1.3.1 Factors Influencing the Complexation of DNA by Cationic
Polymers
The complexation of DNA and polycations is a function of the intrinsic properties
of the two components. For instance, from the use of synthetic polycations for
complexing DNA also arises the problem of polydispersity of polymers (a polymer
sample is usually composed of macromolecular species of differing molar masses)
compared with DNA, which is monodisperse. Because the polydispersity of
the polycation could be an issue in studies of IPECs, sugar-based polymers
(usually polydisperse except if fractionated), conjugated polymers (polydispersity,
M w /M n > 2), branched PEI derivatives, and hyperbranched polymers are out of the
scope of this review, as already mentioned. Only polymers synthesized via controlled or living polymerization methods will be discussed [55–57].
Although the interaction between multivalent polymeric cations with DNA is
electrostatic in origin, the flexibility of the polymer backbones (rigid versus flexible) and molecular architectures also show great impact on the properties of the
final polyplexes [58]. The molecular weight and topology of both the polymer
(which can possess various architectures such as linear, brush, star, etc.) and the
DNA (linear, circular, and supercoiled) has to be taken into account. On the
polymer side, the composition (block, statistical, random, etc.) and its strength as
a polyelectrolyte also play a role, as its charge density is varied.
As already mentioned, the main driving force of complex formation is the gain
in entropy caused by the release of low molecular weight counterions, but other
interactions such as hydrogen bonding and hydrophobic interactions can also contribute
to the complexation process. Thus, the hydrophilicity/hydrophobicity of the polymer
(influencing both the solubility of the polymer in aqueous media and its complexation
with DNA via hydrophobic interactions) as well as its H-bonding capacity have to be
taken into consideration. Moreover, the importance of counterions or substituents
(inducing screening of charges) is often neglected in the formation of polyplexes.
Extrinsic factors (environment) such as the medium conditions also play a large
part in the complexation process, especially pH and ionic strength (salt and polyelectrolyte concentrations). Also of prime importance is the way that the complexation
itself is conducted, i.e., mixing parameters such as the stoichiometry of the
components, the addition rate, and order of addition of the components (kinetic
versus thermodynamic). Even if this process is fast and kinetically controlled (in
water without added salt), i.e., far from the thermodynamic equilibrium, it can be
followed by a slower stage in which the chains redistribute to a IPEC conformation
closer to equilibrium [59].
1.3.2 Condensation of DNA by Cationic Polymers
DNA can be more simply considered as a particular case of a stiff anionic linear
polyelectrolyte. Monovalent cations will condense on DNA (condensation) but do
Polyelectrolyte Complexes of DNA and Polycations as Gene Delivery Vectors
113
Polymers
The complexation of DNA and polycations is a function of the intrinsic properties
of the two components. For instance, from the use of synthetic polycations for
complexing DNA also arises the problem of polydispersity of polymers (a polymer
sample is usually composed of macromolecular species of differing molar masses)
compared with DNA, which is monodisperse. Because the polydispersity of
the polycation could be an issue in studies of IPECs, sugar-based polymers
(usually polydisperse except if fractionated), conjugated polymers (polydispersity,
M w /M n > 2), branched PEI derivatives, and hyperbranched polymers are out of the
scope of this review, as already mentioned. Only polymers synthesized via controlled or living polymerization methods will be discussed [55–57].
Although the interaction between multivalent polymeric cations with DNA is
electrostatic in origin, the flexibility of the polymer backbones (rigid versus flexible) and molecular architectures also show great impact on the properties of the
final polyplexes [58]. The molecular weight and topology of both the polymer
(which can possess various architectures such as linear, brush, star, etc.) and the
DNA (linear, circular, and supercoiled) has to be taken into account. On the
polymer side, the composition (block, statistical, random, etc.) and its strength as
a polyelectrolyte also play a role, as its charge density is varied.
As already mentioned, the main driving force of complex formation is the gain
in entropy caused by the release of low molecular weight counterions, but other
interactions such as hydrogen bonding and hydrophobic interactions can also contribute
to the complexation process. Thus, the hydrophilicity/hydrophobicity of the polymer
(influencing both the solubility of the polymer in aqueous media and its complexation
with DNA via hydrophobic interactions) as well as its H-bonding capacity have to be
taken into consideration. Moreover, the importance of counterions or substituents
(inducing screening of charges) is often neglected in the formation of polyplexes.
Extrinsic factors (environment) such as the medium conditions also play a large
part in the complexation process, especially pH and ionic strength (salt and polyelectrolyte concentrations). Also of prime importance is the way that the complexation
itself is conducted, i.e., mixing parameters such as the stoichiometry of the
components, the addition rate, and order of addition of the components (kinetic
versus thermodynamic). Even if this process is fast and kinetically controlled (in
water without added salt), i.e., far from the thermodynamic equilibrium, it can be
followed by a slower stage in which the chains redistribute to a IPEC conformation
closer to equilibrium [59].
1.3.2 Condensation of DNA by Cationic Polymers
DNA can be more simply considered as a particular case of a stiff anionic linear
polyelectrolyte. Monovalent cations will condense on DNA (condensation) but do
Polyelectrolyte Complexes of DNA and Polycations as Gene Delivery Vectors
113