Biomedical Engineering Reference
In-Depth Information
4.7.2 Cyclodextrin
CDs are cyclic oligomers consisting of several glucose units ( Fig. 4.19 ). They are
classified depending on the number of glucose units. , , and  CD contain 6, 7, and
8 glucose units, respectively, arranged in a cyclic oligomer structure. CDs are cup-
shaped amphiphilic molecules having hydrophobic cavity and a hydrophilic exte-
rior. CDs are water soluble due to their hydrophilicity. They have the capability to
accommodate hydrophobic molecules by inclusion in their core. The complexes thus
formed are known as inclusion complexes. By virtue of this unique property, CD and
CD derivatives are widely used as solubilizing agents for lipophilic small molecule
drugs. Another promising feature of CDs is that they are safe and pharmacologically
inert. Also, the safety of CDs in humans is well established.
Linear cationic -CD-based polymers (-CD) were used as gene transfer vectors
[364,365] . Linear -CD-based cationic polymers were synthesized by condensation of
diamino -CD monomer (comonomer A) and diimidate comonomer (comonomer B).
Among different polymers synthesized with different numbers (4-10) of methylene
units in monomer B, the polymer with six methylene units demonstrated optimum
transfection efficiency.
The transfection efficiency of the -CD polymers was similar to that of PEI and
lipofectamine. -CD polymers could form compact complexes with DNA. -CD
polymers displayed no mortality in mice after single IV and IP doses as high as
200 mg/kg. It was observed that inclusion of CD moiety in polymer reduces its IC50
by up to three orders of magnitude [365] . It was also revealed that the length of the
alkyl chain ( n ) between CD monomer units influences cytotoxicity of the complex.
Cytotoxicity generally decreases with increase in chain length, perhaps because of a
decrease in charge density.
Nanoparticles of CDs are prepared by the addition of CD polymer solution to
nucleic acid solution at polymer-DNA charge ratios greater than 1. Under favor-
able conditions, the components self-assemble and condense to form uniform and
spherical particles with diameters of 25-150 nm. Nanoparticles containing ODNs are
usually smaller (25-60 nm) than plasmid-loaded particles (60-150 nm). In addition,
particle size can be controlled by changing DNA and polymer concentrations during
formulation [366] .
Linear and branched PEIs grafted with varying percentage of -CD were synthe-
sized and evaluated for transfection efficiency [367] . It was observed that transfec-
tion efficiency was reduced with an increase in CD grafting percentage. The reason
was assumed to be that amine substitution with CD alters the p K a of PEI to hinder its
buffering action in endosomal compartment. However, cytotoxicity of the polymer
was greatly reduced with an increasing percentage of CD.
Due to its cationic nature, in vivo use of CD exhibited formation of aggregates
at high ionic strengths. Although PEGylation can usually reduce the formation of
aggregates, it also reduces the cationic charge density of the polymer. Owing to the
ability of aggregates to form inclusion complex [368] , attempts have been made to
reduce aggregation behavior without affecting cationic charge density by complex-
ation of adamantine-terminated PEG chains with -CD [369] .
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