Nucleic acid-polycation complexes

The weakly immunogenic protamine sulfate USP (1) condenses DNA to form a toroid structure of super-coiled DNA about 50 nm in diameter (2). The DNA in this form or in the preformed LPDI complex cannot be displaced from the protamine by polycations such as spermidine and histones or by other nucleic acids like genomic DNA (2). DNA in this toroid structure is transcriptionally inactive and this conformation allows for protection of DNA from enzymatic degradation by nucleases and other environmental assaults such as mechanical stress (1,2). After the liposome surrounds the toroid, the resulting homogenous LPDI nanoparticles are slightly less than... 

Due to the toxicity of the co-(cyclopolymer) 8, the capability of interferon induction of a great number of polymers has been tested. Thus, interferon is formed by the presence of natural double helix RNA, which occurs in some viruses (Reo-viruses), but also by the synthetically produced complex (40) from poly(inosinic acid) and poly(cytidylic acid) (1 1). An improved and extended interferon induction of such poly(nucleic acid)s can be achieved by complexing with synthetic polycations, as for example diethylaminodextrane (41) or with a polycation (42) of composition 9. 

For nonviral systems to be effective vectors, the polymer must not only condense and deliver DNA intact to the target site but must also enable nucleic acid to be transported through the cell membrane, and be translocated from the cytoplasm to the nucleus. Many researchers have now investigated DNA complexed by electrostatic interactions to cationic polymers as a method by which the therapeutic gene can be transported. In most cases these cationic polymers form condensed complexes with DNA that both contract the nucleic acid to facilitate cellular uptake, and which protect it from serum and cytosolic nuclease degradation. Mechanisms of DNA condensation, cellular uptake and transport to the nucleus, as well as strategies to improve toxicity, transfection potential and nuclear targeting of polycation mediated dehvery systems are discussed below. 

Block polymers of PEG-polycation (A-B) or PEG-polycation-PEG (A- B-A) have been used to condense a nucleic acid dmg, to form PEGylated micelles, with the water-insoluble nucleic add-polycation electrostatic complexes (polyplexes) forming the core of the PEGylated polymeric micelle. In the 2000s, a number of companies (e.g., Alnylam, Roche, Merck, and Galando) have been involved in clinical trials for delivery of siRNA from similar lipoplexes and polyplexes. ... 

Kabanov and associates [14,15] have recently investigated the effectiveness of 2 in appropriating natural cellular processes for possible use in medical treatment. They have found that interpolymer complexes of 2 and nucleic acids can be used to enhance incorporation into plasmid DNA of fragments that carry the genetic information for a desired protein [15]. They have also found that interpolymer complexes of 2 and the sodium salt of poly(methacrylic acid) coprecipitate with virus-antibody complexes [16]. The presence of the antibody does not affect coprecipitation of the virus as part of a polycation-polyanion complex. This property has been used to develop a sensitive immunoenzymic method for detection of viruses. 

The complex formation of polycations with RNA, analyzed by the membrane filter technique in association with the assay of viral RNA infectivity, can be used to study the influence of biologically active substances like carcinogens, viral inhibitors, or heavy metal ions on nucleic acid-protein interaction. 

The CD-based polycations have been synthesized for nucleic acid delivery. Upon mixing them with nucleic adds, the polymers and nudeic acids self-assemble by electrostatic interactions to give nanoparticles, i.e. polyplexes. Polyplexes are able to transfect cultured cells with high effidency and relatively low toxidty. Moreover, CDs on the surface of polyplexes can form inclusion complexes with hydrophobic guest molecules. 

Nanoparticles obtained from CD polycations and nucleic acids were specifically immobilized on adamantane-modified surfaces by formation of CD-adamantane inclusion complexes. The nanoparticles are held on the surface by multivalent inclusion complex formation, and therefore are stably inunobilized, but can also by reversibly released for cellular uptake. 

---