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Liver-targeted cyclosporine A-encapsulated poly (lactic-co-glycolic) acid nanoparticles inhibit hepatitis C virus replication.

Jyothi KR, Beloor J, Jo A, Nguyen MN, Choi TG, Kim JH, Akter S, Lee SK, Maeng CH, Baik HH, Kang I, Ha J, Kim SS - Int J Nanomedicine (2015)

Bottom Line: Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA.Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model.As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.

ABSTRACT
Therapeutic options for hepatitis C virus (HCV) infection have been limited by drug resistance and adverse side effects. Targeting the host factor cyclophilin A (CypA), which is essential for HCV replication, offers a promising strategy for antiviral therapy. However, due to its immunosuppressive activity and severe side effects, clinical application of cyclosporine A (CsA) has been limited as an antiviral agent. To overcome these drawbacks, we have successfully developed a liver-specific, sustained drug delivery system by conjugating the liver-targeting peptide (LTP) to PEGylated CsA-encapsulated poly (lactic-co-glycolic) acid (PLGA) nanoparticles. Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA. Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model. As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.

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Related in: MedlinePlus

Effect of CsA formulations on IL-2 production.Notes: (A) BALB/c mice were treated intravenously with PBS (control), free CsA, CsANP, or CsANP-LTP every other day for a period of 21 days. (B) Splenocytes were isolated and cultured for different time intervals under unstimulated or stimulated conditions. The data are shown as mean ± SD. *P<0.05, **P<0.01, ***P<0.001.Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; SD, standard deviation.
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f5-ijn-10-903: Effect of CsA formulations on IL-2 production.Notes: (A) BALB/c mice were treated intravenously with PBS (control), free CsA, CsANP, or CsANP-LTP every other day for a period of 21 days. (B) Splenocytes were isolated and cultured for different time intervals under unstimulated or stimulated conditions. The data are shown as mean ± SD. *P<0.05, **P<0.01, ***P<0.001.Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; SD, standard deviation.

Mentions: We speculated that a nanoparticle-based drug delivery strategy might be beneficial to overcome the drawbacks of CsA. After treatment with free CsA, CsANP, or CsANP-LTP (CsA 15 mg/kg equivalents, eleven intravenous doses, every other day for 21 days), mice were sacrificed, and isolated splenocytes were further cultured under unstimulated or stimulated conditions (Figure 5A). Interestingly, encapsulation of CsA in both the nontargeted and targeted nanoparticles strongly reduced the immunosuppressive activity (Figure 5B). These results were also supported by both the biodistribution (Figure 4A) and histological analysis (Figure S4A), which showed no deposition of formulated nanoparticles in the spleen. The observed low levels of IL-2 inhibition in CsANP or CsANP-LTP treatments may be due to the slow release of CsA from nanoparticles during its circulation in the blood. We further confirmed the specificity of targeted nanoparticles by testing their ability to be internalized by splenocytes. Alexa-488-labeled CsANP or CsANP-LTP showed no internalization by splenocytes (Figure S4B), thus implying that live-targeted nanoparticles do not exhibit nonspecific delivery to spleen. Taken together, target-specific CsANP might be more advantageous than conventional CsA as an improved nanomedicine for the treatment of HCV.


Liver-targeted cyclosporine A-encapsulated poly (lactic-co-glycolic) acid nanoparticles inhibit hepatitis C virus replication.

Jyothi KR, Beloor J, Jo A, Nguyen MN, Choi TG, Kim JH, Akter S, Lee SK, Maeng CH, Baik HH, Kang I, Ha J, Kim SS - Int J Nanomedicine (2015)

Effect of CsA formulations on IL-2 production.Notes: (A) BALB/c mice were treated intravenously with PBS (control), free CsA, CsANP, or CsANP-LTP every other day for a period of 21 days. (B) Splenocytes were isolated and cultured for different time intervals under unstimulated or stimulated conditions. The data are shown as mean ± SD. *P<0.05, **P<0.01, ***P<0.001.Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321639&req=5

f5-ijn-10-903: Effect of CsA formulations on IL-2 production.Notes: (A) BALB/c mice were treated intravenously with PBS (control), free CsA, CsANP, or CsANP-LTP every other day for a period of 21 days. (B) Splenocytes were isolated and cultured for different time intervals under unstimulated or stimulated conditions. The data are shown as mean ± SD. *P<0.05, **P<0.01, ***P<0.001.Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; SD, standard deviation.
Mentions: We speculated that a nanoparticle-based drug delivery strategy might be beneficial to overcome the drawbacks of CsA. After treatment with free CsA, CsANP, or CsANP-LTP (CsA 15 mg/kg equivalents, eleven intravenous doses, every other day for 21 days), mice were sacrificed, and isolated splenocytes were further cultured under unstimulated or stimulated conditions (Figure 5A). Interestingly, encapsulation of CsA in both the nontargeted and targeted nanoparticles strongly reduced the immunosuppressive activity (Figure 5B). These results were also supported by both the biodistribution (Figure 4A) and histological analysis (Figure S4A), which showed no deposition of formulated nanoparticles in the spleen. The observed low levels of IL-2 inhibition in CsANP or CsANP-LTP treatments may be due to the slow release of CsA from nanoparticles during its circulation in the blood. We further confirmed the specificity of targeted nanoparticles by testing their ability to be internalized by splenocytes. Alexa-488-labeled CsANP or CsANP-LTP showed no internalization by splenocytes (Figure S4B), thus implying that live-targeted nanoparticles do not exhibit nonspecific delivery to spleen. Taken together, target-specific CsANP might be more advantageous than conventional CsA as an improved nanomedicine for the treatment of HCV.

Bottom Line: Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA.Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model.As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.

ABSTRACT
Therapeutic options for hepatitis C virus (HCV) infection have been limited by drug resistance and adverse side effects. Targeting the host factor cyclophilin A (CypA), which is essential for HCV replication, offers a promising strategy for antiviral therapy. However, due to its immunosuppressive activity and severe side effects, clinical application of cyclosporine A (CsA) has been limited as an antiviral agent. To overcome these drawbacks, we have successfully developed a liver-specific, sustained drug delivery system by conjugating the liver-targeting peptide (LTP) to PEGylated CsA-encapsulated poly (lactic-co-glycolic) acid (PLGA) nanoparticles. Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA. Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model. As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.

No MeSH data available.


Related in: MedlinePlus