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Review
. 2011 Apr;2(4):493-521.
doi: 10.4155/tde.11.14.

Advances in polymeric and inorganic vectors for nonviral nucleic acid delivery

Joel C Sunshine  1 , Corey J Bishop, Jordan J Green
Affiliations
Review

Advances in polymeric and inorganic vectors for nonviral nucleic acid delivery

Joel C Sunshine et al. Ther Deliv. 2011 Apr.

Abstract

Nonviral systems for nucleic acid delivery offer a host of potential advantages compared with viruses, including reduced toxicity and immunogenicity, increased ease of production and less stringent vector size limitations, but remain far less efficient than their viral counterparts. In this article we review recent advances in the delivery of nucleic acids using polymeric and inorganic vectors. We discuss the wide range of materials being designed and evaluated for these purposes while considering the physical requirements and barriers to entry that these agents face and reviewing recent novel approaches towards improving delivery with respect to each of these barriers. Furthermore, we provide a brief overview of past and ongoing nonviral gene therapy clinical trials. We conclude with a discussion of multifunctional nucleic acid carriers and future directions.

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Figures

Figure 1
Figure 1. Barriers to intracellular nucleic acid delivery
(1) Nucleic acid must be complexed to the nanocarrier and protected from degradation as it makes its way to the target cell. (2) The nanocarrier and cargo must be internalized successfully. (A) TLR7 is localized to the endosome; for isRNA activity, endosomal escape is not required. For other nucleic acid, (3) endosomal escape is required. (B) (4) For cytoplasmic activity, nucleic acid must be released intracellularly. (5) Nanocarrier degradation is not required, but is useful for reduced toxicity. (C) (6) For DNA, shRNA-encoding plasmids, and agRNA, nuclear import is required for successful effect.
Figure 2
Figure 2
Commonly used cationic polymers and polysaccharides used in gene delivery.
Figure 3
Figure 3. Typical inorganic nanoparticles being investigated for nucleic acid delivery
(A) Transmission electron microscopy (TEM) of gold nanoparticle (AuNP) spheres, adapted from [81]; (B) TEM of AuNP rods, adapted from [82]; (C) AFM topography of AuNP shells coating platinum, adapted from [83]; (D) Multiwalled carbon nanotubes adapted from [276]. (E) Representative TEM of carbon samples produced by catalysis, adapted from [98]; (F) Mesoporous silica nanoparticles, adapted from [134]; (G) Quantum dots - top and bottom row are illuminated under visible and UV, respectively, adapted from [104]; (H) Doxorubicin-loaded superparamagnetic iron oxide nanoparticles with a diameter of 8 ± 2 nm, adapted from [115]; (I) TEM of pristine-layered, double-hydroxide NPs of Mg2Al(OH)6NO3 - inset NPs are associated with siRNA, adapted from [121]. Figures adapted with permission.
Figure 4
Figure 4. β-galactosidase delivered to MG-63 cells with acceptable viability (>90%) and greater transfection efficacy than Transfast™ (1 \g=m\g/ml) using inorganic nanocomposites formed from mineral solutions containing various amounts of CaCl2, KH2PO4, NaCl, KCl, MgSO4, MgCl2 and NaHCO3
Adapted with permission from [144].
Figure 5
Figure 5. Time-lapse video microscopy stills of shape-dependent phagocytosis by macrophage
(A) Shape-switching poly(lactide-co-glycolide)- ester elliptical disk allows macrophage internalization. (B) Poly(lactide-coglycolide)-ester elliptical disk that does not switch shape prevents internalization. Scale bar: 10 μm. Reproduced with permission from [151].
Figure 6
Figure 6. Gene expression of poly(β-amino ester)s compared with adenovirus
(A) Gene expression histogram comparing adenovirus, PBAE and negative control. (B) Comparison of various poly(β-amino ester) formulations with adenovirus with respect to % positive cells and normalized expression. Images of GFP+ cells 24 h post-transfection with (C) PEI, (D) C32–103 and (E) 500 MOI adenovirus. GFP: Green fluorescent protein; MOI: Multiplicity of infection; PEI: Poly(ethylenimine). Reproduced with permission from [170].
Figure 7
Figure 7. Nuclear import through the nuclear pore complex
Adapted with permission from [262].
Figure 8
Figure 8. Transmission electron microscopy images of HeLa cells
(A) PBAE-siRNA-AuNPs; (B) siRNA-AuNPs without PBAE; (C) unmodified AuNPs; (D) no nanoparticles (control). AuNPs: Gold nanoparticles; PBAE: Poly(b-amino ester). Adapted with permission from [93].
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