A new type of polyion complex (PIC) micelle was prepared from lysozyme and the block copolymer, PEG-pAsp(EDA-Cit), that can switch the charge from anionic to cationic at the endosomal pH. The charge-conversion was due to the degradation of the citraconic amide side chain at pH 5.5. This abrupt charge-conversion can make the PIC micelles promptly release the internal protein in response to the endosomal pH. This pH-sensitive charge-conversion polymer is promising for the future design of nanocarriers for early endosomal release.

Special delivery! Polyionic complex (PIC) micelles that contain the charge-conversional moieties citaconic amide or cis-aconitic amide were developed for cytoplasmic protein delivery. The increase of the charge density on the protein cargo helped the stability of the PIC micelles without cross-linking, and the charge-conversion in endosomes induced the dissociation of the PIC micelles to result in efficient endosomal release (see picture).

Polyethylenimine (PEI) shows high transfection efficiency and cytoxicity due to its high amine density. The new disulfide cationic polymer, linear poly(ethylenimine sulfide) (l-PEIS), was synthesized for efficient and safe gene delivery. As the amine density of l-PEIS increased, the transfection efficiency also increased. l-PEIS-6 and l-PEIS-8 show transfection efficiencies that are similar to that of PEI. However, cytotoxicity of l-PEIS was not observed due to the biodegradable disulfide bond. The disulfide bonds are stable in the oxidative extracellular condition and can be degraded rapidly in the reductive intracellular condition. The degradation of l-PEIS in HeLa cells was visualized by fluorescence microscopy using the probe-probe dequenching effect of BODIPY-FL fluorescence dye. l-PEIS was degraded completely within 3 h.

Wrapped for special delivery: A ternary polyplex, with an endosomal disruption moiety based on the charge‐conversion polymer pAsp(DET‐Aco), showed negative charges for serum stability and low cytotoxicity, but the charges became positive and the endosome disruption moiety was exposed (see picture). High transfection efficiency and minimal cytotoxicity were observed with primary cells.

Stand and deliver! Immunoglobulin G (IgG) can be delivered into the cytoplasm of living cells by charge‐conversional modification followed by treatment with a cationic block copolymer to form polyion complex (PIC) micelles (see picture). The bioactivity of the IgG selectively recovers in the cell in a pH‐dependent manner, thereby controlling the growth of human hepatoma cells through IgG binding to intracellular target molecules.

No abstract

The application of polyion complex (PIC) micelles into therapeutic fields is rapidly increasing due to simple and efficient encapsulation of biopharmaceuticals and outstanding biocompatibility among various polymer-based drug delivery carriers. Ionic biopharmaceuticals, such as DNA, RNA, and proteins can interact with ionic block copolymers to form PIC micelles with a core-shell structure. In this review, the development of smart PIC micelles that can respond to biosignals and the application of the biosignal-sensitive PIC micelles to the drug delivery are discussed. The change of ionic strength or pH-dependent protonation-deprotonation can be useful for the selective dissociation of PIC micelles because the ionic interaction between the block copolymer and counter-charged compounds is a main driving force for the formation of PIC micelles. The release of encapsulated biopharmaceuticals of PIC micelles can be effectively controlled by degradation of the chemical bonds in the block copolymer responding to the change of pH or reduction potential. Temperature-dependent hydrophilic-hydrophobic phase transition of block copolymers can also induce the destabilization of PIC micelles. Progress in smart PIC micelle as efficient, specific, and safe drug delivery system is indeed supported by the development of biosignal-sensitive block copolymers.

Applications of siRNA for cancer therapy have been spotlighted in recent years, but the rational design of efficient siRNA delivery carriers is still controversial, especially because of possible toxicity of the carrier components. Previously, a cationic polyaspartamide derivative, poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PAsp(DET)), was reported to exert high transfection efficacy for plasmid DNA with negligible cytotoxicity. However, its direct application for siRNA delivery was fairly limited due to the unstable polymer/siRNA complex formation. In this study, to overcome such instability, stearic acid as a hydrophobic moiety was conjugated to the side chain of PAsp(DET) with various substitution degrees. The stearoyl introduction contributed not only to siRNA complex formation with higher association numbers but also to complex stabilization. The obtained stearoyl PAsp(DET)/siRNA complex significantly accomplished more efficient endogenous gene (BCL-2 and VEGF) knockdown in vitro against the human pancreatic adenocarcinoma (Panc-1) cells than did the unmodified PAsp(DET) complex and commercially available reagents, probably due to the facilitated cellular internalization. This finding suggests that the hydrophobic PAsp(DET)-mediated siRNA delivery is a promising platform for in vivo siRNA delivery.