The intracellular fate of an amphipathic pH-responsive polymer: Key characteristics towards drug delivery

Abstract

Biopolymers have become important drug delivery systems for therapeutic molecules by enhancing their accessibility and efficacy intracellularly. However, the transport of these drugs across the cell membrane and their release into the cytosol remain a challenge. The trafficking of poly (l-lysine iso-phthalamide) grafted with phenylalanine (PP-50) was investigated using an osteosarcoma cell line (SAOS-2). Colocalisation of this amphipathic biopolymer with endocytosis tracers, such as transferrin and lactosylceramide, suggested that PP-50 is partially internalised by both clathrin and caveolin-mediated endocytosis. Macropinocytosis was also investigated, but a smaller correlation was found between this mechanism and PP-50 transport. A significant decrease in polymer-mediated calcein uptake was found when cells were pre-incubated with endocytosis inhibitors, suggesting also the use of a combination of mechanisms for cell internalisation. In addition, PP-50 colocalisation with endosome and lysosome pathway markers showed that the polymer was able to escape the endolysosomal compartment before maturation. This is a critical characteristic of a biopolymer towards use as drug delivery systems and biomedical applications.

Enhancing Membrane-Disruptive Activity via Hydrophobic Phenylalanine and Lysine Tethered to Poly(aspartic acid)

“…Amphiphilic and pH-responsive polymers with biocompatibility and biodegradability carrying weakly ionizable groups such as anionic groups can respond to pH variation due to the protonation or deprotonation equilibrium in the aqueous solution, − via mimicking the amphiphilic structure and the pH-dependent membrane-disruptive behavior of fusogenic viral peptides. , Amphipathic cell-penetrating peptides can induce membrane penetration through the interactions of hydrophobic and hydrophilic groups with the membrane bilayer. , A series of biodegradable poly­( l -lysine iso -phthalamide) pseudopeptides with hydrophobic backbone and pendant carboxyl groups were reported by Slater et al, showing a pH-sensitivity and weak cell-membrane-disruptive capacity. , Modification of the pseudopeptides by grafting hydrophobic monomers was conducted to improve the cell-membrane-disruptive activity with almost trivial hemolysis at the physiological pH 7.4 value. ,− Furthermore, the lysine-based hyperbranched polymers demonstrated pH-induced considerable membrane destabilization . It was considered that the amphiphilic and pH-responsive polymers with membrane-disruptive activity exhibited efficient cytoplasmic drug delivery.…”

A Versatile Polymer‐Based Platform for Intracellular Delivery of Macromolecules

“…We demonstrate that transient mildly acidic extracellular pH during the treatment greatly enhances delivery efficiency and allows for a level of control in potential future experimental design. Fluorescently labeled PP50 applied to human osteosarcoma cells at neutral pH was shown to internalize mostly via clathrin‐ and caveolin‐mediated endocytosis as well as macropinocytosis . Other researchers have reported that endocytosed macromolecules are trafficked from early endosomes to late endosomes and then lysosomes within several hours .…”

In vitroanticancer potentiality and molecular modelling study of novel amino acid derivatives based onN1,N3-bis-(1-hydrazinyl-1-oxopropan-2-yl) isophthalamide

“…Amongst this class of materials, amphiphilic polymers can successfully transport a variety of molecules across mammalian cell membranes, such as cancer therapy candidates and proteins 9 , 10 . The transport of these polymers along different drugs to a particular site within cells has shown a great improvement in the efficacy and accessibility of therapeutics 11 , 12 . The parent polyamide, poly ( l -lysine isophthalamide) ( I ) (Figure 1), was grafted with hydrophobic amino acids onto its pendant carboxylic acid groups to manipulate its amphiphilicity and structure 13 .…”