple technique to conjugate a widely-used chemotherapeutic agent, doxorubicin (Dox), to AS1411 to form a synthetic Drug-DNA Adduct (DDA), termed as AS1411-Dox. We demonstrate the utility of AS1411-Dox in the treatment of hepatocellular carcinoma (HCC) by evaluating the targeted delivery of Dox to Huh7 cells in vitro and in a murine xenograft model of HCC.
Highlights
To date the only curative treatments for liver cancer are liver transplant or tumor resection
As AS1411 works by first binding to cell membrane nucleolin [19], we sought to determine the presence of cell-surface nucleolin expression in the hepatocellular carcinoma (HCC) cell line Huh7 and in a culture of human primary hepatocytes Hu767
We show that the AS1411-Dox adduct is able to efficiently deliver Dox into Huh7 cells with the same efficiency as free doxorubicin; this shows that conjugation with the aptamer does not prevent the drug from being released into cancer cells
Summary
To date the only curative treatments for liver cancer are liver transplant or tumor resection. Sorafenib and doxorubicin are drugs which form the basis of systemic chemotherapy treatments used to treat liver cancer. These treatments are palliative and only delay tumor development and progression. These untargeted treatments of liver cancer are not highly successful, and may cause iatrogenic disease due to off-target side effects. Treatment approaches that target tumor tissue are highly desirable. Nucleic acid aptamers are single-stranded (ss) oligonucleotides with unique intramolecular conformations with the ability to recognize specific molecular targets.
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