Growth inhibition of human mammary carcinoma by liposomal hexadecylphosphocholine: Participation of activated macrophages in the antitumor mechanism

Abstract

This study was undertaken to investigate the antitumor effect of liposomal hexadecylphosphocholine (L-HPC), a synthetic phospholipid encapsulated into multilamellar vesicles (MLV). The effect of these liposomes was tested in an orthotopic nude mouse model using the human mammary carcinomas MDA-MB 435 and 231. The main interest of the investigation was to study whether activated macrophages are substantially involved in the tumor growth inhibition mechanism. The growth of both MDA-MB 435 and 231 tumors in the mammary fat pad was significantly inhibited by a 14-day intraperitoneal therapy with L-HPC. The remaining tumors were shown to be heavily infiltrated with macrophages. In vitro studies of mPEM demonstrated a significant induction of macrophage-mediated tumor cytotoxicity (MMCTX) against the 2 cell lines by L-HPC. The L-HPC-mediated activation mechanism was characterized to be IL-6 and TNF␣ dependent but rather independent of IL-1␣ and nitric oxide (NO). NMA, a specific inhibitor of NO production, did not inhibit L-HPC-induced MMCTX. Furthermore, L-HPC was shown to upregulate the matrixmetalloproteinases MMP-9 and MMP-2 secretion into the supernatant. Considering cytokine release and production of collagenases, the L-HPC-induced macrophage activation cascade is assumed to be comparable with that of classical activators such as lipopolysaccharide (LPS) and interferon (IFN) ␥. As far as NO production is considered, the L-HPC activation mechanism differs from that caused by LPS and IFN ␥.

Macrophage roles following myocardial infarction

“…Several groups have proposed using macrophages to target drug delivery, and whether this strategy will be effective remains to be determined 6, 90, 95, 165, 166…”

Cellular Transport and Lipid Interactions of Miltefosine

“…These effects were demonstrated in rat liver Kupffer cells [89], the human histiocytic line U937 [90] and in peritoneal macrophages harvested from mice that had been treated with HePC-containing liposomes in vivo [91]. The role of mediators released by activated macrophages in the antitumor mechanism of HePC was investigated by Eue [92] using a human mammary carcinoma growing in nude mice. In this study, the most important macrophage products were found to be TNF and interleukin-6.…”

Triggered Activation and Release of Liposomal Prodrugs and Drugs in Cancer Tissue by Secretory Phospholipase A2

“…The severe lytic side effects against red blood cells have prohibited intravenous administration of sufficiently high therapeutic concentrations of the AELs. To circumvent the hemolytic effect, various preclinical formulation and administration strategies have been developed including oral and intraperitoneal administration as well as the development of liposomes incorporated with a low amount of the AELs [65,66]. In the clinic, a particular anticancer lipid named hexadecylphosphocholine, has successfully been used in topical treatment of cutaneous breast cancer metastases [67].…”