Mechanisms of Drug Resistance Reversal in Dox-Resistant MCF-7 Cells by pH-Responsive Amphiphilic Polyphosphazene Containing Diisopropylamino Side Groups

pH-responsive drug carriers derived from polymers containing weak base groups have been shown to improve the antitumor effect of chemotherapeutics. The common interpretation is that a proton sponge effect caused by pH-responsive polymers facilitates endosomal membrane destruction and accelerates cytoplasmic drug release in tumor cells. However, the mechanisms by which pH-responsive weak base polymers disrupt membranes have not been expatiated clearly. Herein, we synthesized a series of pH-responsive amphiphilic polyphosphazenes containing diisopropylamino (DPA) side groups with various contents and investigated the effect of DPA content on the actions of polymers with cell membranes. In a certain pH range, the polymers with elevated DPA content showed enhanced membrane disruptive activity. Electrical interactions between the protonated DPA groups of polymers and the cell lipid bilayer are critical for pH-dependent membrane disruption, which can be competitively prevented by serum proteins. On the other hand, the hydrophobic unprotonated DPA moieties can insert into lipophilic regions of cell membrane. These synergic actions caused the alteration of biomembrane permeability consequently. More interestingly, it was also found that DPA-rich polymers exhibit higher P-glycoprotein (P-gp) inhibition activity as compared with the polymer containing only low levels of DPA by efficiently blocking the internal epitope of P-gp. These findings strongly provide rational support for pH-responsive amphiphilic polyphosphazenes containing DPA side groups to be quite promising drug carriers for intracellular drug delivery applications, especially the treatment of P-gp overexpressing, drug-resistant tumors.