Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide

Abstract

Arsenic trioxide (As2O3) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As2O3 encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic “nanobins” are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)–positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As2O3 or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As2O3 with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As2O3 efficacy in relatively insensitive solid tumor–derived cells and holds the promise of improving drug therapeutic index.

Microfluidic synthesis of multifunctional liposomes for tumour targeting

“…The human ovarian carcinoma SKOV3 is a widely used folate receptor positive cell line, however for human breast carcinoma MCF-7 cell line, different literature reports quite contradictory folate receptor expression levels. Jie et al employed MCF-7 as a folate receptor overexpressed cell line [31] while Haimei et al used MCF-7 as a negative control [32]. In this study, we tested the folate receptor expression level of the MCF-7 and SKOV3 cell lines.…”

Antitumoral activity of L-ascorbic acid-poly-D,L-(lactide-co-glycolide) nanoparticles containing violacein

“…It has been shown that uptake of folate-targeted drug delivery systems is decreased in tumoral models which have lower density of folate receptors, such as HeLa and MCF-7 cells. 37 Thus, the spectra of uses of those molecules are restricted depending on the cell model studied. On the other hand, the role of ascorbic acid in cancer metabolism is well described for several tumoral lineages and its high uptake is a characteristic common to most solid or nonsolid tumors analyzed, [38][39][40] which makes it an interesting molecule to target a broader spectra of tumors.…”

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

“…Li and Huang showed that targeted liposomes are able to localize to and effectively deliver siRNA to tumors in a xenograft model of human lung cancer [37]. Folate-targeted liposomes encapsulating arsenic trioxide, a toxic chemical with a low therapeutic index that has been used in the treatment of some forms of leukemia, was recently shown to be effective against malignant cells that express the folate receptor [38].…”