Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

Abstract

Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53−/−. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo.

Acetate Induces Growth Arrest in Colon Cancer Cells Through Modulation of Mitochondrial Function

“…Although the effect on cell proliferation observed was small, this was in response to acute acetate treatment. Our previous study showed that chronic acetate treatment reduces tumor volume by half (1). Under normoxia, we found no effect at zero or 24 h in mitochondrial function but continuous measurements showed that acetate treatment increased oxygen consumption and reduced glycolysis in both HT29 and HCT116 cells lines, reversing the Warburg effect.…”

“…Schulz et al demonstrated that growth and colony formation of several colon cancer cell lines can be reduced by reversing the Warburg effect through increasing mitochondrial oxygen consumption (26,27). We have previously shown that while acetate can enhance the mitochondrial function of non-cancerous cells (14), it can also reduce tumor sizes in xenograph models of colon cancer (1). We therefore hypothesized that the impact of acetate on mitochondrial function could be the underlying mechanism.…”

“…Acetate, one of the main short chain fatty acids produced as a result of ingestion of fermentable carbohydrates has previously been shown to demonstrate anti-tumorigenic effects following its delivery as acetate encapsulated in liposomes (1). However, there is conflicting evidence regarding its effects; acetate has been shown to reduce cell viability of colon cancer cells in vitro (2,3) and reduce cancer cell proliferation in the liver in vivo (4).…”

<p>Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke</p>

“…However, induction of MCAO has been shown to significantly disrupt the BBB for up to 4 weeks following reperfusion. 33 Furthermore, increased BBB permeability has an "enhanced permeability and retention effect", 34 similar to that observed in tumors, 31 during which considerable uptake of LITA into the brain may occur; a recent review reports the brain accumulation of liposomes in experimental stroke models. 35 In addition, LITA are significantly PEGylated, which prolongs their circulation time, resulting in preferential accumulation at sites of leaky vasculature such as tumors or brain tissue following BBB disruption.…”

“…We have previously shown that LITA nanoparticles can effectively modulate metabolic processes associated with mitochondrial function and lipid metabolism in peripheral healthy tissues and ectopic tumors. 23,31 LITA has been shown to attenuate peripheral inflammatory responses, 23 and Wang et al 19 have demonstrated significant contribution of the periphery to MCAO-induced brain damage. Here, we extend this work to show that these nanoparticles can also have beneficial effects on cerebral tissue following MCAO.…”