Blocking ACAT-1 Activity for Tumor Therapy with Fluorescent Hyperstar Polymer-Encapsulated Avasimible
Ting Bai1, Bobo Zhu2, Dongyan Shao2
1Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an, 710072, P. R. China.
Abstract:
Targeting the distinct cholesterol metabolism of tumor cells is proposed as a novel way to treat tumors. Blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1) by the inhibitor avasimible (Ava), which elevates intracellular free cholesterol levels, is shown to effectively induce apoptosis. However, Ava faces disadvantages of poor water solubility, a short half-life, and no capability for fluorescence detection, which have greatly limited its application. Herein, a fluorescent hyperstar polymer (FHSP) is developed to encapsulate Ava to improve its ability to inhibit HeLa cells and K562 cells. The results of this study show that the obtained Ava-FHSP micelles possess a high drug loading capacity of 22.7% and bright green fluorescence. Ava and Ava-FHSP are cytotoxic to both HeLa and K562 cells and cause reductions in cell size, nuclear lysis, and chromatin condensation and hindered proliferation of both cell types by causing S phase cell cycle arrest. Further mechanistic analysis indicates that Ava-FHSP reduces the protein and messenger RNA expression of ACAT-1 and significantly increases intracellular free cholesterol levels, which can increase endoplasmic reticulum stress and finally cause cell apoptosis. All these results suggest that this fluorescent hyperstar polymer represents a potential therapeutic tumor strategy by changing the cholesterol metabolism of tumor cells.
Insights
Researchers developed a fluorescent polymer to deliver avasimible, an acyl-CoA cholesterol acyltransferase-1 inhibitor, enhancing its tumor-killing properties. This novel approach improves drug delivery and enables fluorescence detection for better cancer treatment strategies.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Tumor cells exhibit unique cholesterol metabolism, presenting a therapeutic target.
- Acyl-CoA cholesterol acyltransferase-1 (ACAT-1) inhibition elevates intracellular free cholesterol, inducing cancer cell apoptosis.
- Avasimible (Ava), an ACAT-1 inhibitor, has poor solubility, short half-life, and lacks fluorescence, limiting its clinical use.
Purpose of the Study:
- To develop a novel drug delivery system for avasimible using a fluorescent hyperstar polymer (FHSP).
- To enhance the anti-tumor efficacy and enable fluorescence detection of avasimible in cancer cells.
- To investigate the mechanism of action of Ava-FHSP on tumor cell cholesterol metabolism and apoptosis.
Main Methods:
- Encapsulation of avasimible (Ava) within a fluorescent hyperstar polymer (FHSP) to create Ava-FHSP micelles.
- Assessment of drug loading capacity and fluorescence properties of Ava-FHSP.
- Evaluation of the cytotoxicity and cell cycle effects of Ava and Ava-FHSP on HeLa and K562 cancer cell lines.
- Mechanistic studies involving protein and mRNA expression analysis of ACAT-1, intracellular free cholesterol levels, endoplasmic reticulum stress, and apoptosis induction.
Main Results:
- Ava-FHSP micelles demonstrated a high drug loading capacity (22.7%) and bright green fluorescence.
- Both Ava and Ava-FHSP exhibited cytotoxicity against HeLa and K562 cells, inducing apoptosis.
- Ava-FHSP treatment led to S phase cell cycle arrest, reduced cell size, nuclear lysis, and chromatin condensation.
- Ava-FHSP effectively reduced ACAT-1 expression, increased intracellular free cholesterol, induced endoplasmic reticulum stress, and promoted apoptosis.
Conclusions:
- Fluorescent hyperstar polymer encapsulation significantly improves avasimible's anti-cancer properties and enables fluorescence tracking.
- The Ava-FHSP system offers a promising strategy for targeting tumor cholesterol metabolism and inducing apoptosis.
- This nanomedicine approach holds potential for developing advanced cancer therapeutics with enhanced delivery and monitoring capabilities.
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