The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells

Abstract

Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH 2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH 2 was much lower and exocytosis of PAMAM-NH 2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH 2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH 2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH 2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH 2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH 2 as a drug and gene vector in resistant cells.

PAMAM dendrimers as a carbamazepine delivery system for neurodegenerative diseases: A biophysical and nanotoxicological characterization

“…However, cytotoxicity measured as reduction of NR uptake was observed at the higher concentration of free dendrimers and D-CBZ complexes. This effect on lysosomes produced by dendrimers was previously described (Mukherjee et al, 2010;J. Zhang et al, 2016).…”

Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system

“…In light of the two studies mentioned earlier, it can be inferred that the present carriers may possibly be taken up by a mechanism involving nonspecific macropinocytosis, an internalization process that does not rely on the formation of the early endosome. 43 In this manner, the intracellular escape of cargo is facilitated and efficient owing to the leaky macropinosomes formed. 5 The proposed mechanism for siRNA-loaded A-L transportation across the cellular membrane and escape into cytoplasm was illustrated in Figure 12.…”

Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

“…Although we have not studied the cellular mechanisms of synthesized conjugates penetration, the confocal microscopy images showed that all absorbed conjugates remained in endocytic and in lysosomal vesicles, with a small part of the dendrimer present in the cytoplasm of the cells (Figure 12). The influx of studied compounds also can be executed by charge-mediated adsorptive endocytosis, since each conjugate has a non-substituted free amino groups, generating positive surface charge [13,[42][43][44].…”