An Acid-Labile Block Copolymer of PDMAEMA and PEG as Potential Carrier for Intelligent Gene Delivery Systems

Abstract

Intelligent gene delivery systems based on physiologically triggered reversible shielding technology have evinced enormous interest due to their potential in vivo applications. In the present work, an acid-labile block copolymer consisting of poly(ethylene glycol) and poly(2-(dimethylamino)ethyl methacrylate) segments connected through a cyclic ortho ester linkage (PEG- a-PDMAEMA) was synthesized by atom transfer radical polymerization of DMAEMA using a PEG macroinitiator with an acid-cleavable end group. PEG- a-PDMAEMA condensed with plasmid DNA formed polyplex nanoparticles with an acid-triggered reversible PEG shield. The pH-dependent shielding/deshielding effect of PEG chains on the polyplex particles were evaluated by zeta potential and size measurements. At pH 7.4, polyplexes generated from PEG- a-PDMAEMA exhibited smaller particle size, lower surface charge, reduced interaction with erythrocytes, and less cytotoxicity compared to PDMAEMA-derived polyplexes. At pH 5.0, zeta potential of polyplexes formed from PEG- a-PDMAEMA increased, leveled up after 2 h of incubation and gradual aggregation occurred in the presence of bovine serum albumin (BSA). In contrast, the stably shielded polyplexes formed by DNA and an acid-stable block copolymer, PEG- b-PDMAEMA, did not change in size and zeta potential in 6 h. In vitro transfection efficiency of the acid-labile copolymer greatly increased after 6 h incubation at pH 5.0, approaching the same level of PDMAEMA, whereas there was only slight increase in efficiency for the stable copolymer, PEG- b-PDMAEMA.

Synthesis, self-assembly and stimuli responsive properties of cholesterol conjugated polymers

“…6 To overcome these drawbacks non-viral transfection vectors such as cationic polymers have been developed to protect an siRNA and enhance its intracellular delivery. Polycationic nonviral gene carriers benefit from greater flexibility, improved safety, and facile manufacturing, 7,8 as they offer advanced therapeutic efficacy with doses of siRNA that are substantially lower and/or delivered less frequently than otherwise. 9 Synthetic cationic polymers which have been used in gene transfection include poly(ethylenimine) (PEI), 10 poly(amidoamine) (PAMAM) dendrimer, 11 poly(histidine), 12 poly(L-lysine), 12,13 and chitosan.…”

Peptides as Promising Non-Viral Vectors for Gene Therapy

“…PEGylation refers to the surface decoration of carriers with flexible chains of polyethylene glycol (PEG), which is a highly hydrophilic polymer capable of making a surface less susceptible to protein adsorption (Duncan, 2006). Having said that, a major concern is that PEGylation obstructs the positive charges, resulting in carriers which are less efficient in DNA binding and transfection (Lin et al, 2008;Meyer et al, 2008). Moreover, while PEGylated drug formulations are already in clinical use, PEG is non-biodegradable and its chronic use may be a concern (Urakami & Guan, 2008).…”

“…A series of novel enzyme-degradable polycarbonates (PC) with various aliphatic side-chains attached were prepared and shown to effectively transfect cells with virtually no toxicity (Seow & Yang, 2009a). Poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) was also shown to transfect cells with high efficiency (Lin et al, 2008). Indeed, there are so many other classes of polymers being developed that it is impossible to do all justice with this paragraph.…”

pH-labile sheddable block copolymers by RAFT polymerization: Synthesis and potential use as siRNA conjugates

“…In recent years, a number of pH-labile dynamic carriers adopting similar ''dePEGylation'' strategies have been developed, in general by modification of preready polymers, for intracellular delivery of genes and siR-NA [7,8,[29][30][31][32][33][34][35]. More recently, Lin et al reported the in situ synthesis of a block copolymer that employed the pH-dependent dePEGylation strategy, by atom transfer radical polymerization [36]. This block copolymer consisted of poly(ethylene glycol) and poly(2-(dimethylamino)ethyl methacrylate) segments connected through an acid-labile cyclic ortho ester linkage was prepared directly from an ortho ester group-modified PEG-based ATRP initiator synthesized in five-steps.…”