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Polyethyleneimine-functionalized boron nitride nanospheres as efficient carriers for enhancing the immunostimulatory effect of CpG oligodeoxynucleotides.

Zhang H, Feng S, Yan T, Zhi C, Gao XD, Hanagata N - Int J Nanomedicine (2015)

Bottom Line: Furthermore, the positively charged surface of the BNNS-PEI complexes greatly improved the loading capacity and cellular uptake efficiency of CpG ODNs.Class B CpG ODNs loaded on the BNNS-PEI complexes enhanced the production of interleukin-6 and tumor necrosis factor-α from peripheral blood mononuclear cells compared with CpG ODNs directly loaded on BNNS.Therefore, BNNS-PEI complexes can be used to enhance the immunostimulatory effect and therapeutic activity of CpG ODNs and the treatment of diseases requiring interleukin-6, tumor necrosis factor-α, and interferon-α.

View Article: PubMed Central - PubMed

Affiliation: The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, People's Republic of China.

ABSTRACT
CpG oligodeoxynucleotides (ODNs) stimulate innate and adaptive immune responses. Thus, these molecules are promising therapeutic agents and vaccine adjuvants against various diseases. In this study, we developed a novel CpG ODNs delivery system based on polyethyleneimine (PEI)-functionalized boron nitride nanospheres (BNNS). PEI was coated on the surface of BNNS via electrostatic interactions. The prepared BNNS-PEI complexes had positive zeta potential and exhibited enhanced dispersity and stability in aqueous solution. In vitro cytotoxicity assays revealed that the BNNS-PEI complexes with concentrations up to 100 μg/mL exhibited no obvious cytotoxicity. Furthermore, the positively charged surface of the BNNS-PEI complexes greatly improved the loading capacity and cellular uptake efficiency of CpG ODNs. Class B CpG ODNs loaded on the BNNS-PEI complexes enhanced the production of interleukin-6 and tumor necrosis factor-α from peripheral blood mononuclear cells compared with CpG ODNs directly loaded on BNNS. Contrary to the free CpG ODNs or CpG ODNs directly loaded on BNNS, class B CpG ODNs loaded on the BNNS-PEI complexes induced interferon-α simultaneously. PEI coating may have changed the physical form of class B CpG ODNs on BNNS, which further affected their interaction with Toll-like receptor 9 and induced interferon-α. Therefore, BNNS-PEI complexes can be used to enhance the immunostimulatory effect and therapeutic activity of CpG ODNs and the treatment of diseases requiring interleukin-6, tumor necrosis factor-α, and interferon-α.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of the process for preparation and application of the PEI-functionalized BNNS as an efficient CpG ODNs carrier.Notes: (A) Preparation of the PEI-functionalized BNNS for CpG ODNs loading. (B) Application of the PEI-functionalized BNNS as a carrier for enhancing the immunostimulatory effects of the CpG ODNs.Abbreviations: BNNS, boron nitride nanospheres; IFN, interferon; IL-6, interleukin-6; IRF, interferon regulatory factor; NFκB, nuclear factor κB; ODN, oligodeoxynucleotide; PEI, polyethyleneimine; TLR-9, Toll-like receptor 9; TNF, tumor necrosis factor.
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f1-ijn-10-5343: Schematic illustration of the process for preparation and application of the PEI-functionalized BNNS as an efficient CpG ODNs carrier.Notes: (A) Preparation of the PEI-functionalized BNNS for CpG ODNs loading. (B) Application of the PEI-functionalized BNNS as a carrier for enhancing the immunostimulatory effects of the CpG ODNs.Abbreviations: BNNS, boron nitride nanospheres; IFN, interferon; IL-6, interleukin-6; IRF, interferon regulatory factor; NFκB, nuclear factor κB; ODN, oligodeoxynucleotide; PEI, polyethyleneimine; TLR-9, Toll-like receptor 9; TNF, tumor necrosis factor.

Mentions: In this study, we developed a novel CpG ODNs delivery system based on polyethyleneimine (PEI)-functionalized BNNS (Figure 1). PEI is the “gold standard” cationic polymer for nucleic acid delivery, either used alone or for surface coating of nanoparticles, to bind negatively charged nucleic acid drugs.31,32 PEI exhibits high transfection efficiency because of enhanced cellular uptake and endosomal escape. Compared with high–molecular weight PEIs, low–molecular weight PEIs are less toxic and more effective as a coating material for nanoparticles to enhance the immunostimulatory effect of CpG ODNs.33 We found that PEI can be coated on negatively charged BNNS through electrostatic interactions, forming BNNS–PEI complexes highly enriched in positive charges that allowed the effective loading of CpG ODNs via a similar process. The formed BNNS–PEI complexes showed no cytotoxicity and significantly enhanced the loading capacity and cellular uptake of CpG ODNs, further inducing a robust cytokine response. Contrary to free CpG ODNs or free CpG ODNs directly loaded on BNNS, class B CpG ODNs loaded on the BNNS–PEI complexes can induce IFN-α. This phenomenon suggests that coating of PEI on BNNS increased the cytokines stimulated by CpG ODNs possibly by altering signal transduction through the interaction of CpG ODNs with TLR-9. Further investigation on the mechanism underlying this phenomenon is currently underway. The current work may provide a promising strategy to enhance the delivery efficiency and immunostimulatory effect of CpG ODNs. Class B CpG ODNs loaded on the BNNS–PEI complexes can simultaneously induce IL-6, TNF-α, and IFN-α. Thus, this study may be beneficial for treating diseases (eg, cancer) requiring the three aforementioned cytokines.


Polyethyleneimine-functionalized boron nitride nanospheres as efficient carriers for enhancing the immunostimulatory effect of CpG oligodeoxynucleotides.

Zhang H, Feng S, Yan T, Zhi C, Gao XD, Hanagata N - Int J Nanomedicine (2015)

Schematic illustration of the process for preparation and application of the PEI-functionalized BNNS as an efficient CpG ODNs carrier.Notes: (A) Preparation of the PEI-functionalized BNNS for CpG ODNs loading. (B) Application of the PEI-functionalized BNNS as a carrier for enhancing the immunostimulatory effects of the CpG ODNs.Abbreviations: BNNS, boron nitride nanospheres; IFN, interferon; IL-6, interleukin-6; IRF, interferon regulatory factor; NFκB, nuclear factor κB; ODN, oligodeoxynucleotide; PEI, polyethyleneimine; TLR-9, Toll-like receptor 9; TNF, tumor necrosis factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554408&req=5

f1-ijn-10-5343: Schematic illustration of the process for preparation and application of the PEI-functionalized BNNS as an efficient CpG ODNs carrier.Notes: (A) Preparation of the PEI-functionalized BNNS for CpG ODNs loading. (B) Application of the PEI-functionalized BNNS as a carrier for enhancing the immunostimulatory effects of the CpG ODNs.Abbreviations: BNNS, boron nitride nanospheres; IFN, interferon; IL-6, interleukin-6; IRF, interferon regulatory factor; NFκB, nuclear factor κB; ODN, oligodeoxynucleotide; PEI, polyethyleneimine; TLR-9, Toll-like receptor 9; TNF, tumor necrosis factor.
Mentions: In this study, we developed a novel CpG ODNs delivery system based on polyethyleneimine (PEI)-functionalized BNNS (Figure 1). PEI is the “gold standard” cationic polymer for nucleic acid delivery, either used alone or for surface coating of nanoparticles, to bind negatively charged nucleic acid drugs.31,32 PEI exhibits high transfection efficiency because of enhanced cellular uptake and endosomal escape. Compared with high–molecular weight PEIs, low–molecular weight PEIs are less toxic and more effective as a coating material for nanoparticles to enhance the immunostimulatory effect of CpG ODNs.33 We found that PEI can be coated on negatively charged BNNS through electrostatic interactions, forming BNNS–PEI complexes highly enriched in positive charges that allowed the effective loading of CpG ODNs via a similar process. The formed BNNS–PEI complexes showed no cytotoxicity and significantly enhanced the loading capacity and cellular uptake of CpG ODNs, further inducing a robust cytokine response. Contrary to free CpG ODNs or free CpG ODNs directly loaded on BNNS, class B CpG ODNs loaded on the BNNS–PEI complexes can induce IFN-α. This phenomenon suggests that coating of PEI on BNNS increased the cytokines stimulated by CpG ODNs possibly by altering signal transduction through the interaction of CpG ODNs with TLR-9. Further investigation on the mechanism underlying this phenomenon is currently underway. The current work may provide a promising strategy to enhance the delivery efficiency and immunostimulatory effect of CpG ODNs. Class B CpG ODNs loaded on the BNNS–PEI complexes can simultaneously induce IL-6, TNF-α, and IFN-α. Thus, this study may be beneficial for treating diseases (eg, cancer) requiring the three aforementioned cytokines.

Bottom Line: Furthermore, the positively charged surface of the BNNS-PEI complexes greatly improved the loading capacity and cellular uptake efficiency of CpG ODNs.Class B CpG ODNs loaded on the BNNS-PEI complexes enhanced the production of interleukin-6 and tumor necrosis factor-α from peripheral blood mononuclear cells compared with CpG ODNs directly loaded on BNNS.Therefore, BNNS-PEI complexes can be used to enhance the immunostimulatory effect and therapeutic activity of CpG ODNs and the treatment of diseases requiring interleukin-6, tumor necrosis factor-α, and interferon-α.

View Article: PubMed Central - PubMed

Affiliation: The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, People's Republic of China.

ABSTRACT
CpG oligodeoxynucleotides (ODNs) stimulate innate and adaptive immune responses. Thus, these molecules are promising therapeutic agents and vaccine adjuvants against various diseases. In this study, we developed a novel CpG ODNs delivery system based on polyethyleneimine (PEI)-functionalized boron nitride nanospheres (BNNS). PEI was coated on the surface of BNNS via electrostatic interactions. The prepared BNNS-PEI complexes had positive zeta potential and exhibited enhanced dispersity and stability in aqueous solution. In vitro cytotoxicity assays revealed that the BNNS-PEI complexes with concentrations up to 100 μg/mL exhibited no obvious cytotoxicity. Furthermore, the positively charged surface of the BNNS-PEI complexes greatly improved the loading capacity and cellular uptake efficiency of CpG ODNs. Class B CpG ODNs loaded on the BNNS-PEI complexes enhanced the production of interleukin-6 and tumor necrosis factor-α from peripheral blood mononuclear cells compared with CpG ODNs directly loaded on BNNS. Contrary to the free CpG ODNs or CpG ODNs directly loaded on BNNS, class B CpG ODNs loaded on the BNNS-PEI complexes induced interferon-α simultaneously. PEI coating may have changed the physical form of class B CpG ODNs on BNNS, which further affected their interaction with Toll-like receptor 9 and induced interferon-α. Therefore, BNNS-PEI complexes can be used to enhance the immunostimulatory effect and therapeutic activity of CpG ODNs and the treatment of diseases requiring interleukin-6, tumor necrosis factor-α, and interferon-α.

No MeSH data available.


Related in: MedlinePlus