Nucleic acids, drugs, delivery

A. Angelova, B. Angelov, R. Mutafchieva, S. Leieur, P. Couvreur, Self-assembled multicompartment hquid crystalline lipid carrier for protein, peptide, and nucleic acid drug delivery. Acc. Chem. Res. 44, 147-156 (2011)... 

Fig. 1 Extracellular barriers to nucleic acid drug delivery...

The final stage in nucleic acid drug delivery is penetration through the nuclear envelope. Along with the plasma membrane and the endosomal membrane... 

Mukai, H., Ozaki, D., Cui, Y., Kuboyama, T., Yamato-Nagata, H., Onoe, K., Takahashi, M., Wada, Y, Imanishi, T., Kodama, T., Obika, S., Suzuki, M., Doi, H., Watanabe, Y., 2014. Quantitative evaluation of the improvement in the pharmacokinetics of a nucleic acid drug delivery system by dynamic PET imaging with F-incorporated oligodeoxynucle-otides. J. Control. Release 180, 92-99. 

Nanosized objects perform various functions in the biomedical field. In the human body, nanosized particulate substances behave very differently from larger particles. In 1986, Maeda et al. found that the stained albumin, having a size of several nanometers, naturally accumulates in the region of cancerous tissues, which is now well known as the enhanced permeability and retention (EPR) effect. Many studies in the field of nanoparticles are based on this finding. Another application of nanoparticles is the delivery system using various polyplexes that are composed of carrier molecules and plasmid DNA or nucleic acid drugs such as antisenses and siRNA. In addition, nanofibers are mainly used for biodegradable scaffolds in tissue... 

Berdugo, M., et al. 2003. Delivery of antisense oligonucleotide to the cornea by iontophoresis. Antisense Nucleic Acid Drug Dev 13 107. 

Worldwide on-going work in the field of nucleic acid-based gene therapy targets the question of the delivery, transport, and in-vivo activity of nucleic acid drugs. The results obtained from these studies will be taken into consideration for the in-vivo design of twin ribozymes after the in-vitro assay has proven successful. 

In case of systemic delivery of nucleic acid drugs via the oral route only comparatively small therapeutic agents such as oligonucleotides seem to reach the systemic circulation in significant quantities via the paracellular route of uptake. 

Aynie, I. Vauthier, C. Chacun, H. Fattal, E. Couvreur, P. Spongelike alginate nanopartides as a new potential system for the delivery of antisense oligonucleotides, antisense. Nucleic Acid Drug Dev. 1999, 9, 301-312. 

Since the chemistry used in nucleic acid drug research has reached the current level, the major limiting step is delivery of the therapeutic, and several technological challenges need to be overcome in terms of stability, efficient and controlled delivery as well as addressing safety. So the limited number of currently registered products is by no means indicative of failure of these potentially revolutionary types of drugs. 

Moulton H M, Hase M C, Smith K M, et al. (2003). HIV Tat peptide enhances cellular delivery of antisense morpholino oligomers. Antisense Nucleic Acid Drug Dev. 13 31-43. 

Templin M V, Levin A A, et al. (2000). Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. Anti-sense Nucleic Acid Drug Dev. 10 359-368. 

Manoharan M (2002) Oligonucleotide conjugates as potential antisense drugs with improved uptake, biodistribution, targeted delivery, and mechanism of action. Antisense Nucleic Acid Drug Dev 12 103-128... 

Biological Barriers in the Delivery of Nucleic Acid Drugs... 

Although asDNA and siRNA finish their journey at the cytosol just after endosomal escape, other nucleic acid drugs such as pDNA must be delivered through the cytosol into the nucleus for the transcription of the therapeutic gene. Cytosol is not a simple liquid phase that enables free diffusion of macromolecules, but a gel-like phase with a fine mesh structure primarily composed of actin filaments [42]. The diffusion rate of large molecules over a hydrodynamic diameter of 85 nm is significantly lower than that of small molecules in cytosol due to the molecular exclusion effect [43]. In addition, the cytosolic concentration of free DNA was shown to rapidly decrease, with a half-life of 90 min, by the action of nucleases preventing the invasion of viral DNA or RNA [44]. Hence, protection of pDNA from nuclease attack is needed for delivery to the nucleus without loss of activity. 

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. 

Similar to the case of PEL, complexation with PEI can protect nucleic acid drugs from nuclease attack. The major bottleneck of PEI-based carriers for DNA delivery is probably entry into the nucleoplasm because their endosomal escape is highly efficient [74]. Only a small portion of the pDNA can reach the nucleoplasm, and the efficiency is further decreased when the cell cycle is synchronized to the early G1 phase [47]. Linear PEI has shown less dependence of delivery efficiency on the cell cycle than has branched PEI [51]. 

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