pH-Sensitive Nanoformulated Triptolide as a Targeted Therapeutic Strategy for Hepatocellular Carcinoma
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- 作者：Daishun Ling ; Hongping Xia ; Wooram Park ; Michael J. Hackett ; Changyeong Song ; Kun Na ; Kam Man Hui ; Taeghwan Hyeon
- 刊名：ACS Nano
- 出版年：2014
- 出版时间：August 26, 2014
- 年：2014
- 卷：8
- 期：8
- 页码：8027-8039
- 全文大小：926K
- ISSN：1936-086X
文摘
Hepatocellular carcinoma (HCC) has one of the worst prognoses for survival as it is poorly responsive to both conventional chemotherapy and mechanism-directed therapy. This results from a lack of therapeutic concentration in the tumor tissue coupled with the highly toxic off-site effects exhibited by these compounds. Consequently, we believe the best packaging for holistic therapy for HCC will involve three components: a potent therapeutic, a rationally designed drug delivery vehicle to enrich the target site concentration of the drug, and a surface ligand that can enable a greater propensity to internalization by tumor cells compared to the parenchyma. We screened a library containing hundreds of compounds against a panel of HCC cells and found the natural product, triptolide, to be more effective than sorafenib, doxorubicin, and daunorubicin, which are the current standards of therapy. However, the potential clinical application of triptolide is limited due to its poor solubility and high toxicity. Consequently, we synthesized tumor pH-sensitive nanoformulated triptolide coated with folate for use in an HCC-subpopulation that overexpresses the folate receptor. Our results show triptolide itself can prevent disease progression, but at the cost of significant toxicity. Conversely, our pH-sensitive nanoformulated triptolide facilitates uptake into the tumor, and specifically tumor cells, leading to a further increase in efficacy while mitigating systemic toxicity.