Hepatic Tumor Metastases Cause Enhanced PEGylated Liposome Uptake by Kupffer Cells

Abstract

Kupffer cells in livers bearing tumor metastases were found to have promoted tumor invasion and exacerbated the metastasis. This implies that the function of Kupffer cells might differ between animals bearing hepatic metastases and those that are healthy. Kupffer cells are considered responsible for the accumulation of liposomes in the liver. In this study, we hypothesized that the alteration in the function of Kupffer cells by hepatic metastasis would also affect the biodistribution of liposomes following intravenous administration. The hepatic accumulation and the blood concentration of PEGylated liposomes were compared between healthy mice and tumor-bearing mice. We noted that hepatic accumulation and elimination from the blood were significantly accelerated in tumor-bearing mice, indicating that our hypothesis was correct. In the tumor-bearing mice, the proportion of Kupffer cells taking up liposomes was significantly increased. Intravenous injection of oxaliplatin (l-OHP) containing PEGylated liposomes decreased the fraction of Kupffer cells, but this administration caused no injury to the hepatocytes. These results suggest that PEGylated liposomes containing l-OHP may have the potential to treat metastatic hepatic cancer-not only via the direct killing of the cancer cells but also via a reduction in tumor-supportive Kupffer cells. Key words PEGylated liposome; oxaliplatin (l-OHP); liver metastasis; Kupffer cellThe liver is known as a favored site for cancer metastasis due to its abundant blood flow. The general treatment for hepatic metastases is surgical resection. Chemotherapy is usually performed for preoperative treatment, preventing recurrence after surgery, or treating nonresectable tumors. However, a prescription regimen has not been well-established for hepatic metastases, particularly from noncolorectal primaries.

Lipid Nanoparticles-Based Therapy in Liver Metastasis Management: From Tumor Cell-Directed Strategy to Liver Microenvironment-Directed Strategy

“… 74 Despite its pro-metastatic effect, KCs would eliminate the circulatory liposomes, which were thought to be responsible for liposomal chemotherapy resistance. 82 In that, the depletion of KCs in liver microenvironment would be a possible strategy to inhibit the progression of liver metastasis and improve treatment resistance. Clodronate has been found to kill the host macrophages upon phagocytosis.…”

“…Another possible Kupffer cell-targeting strategy was the use of liposomal oxaliplatin. Ukawa et al 82 found that the injection of liposomal oxaliplatin would decrease the number of KCs without injury to normal hepatocytes. Regarding liposomal RNAi therapy, Pattipeiluhu et al 80 found that RNAi-containing anionic LNPs would specifically target KCs evidenced by threefold targeting enhancement in murine KCs compared to murine hepatocytes.…”

The Biological Function of Kupffer Cells in Liver Disease

“…In the metastatic hepatic cancer, KCs taking up liposomes were significantly increased, and PEGylated can reverse this result through a reduction in tumor-supportive KCs [189]. Primary pancreatic tumor cells release exosomes that contain migration inhibitory factor (MIF) into the blood circulation.…”

Therapeutic effect of combined hyperbaric oxygen and radiation therapy for single brain metastasis and its influence on osteopontin and MMP‑9

“…Brain metastases are malignant tumors in the brain, which have been transferred from other organs; the majority are originally transferred from the lungs and these tumors make up 20-40% of all brain metastases (1). Patients with brain metastases typically have a poor prognosis (1-year overall survival rate of ~60%) (2), however combined modality therapy may improve their overall survival rate (3).…”