PLGA NPs. Mahor et al. [52] used branched PEI as a transfecting agent for DNA
encapsulated in HA biomaterials and obtained significantly higher expression
levels than for naked DNA.
PIC Micelles
PIC micelles are self-assembling co-polymers consisting of a core of hydrophobic blocks (e.g. PLL, PEI) stabilized by a corona of hydrophilic polymeric chains
(e.g. PEG). They have a core–shell structure with high water-solubility and
colloidal stability and have polycation properties that are capable of condensing
and compacting the negatively charged DNA. Attachment of disulfite linkages to
the PIC micelles impart bioreducible properties, with reduced cytotoxicity and
increased ability to release the loaded DNA inside the cells. Kakizawa et al. [57]
showed that thiolated PEG–PLL micelles could successfully encapsulate the
oligonucleotides, enter the cells by endocytosis and efficiently release the loaded
oligonucleotides in response to the reducing intracellular environment of the
cells. Oishi et al. [58] used thiolated PEG–PEI to take advantage of the “proton
sponge effect” of the PEI in endosomal release. These PIC micelles showed
higher gene delivery efficiency than those of thiolated PEG–PLL. When
oligonucleotides were conjugated to PEG via disulfide linkages and complexed
with PEI to form polyelectrolyte complex (PEC) micelles, a further enhancement
was observed due to more effective endosomal escape [59]. The potential of
complexes formed with naturally occurring biomaterials, protamine and HA
conjugates via a disulfide linkage has also been reported as a safe and effective
non-viral gene delivery option [60].
Polyamidoamine
PAAs can be synthesized by Michael reaction of amine monomers and acrylamide
monomers. Lin et al. [61] reported a series of novel bioreducible PAAs by Michaeltype polyaddition of various primary amines [4-amino-1-butanol (ABOL), 5-amino1-pentanol (APOL), N,N-dimethyl-1,3-ethylenediamine (DMEA), 2-(2-aminoethoxy)
ethanol (AEEOL), 3-methoxypropylamine (MOPA), 3-morpholinopropylamine
(MPA) or histamine (HIS)] with disulfide bond-containing cystamine bisacrylamide
(CBA). These bioreducible PAAs had higher buffer capacities than PEI in the
endosomal pH range and, therefore, contributed to the greater endosomal escape
of the polyplexes. Of the above, bioreducible PAAs containing amino alcohol
pendant groups (pAPOL, pABOL) exhibited the highest gene delivery efficiency
[62]. In another study, Lin et al. [63] reported the syntheses of bioreducible PAA
consisting of bioreducible CBA and two amino groups with distinctly different
60
P. Pushp et al.
encapsulated in HA biomaterials and obtained significantly higher expression
levels than for naked DNA.
PIC Micelles
PIC micelles are self-assembling co-polymers consisting of a core of hydrophobic blocks (e.g. PLL, PEI) stabilized by a corona of hydrophilic polymeric chains
(e.g. PEG). They have a core–shell structure with high water-solubility and
colloidal stability and have polycation properties that are capable of condensing
and compacting the negatively charged DNA. Attachment of disulfite linkages to
the PIC micelles impart bioreducible properties, with reduced cytotoxicity and
increased ability to release the loaded DNA inside the cells. Kakizawa et al. [57]
showed that thiolated PEG–PLL micelles could successfully encapsulate the
oligonucleotides, enter the cells by endocytosis and efficiently release the loaded
oligonucleotides in response to the reducing intracellular environment of the
cells. Oishi et al. [58] used thiolated PEG–PEI to take advantage of the “proton
sponge effect” of the PEI in endosomal release. These PIC micelles showed
higher gene delivery efficiency than those of thiolated PEG–PLL. When
oligonucleotides were conjugated to PEG via disulfide linkages and complexed
with PEI to form polyelectrolyte complex (PEC) micelles, a further enhancement
was observed due to more effective endosomal escape [59]. The potential of
complexes formed with naturally occurring biomaterials, protamine and HA
conjugates via a disulfide linkage has also been reported as a safe and effective
non-viral gene delivery option [60].
Polyamidoamine
PAAs can be synthesized by Michael reaction of amine monomers and acrylamide
monomers. Lin et al. [61] reported a series of novel bioreducible PAAs by Michaeltype polyaddition of various primary amines [4-amino-1-butanol (ABOL), 5-amino1-pentanol (APOL), N,N-dimethyl-1,3-ethylenediamine (DMEA), 2-(2-aminoethoxy)
ethanol (AEEOL), 3-methoxypropylamine (MOPA), 3-morpholinopropylamine
(MPA) or histamine (HIS)] with disulfide bond-containing cystamine bisacrylamide
(CBA). These bioreducible PAAs had higher buffer capacities than PEI in the
endosomal pH range and, therefore, contributed to the greater endosomal escape
of the polyplexes. Of the above, bioreducible PAAs containing amino alcohol
pendant groups (pAPOL, pABOL) exhibited the highest gene delivery efficiency
[62]. In another study, Lin et al. [63] reported the syntheses of bioreducible PAA
consisting of bioreducible CBA and two amino groups with distinctly different
60
P. Pushp et al.