Effect of size on biological properties of nanoparticles employed in gene delivery

Figures & data

Figure 1. Different types of nanoparticles (A) Nanospheres where drug is either entrapped in the polymer matrix or adsorbed onto surface or both. (B) Nanocapsules where drug is either entrapped inside the hollow capsule or adsorbed onto surface or both.

Figure 2. Schematic representation of the mechanism of gene delivery. It is a multi-step process that involves condensation of DNA (1), the cellular uptake of complexes (2), escape from degradation vesicles (3), intracellular movement or ‘trafficking’ (4), nuclear translocation (5) and finally unpacking followed by translation (6).

Figure 3. Endocytosis categorization based on endocytosis proteins involved in the entry of particles and solutes.

Table I. Effect of nanoparticles size on internalization.

Vector	Proposed study	Outcome	References
Latex particles	Uptake of particles of size 10–1000 nm in non-phagocytic B16 cells	Particles of size < 200 nm internalize via clathrin-dependent endocytosis and above 200 nm through caveolae-mediated internalization.	Rejman et al. (2004)
Carboxyl-modified fluorescent polystyrene nanoparticles	Uptake of nanoparticles of size 24–43 nm in HeLa and HUVEC cells	24 nm-size particles enters cell via caveolae- and clathrin-independent mechanism while 43 nm particles enters via clathrin mediated endcytosis	Lai et al. (2007)
PLGA nano- and microparticcles	Uptake of PLGA particles of size 100 nm–10 μm in Caco-2 cells	100 nm-size nanoparticles showed 2.5-fold and 6-fold higher uptake compared to 1 and 10 μm microparticles, respectively	Gratton et al. (2008)
PLGA nano- and microparticcles	Uptake of PLGA particles of size 100 nm–10 μm in rat in situ intestinal loop model	Uptake efficiency of 100 nm-size nanoparticles was 15–250 fold higher than larger size (1 and 10 μm) microparticles	Gregoriadis (1988)
Polystyrene particles	Uptake of particles of size 93 nm–1 μm in various cells	Particles of size of 93 and 220 nm were internalized in Hepa 1–6, HepG2 cells while particles up to at least 1 μm internalized in ECV 304, HUVEC and HNX 14C cells.	He et al. (2010)
PLGA nanoparticles	Uptake of PLGA particles of size 380 and 520 nm in HAVSMCs cells	Lower internalization of nanoparticles of size 380 nm as compared to that of 520 nm	Huang et al. (2009)
Polystyrene particles	Uptake of particles of size 40 nm–15 μm in dendritic cells	approximately 30% of the cells interacted with 500 nm particles and more than 60% interacted with 100 nm particles.	Foged et al. (2005)
Cross-linked PEG hydrogels	Uptake of particles of nano- and microparticles in Hela cells	The internalization of nanoparticles dependent on size and volume of nanoparticles	Gratton et al. (2008)
Herceptin functionalized AuNPs	Uptake of nanoparticles of size 14–100 nm in SK-BR-3 cells	Maximal uptake of nanoparticles between 25 and 50 nm range	Jiang et al. (2008)
AuNPs	Uptake of particles of size 14, 50, and 74 nm in HeLa cells	Nanoparticles with size of 50 nm resulted in maximal uptake	Chithrani and Chan (2007), Chithrani et al. (2006)

Table II. Effect of nanoparticles size on transfection efficiency.

Vector	Proposed study	Outcome	References
PEI/DNA nanoparticles	Transfection with nanoparticles of size 30–60 nm and 300–600 nm in Neuro2α cells	Large-sized nanoparticles mediated a 100- to 500-fold higher gene expression	Mayer et al. (2005)
Transferrin-PEI800/DNA complexes	Transfection with large and small sized complexes in various cell lines	Larger size (> 500 nm) showed higher transfection efficiency than smaller size (40–100 nm)	Ogris et al. (1998), Ogris et al. (2001)
γ-PGA-chitosan/DNA complexes	Comparison of transfection efficacy of different size nanoparticles in HT1080 cells	204-nm sized nanoparticles showed 4-fold higher transfection than 140 nm ones	Peng et al. (2009)
Transferrin-polylysine/DNA complexes	Transfection studies with small and large sized complexes in K-562 cells	80–100 nm complexes possess higher transfection activity than larger complexes	Wagner et al. (1991)
Ca-Mg phosphate nanoprecipitate	Comparison of transfection efficacy of 2.5 μm particles with 500 nm particles in HeLa cells	40-fold higher transfection with 500 nm particles as compared to 2.5 μm	Chowdhury et al. (2004)
Poly(amidoamine)/DNA complexes	Comparison of transfection efficacy of 200 and 600 nm complexes in A549 cells	Higher transfection efficacy with 200 nm particles	Jones et al. (2000)
Au-PEI nanoparticles	Comparison of transfection efficiency of approximately 6 and 70 nm Au-PEI nanoparticles in Saos-2 cells	Efficient transfection with approximately 6 nm Au-PEI nanoparticles as compared to approximately 70 nm	Cebrian et al. (2011)
PLGA nanoparticles	Comparison of transfection efficiency of approximately 70 and 200 nm nanoparticles in COS-1 cells	27-fold higher transfection with samller nanoparticles	Prabha et al. (2002)
DNA/transferrin-PEI/PEG complexes	Comparison of transfection efficiency of 40 nm complexes with large aggregated in K562 and Neuro2α cells	Efficient transfection efficiency with 40 nm complexes	Ogris et al. (1999)
PEI-Chol/DNA complexes	Comparison of transfection mediated by 110–205 nm and 384 ± 300 nm complexes in Jurkat cells	Small-size complexes showed efficient transfection	Wang et al. (2002)

Table III. Effect of nanoparticles size on cytotoxicity.

Vector	Proposed study	Outcome	References
PLGA nanoparticles	Comparison of cytotoxicity of 60, 100, and 200 nm nanoparticles in RAW264.7 and BEAS-2B cells	Smaller particles (60 and 100 nm) triggered more release of cytokine TNF-α in RAW264.7 cells	Xiong et al. (2013)
Poly (acrylic acid) coated AuNPs	Cytotoxicity studies with 5 and 20 nm nanoparticles	5 nm nanoparticles showed more fibrinogen binding	Deng et al. (2011)
Water soluble AuNPs	Comparison of cytotoxicity of 0.8 and 15 nm AuNPs in a variety of cell types	0.8 nm nanoparticles highly toxic while 15 nm non-toxic up to 60-fold concentration	Pan et al. (2007)
AuNPs	Investigation of mechanism of cytotoxicity	1.4-nm AuNPs caused necrosis while 1.8 nm lead to programmed cell death	Pan et al. (2007)

Table IV. Effect of nanoparticles size on pharmacokinetics and biodistribution.

Vector	Proposed study	Outcome	References
PEGylated nanoparticles	Study of effect of size on pharmacokinetics and biodistribution	The blood residence of the PLGA/PLGA(45)-PEG(5) nanoparticles increased as their PLGA-PEG content was increased.	Stolnik et al. (2001), Mosquiera et al. (2001), Avgoustakis et al. (2003)
PEG-PHDCA nanoparticles	Influence of particle size on the elimination half-lives of rHuTNF-α loaded in PEG-PHDCA nanoparticles	80 nm nanoparticles having the longest circulation time	Fang et al. (2006)
PEG-modified poly-ϵ-caprolactone (PCL) nanoparticles	PCL nanoparticles for systemic delivery of tamoxifen in breast cancer	PEG modification reduced particle size and aggregation, and enhanced the circulation time	Shenoy and Amiji (2005)
Rhodamine B (RhB) labeled carboxymethyl chitosan grafted nanoparticles (RhB-CMCNP) and chitosan hydrochloride grafted nanoparticles (RhB-CHNP)	In vivo biodistribution studies	negative charges and particle size of 150 nm were tended to accumulate in tumor cells more efficiently	He et al. (2010)
Block copolymer micelles (BCMs)	To study size distribution in vivo	BCMs of 25 nm size were rapidly cleared from the plasma compared to 60 nm size	Lee et al. (2010)
AuNPs	In vivo biodistribution studies	AuNPs of size 10 nm were found to localize in various organ	De Jong et al. (2008)
AuNPs coated with thioctic acid terminated PEG	In vivo biodistribution studies	Nude mice bearing subcutaneous A431 squamous tumors showed that the 20nm AuNPs	Zhang et al. (2009)

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