Abstract
BackgroundPolyamidoamine (PAMAM) dendrimer applications have extended from tumor cells to multidrug-resistant tumor cells. However, their transportation in multidrug-resistant tumor cells remains unclear. Herein, we investigated the exocytosis rule and mechanism of PAMAM dendrimers in multidrug-resistant tumor cells.ResultsUsing a multidrug-resistant human breast cancer cell model (MCF-7/ADR), we performed systematic analyses of the cellular exocytosis dynamics, pathways and mechanisms of three PAMAM dendrimers with different surface charges: positively charged PAMAM-NH2, neutral PAMAM-OH and negatively charged PAMAM-COOH. The experimental data indicated that in MCF-7/ADR cells, the exocytosis rate was the highest for PAMAM-NH2 and the lowest for PAMAM-OH. Three intracellular transportation processes and P-glycoprotein (P-gp) participated in PAMAM-NH2 exocytosis in MCF-7/ADR cells. Two intracellular transportation processes, P-gp and multidrug resistance (MDR)-associated protein participated in PAMAM-COOH exocytosis. P-gp and MDR-associated protein participated in PAMAM-OH exocytosis. Intracellular transportation processes, rather than P-gp and MDR-associated protein, played major roles in PAMAM dendrimer exocytosis. PAMAM-NH2 could enter MCF-7/ADR cells by forming nanoscale membrane holes, but this portion of PAMAM-NH2 was eliminated by P-gp. Compared with PAMAM-OH and PAMAM-COOH, positively charged PAMAM-NH2 was preferentially attracted to the mitochondria and cell nuclei. Major vault protein (MVP) promoted exocytosis of PAMAM-NH2 from the nucleus but had no effect on the exocytosis of PAMAM-OH or PAMAM-COOH.ConclusionsPositive charges on the surface of PAMAM dendrimer promote its exocytosis in MCF-7/ADR cells. Three intracellular transportation processes, attraction to the mitochondria and cell nucleus, as well as nuclear efflux generated by MVP led to the highest exocytosis observed for PAMAM-NH2. Our findings provide theoretical guidance to design a surface-charged tumor-targeting drug delivery system with highly efficient transfection in multidrug-resistant tumor cells. Especially, to provide more DNA to the nucleus and enhance DNA transfection efficiency in multidrug-resistant tumor cells using PAMAM-NH2, siRNA-MVP or an inhibitor should be codelivered to decrease MVP-mediated nuclear efflux.Graphical abstract
Highlights
Polyamidoamine (PAMAM) dendrimer applications have extended from tumor cells to multidrug-resistant tumor cells
Dendrimer surface charges could lead to toxicity [1, 5, 13], and cancer cells could become resistant to the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents owing to multidrug resistance (MDR), so resistant tumor cells may show MDR against PAMAM dendrimers with different surface charges
Our previous research indicated that a portion of PAMAM dendrimers could be internalized into MCF-7/ADR cells through endocytosis and trapped in endosomes/lysosomes [12] and that FITC may dissociate from the surface of the PAMAM dendrimers during this process
Summary
Polyamidoamine (PAMAM) dendrimer applications have extended from tumor cells to multidrug-resistant tumor cells. Polyamidoamine (PAMAM) dendrimers are monodisperse, highly branched polymeric macromolecules with a uniform size and shape [1, 2] Their basic structure includes three main components: a central core, repeated branching units, and terminal groups [1]. Because of their distinct structure, PAMAM dendrimers have steadily grown in popularity in the fields of drug delivery and gene therapy for antitumor treatment and the reversal of multidrug resistance (MDR) [3]. One of the MDR mechanisms is increasing drug influx [14,15,16], so the exocytosis of PAMAM dendrimers with different surface charges may be different in resistant tumor cells
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