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. 2015 Jan 7:10:371-85.
doi: 10.2147/IJN.S73017. eCollection 2015.

Cationic additives in nanosystems activate cytotoxicity and inflammatory response of human neutrophils: lipid nanoparticles versus polymeric nanoparticles

Tsong-Long Hwang  1 , Ibrahim A Aljuffali  2 , Chwan-Fwu Lin  3 , Yuan-Ting Chang  4 , Jia-You Fang  5
Affiliations

Cationic additives in nanosystems activate cytotoxicity and inflammatory response of human neutrophils: lipid nanoparticles versus polymeric nanoparticles

Tsong-Long Hwang et al. Int J Nanomedicine. .

Abstract

This report compares the effect of lipid and polymeric nanoparticles upon human neutrophils in the presence of cationic surfactants. Nanostructured lipid carriers and poly(lactic-co-glycolic) acid nanoparticles were manufactured as lipid and polymeric systems, respectively. Some cytotoxic and proinflammatory mediators such as lactate dehydrogenase (LDH), elastase, O2(•-), and intracellular Ca(2+) were examined. The nanoparticles showed a size of 170-225 nm. Incorporation of cetyltrimethylammonium bromide or soyaethyl morpholinium ethosulfate, the cationic surfactant, converted zeta potential from a negative to a positive charge. Nanoparticles without cationic surfactants revealed a negligible change on immune and inflammatory responses. Cationic surfactants in both nanoparticulate and free forms induced cell death and the release of mediators. Lipid nanoparticles generally demonstrated a greater response compared to polymeric nanoparticles. The neutrophil morphology observed by electron microscopy confirmed this trend. Cetyltrimethylammonium bromide as the coating material showed more significant activation of neutrophils than soyaethyl morpholinium ethosulfate. Confocal microscope imaging displayed a limited internalization of nanoparticles into neutrophils. It is proposed that cationic nanoparticles interact with the cell membrane, triggering membrane disruption and the following Ca(2+) influx. The elevation of intracellular Ca(2+) induces degranulation and oxidative stress. The consequence of these effects is cytotoxicity and cell death. Caution should be taken when selecting feasible nanoparticulate formulations and cationic additives for consideration of applicability and toxicity.

Keywords: cationic surfactant; inflammation; nanoparticle; neutrophil.

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Figures

Figure 1
Figure 1
Effects of nanosystems and cationic surfactants at different concentrations on human neutrophil survival rate. Notes: (A) Blank nanosystems; (B) CTAB-loaded nanosystems; (C) SME-loaded nanosystems; (D) free cationic surfactants. All data are expressed as the mean ± SEM (n=4). *P<0.05; ***P<0.001 compared to the control. Abbreviations: CTAB, cetyltrimethylammonium bromide; N-b, blank NLCs; N-c, CTAB-coated NLCs; NLCs, nanostructured lipid carriers; N-s, SME-coated NLCs; P-b, blank PLGA nanoparticles; P-c, CTAB-coated PLGA nanoparticles; PLGA, poly(lactic-co-glycolic) acid; P-s, SME-coated PLGA nanoparticles; SEM, standard error of the mean; SME, soyaethyl morpholinium ethosulfate.
Figure 2
Figure 2
Effects of nanosystems and free cationic surfactants at different concentrations on LDH release from human neutrophils. Notes: (A) Blank nanosystems; (B) CTAB-loaded nanosystems; (C) SME-loaded nanosystems; (D) free cationic surfactants. All data are expressed as the mean ± SEM. (n=4). **P<0.01; ***P<0.001 compared to the control. Abbreviations: CTAB, cetyltrimethylammonium bromide; LDH, lactate dehydrogenase; N-b, blank NLCs; N-c, CTAB-coated NLCs; NLCs, nanostructured lipid carriers; N-s, SME-coated NLCs; P-b, blank PLGA nanoparticles; P-c, CTAB-coated PLGA nanoparticles; PLGA, poly(lactic-co-glycolic) acid; P-s, SME-coated PLGA nanoparticles; SEM, standard error of the mean; SME, soyaethyl morpholinium ethosulfate.
Figure 3
Figure 3
Effects of nanoparticles and cationic surfactants on elastase release from human neutrophils. Notes: (A) Lipid nanoparticles; (B) polymeric nanoparticles; (C) cationic surfactants. All data are expressed as the mean ± SEM (n=4). *P<0.05; ***P<0.001 compared to the control. Abbreviations: CTAB, cetyltrimethylammonium bromide; N-b, blank NLCs; N-c, CTAB-coated NLCs; NLCs, nanostructured lipid carriers; N-s, SME-coated NLCs; P-b, blank PLGA nanoparticles; P-c, CTAB-coated PLGA nanoparticles; PLGA, poly(lactic-co-glycolic) acid; P-s, SME-coated PLGA nanoparticles; SEM, standard error of the mean; SME, soyaethyl morpholinium ethosulfate.
Figure 4
Figure 4
Effects of nanoparticles and cationic surfactants on O2•− production of human neutrophils. Notes: (A) Lipid nanoparticles; (B) polymeric nanoparticles; (C) cationic surfactants. All data are expressed as the mean ± SEM (n=4). *P<0.05; **P<0.01; compared to the control. Abbreviations: CTAB, cetyltrimethylammonium bromide; HE, hydroethidine; N-b, blank NLCs; N-c, CTAB-coated NLCs; NLCs, nanostructured lipid carriers; N-s, SME-coated NLCs; P-b, blank PLGA nanoparticles; P-c, CTAB-coated PLGA nanoparticles; PLGA, poly(lactic-co-glycolic) acid; P-s, SME-coated PLGA nanoparticles; SEM, standard error of the mean; SME, soyaethyl morpholinium ethosulfate.
Figure 5
Figure 5
The effect of nanoparticles and cationic surfactants on Ca2+ mobilization in human neutrophils. Notes: Typical traces and intracellular Ca2+ of the effect of (A) lipid nanoparticles, (B) polymeric nanoparticles, and (C) cationic surfactants. Intracellular Ca2+ of human neutrophils treated with nanoparticles and cationic surfactants was determined with or without BAPTA-AM (20 μM). Some formulations were excluded in the BAPTA-AM experiment due to the lack of elevation of these mediators in the absence of BAPTA-AM. *P<0.05; **P<0.01; ***P<0.001 compared to the control. #P<0.05; ##P<0.01; compared to the corresponding control. Abbreviations: BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid; CTAB, cetyltrimethylammonium bromide; N-b, blank NLCs; N-c, CTAB-coated NLCs; NLCs, nanostructured lipid carriers; N-s, SME-coated NLCs; P-b, blank PLGA nanoparticles; P-c, CTAB-coated PLGA nanoparticles; PLGA, poly(lactic-co-glycolic) acid; P-s, SME-coated PLGA nanoparticles; s, seconds; SME, soyaethyl morpholinium ethosulfate.
Figure 6
Figure 6
Effects of treatment of human neutrophils with nanoparticles and cationic surfactants with or without BAPTA-AM (20 μM). Notes: (A) LDH release; (B) elastase release; (C) O2•− production. Some formulations were excluded in the BAPTA-AM experiment due to the lack of elevation of these mediators in the absence of BAPTA-AM. *P<0.05; **P<0.01; ***P<0.001 compared to the control. #P<0.05; compared to the corresponding control. Abbreviations: BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid; CTAB, cetyltrimethylammonium bromide; HE, hydroethidine; LDH, lactate dehydrogenase; N-c, CTAB-coated NLCs; NLCs, nanostructured lipid carriers; N-s, SME-coated NLCs; P-c, CTAB-coated PLGA nanoparticles; PLGA, poly(lactic-co-glycolic) acid; P-s, SME-coated PLGA nanoparticles; SME, soyaethyl morpholinium ethosulfate.
Figure 7
Figure 7
Confocal laser scanning microscopy. Notes: Cell morphology (A) and cellular uptake (B) of human neutrophils treated with free rhodamine 800 and N-c and P-c, and examined by confocal laser scanning microscopy. Abbreviations: CTAB, cetyltrimethylammonium bromide; HBSS, Hank’s balanced salt solution; N-c, CTAB-coated nanostructured lipid carriers; P-c, CTAB-coated poly(lactic-co-glycolic) acid nanoparticles.
Figure 8
Figure 8
The morphology of human neutrophils examined by scanning electron microscopy. Notes: Human neutrophils were examined after treatment with (A) HBSS (control), (B) N-c, and (C) P-c. Abbreviations: CTAB, cetyltrimethylammonium bromide; HBSS, Hank’s balanced salt solution; N-c, CTAB-coated nanostructured lipid carriers; P-c, CTAB-coated poly(lactic-co-glycolic) acid nanoparticles.
Figure 9
Figure 9
Chemical structures of (A) cetyltrimethylammonium bromide and (B) soyaethyl morpholinium ethosulfate.
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