Polymer-based carriers

This section highlights advances in the use of polymer-based carriers in drug delivery. It shows how utilisation of polymers in a smart fashion could result in multiple responses at the desired point of action. The criteria and manufacturing requirements of a polymer-based nanocarrier are described in detail. Progress and innovations in drug-delivery technologies are also recounted. 

This review is focused on the design and application of polymer-based carriers for the delivery of nucleic acid drags. After a short discussion of the biological... 

Various polymer-based carriers for nucleic acid delivery include a moiety to disrupt the endosomal membrane in a pH-dependent maimer. Polymers with protonatable amine moieties with a pA"a value of 5-6 can rupture the endosomal membrane, probably as a result of endosome buffering and osmotic swelling [39]. Direct contact of the polymer-based carriers with the endosomal membrane [40] and the pH-sensitive a-helix formation of a specific peptide [41] also induced endosomolysis. The introduction of various moieties for efficient endosomal escape will be discussed in detail. 

Thousands of polymers have been developed for the delivery of nucleic acid drugs. Although some polymer-based carriers have introduced totally different concepts into the design of their backbones, most of the polymer-based carriers rely on a few basic polymers. In this section, we will describe three basic polymers, poly (L-lysine) (PLL), poly(ethylenimine) (PEI), and poly(amidoamine) (PAMAM) dendrimer in order to survey the standard concepts of polymer-based carriers. 

Thiol residues for disulfide crosslinking can be introduced to polymer-based carriers by various methods (Fig. 8). Cysteine residues are often selected [106], and other reagents such as 2-iminothiolane or A -succinimidyl-3-(2-pyridyldithio) propionate (SPDP) are also commercially available for the thiolic functionalization of polymers. Disulfide bonds can be formed through oxidation in aqueous solution, but the crosslinking can be accelerated by other oxidants, DMSO, or oxygen gas [107]. The resulting disulfide crosslinking provides sufficient stability in the delivery of DNA [108] or siRNA [109], and even in lyophilization [110]. 

The introduction of a lipophilic moiety into cationic polymers provides a way to reduce the cationic charge density of the polymeric carriers while maintaining high delivery efficiency. Lipophilic or hydrophobic moieties that are introduced to the polymer-based carriers can directly interact with the plasma membranes of cells to induce the uptake of the carriers into the cytoplasm [98]. The thermosensitive polymer PNIPAAM can be used as a hydrophobic moiety. PNIPAAM acts as a hydrophilic moiety below the LCST point, but turns into a hydrophobic moiety that destabilizes the plasma membrane for efficient internalization at temperatures... 

Most polymer-based carriers for the delivery of nucleic acid drugs must escape the endosomes before complete acidification, which activates lysosomal digestion. After the discovery of the powerful endosomal destabilization activity of PEI [66], many polymer-based carriers have mimicked the structure of PEI for endosomal escape. As explained in Sect. 3.2, the proton-sponge effect of xmprotonated tertiary amines and direct contact of protonated polyamines with the endosomal membrane are two possible mechanisms of endosomal disruption by PEI. Because pH-dependent protonation is critical in both mechanisms, polymers with a high density of protonable amines during the early endosomal acidification firom pH 7.4 to 5.5 are one of the main kinds of polymer-based carriers with an endosomal escape function. Like tertiary amines in PEI, protonable moieties with low p Ta values have been frequently introduced into the polymer-based carriers. An imidazole moiety with pA"a of around 6.0 was one such candidate. The introduction of polyhistidine with an imidazole moiety on a PLL backbone showed significant increase in endosomal escape efficiency [169]. 

Because cationic amines are also required for the condensation of anionic nucleic acid dmgs, some polymer-based carriers separate the functions of condensation and endosomal dismption in moieties with high and low pK, respectively. For example, the PLL block in the ABC-type block copolymer, PEG-6-poly [(3-morpholinopropyl)aspartamide]-b-poly(L-lysine) (PEG-PMPA-PLL), condenses... 

We have reviewed the evolution of polymer-based carriers for the delivery of nucleic acid drugs starting from the basic polymers of PLL, PEI, and PAMAM. At the beginning, research was focused on the development of efficient and safe carriers for pDNA delivery. Then, the discovery of siRNA, which can selectively control the translation of a specific mRNA, boosted the development of the siRNA delivery carriers. 

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