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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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Physicochemical characterization and in vitro CsA release profile of engineered nanoparticles.Notes: (A) Average zeta size distribution. (B) Scanning electron microscope images (magnification 30,000×, voltage 15 kV). The data are shown as the mean ± SD. (C) Release profile of CsA from CsANP-LTP. The data are shown as mean ± SD. Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; SD, standard deviation.
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f2-ijn-10-903: Physicochemical characterization and in vitro CsA release profile of engineered nanoparticles.Notes: (A) Average zeta size distribution. (B) Scanning electron microscope images (magnification 30,000×, voltage 15 kV). The data are shown as the mean ± SD. (C) Release profile of CsA from CsANP-LTP. The data are shown as mean ± SD. Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; SD, standard deviation.

Mentions: The physicochemical properties of the non-PEGylated, PEGylated nontargeted (CsANP), and PEGylated liver-targeted CsA-encapsulated PLGA nanoparticles (CsANP-LTP) were analyzed using DLS and SEM. The size distribution of all the prepared nanoparticles was homogenous and appropriate for both in vitro and in vivo studies. Generally, the clinically applicable size of nanomedicines is less than 250 nm, as this size tends to have a similar range of properties based on physiological and anatomical consequences.33 Our non-PEGylated nanoparticles, CsANP, AND CsANP-LTP particles had an average size of 188 nm with a polydispersity index (PDI) value of 0.088, 212 nm with a PDI value of 0.125, and 229 nm with a PDI value of 0.912, respectively (Figure 2A). These results were further supported by SEM images, which showed evenly-dispersed morphology (Figure 2B). In order to evaluate the surface properties of the nanoparticles, we again utilized DLS analysis to measure the ζ potential. The ζ potential values were found to vary depending upon the surface modification of nanoparticles. The non-PEGylated nanoparticles possessed the highest negative charge, at −32.5 mV, followed by the CsANP (−17.4 mV) and CsANP-LTP (−8.2 mV) (Table 1). The reduction in the negative charge on CsANP or CsANP-LTP indirectly indicates the decreased number of carboxyl groups and addition of amine groups on the surface of the nanoparticles which contribute toward the net surface charge. Targeted nanoparticles with LTP possessed increased ζ potential values on average, owing to the additional positive charge amino acids in the peptide.


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)

Physicochemical characterization and in vitro CsA release profile of engineered nanoparticles.Notes: (A) Average zeta size distribution. (B) Scanning electron microscope images (magnification 30,000×, voltage 15 kV). The data are shown as the mean ± SD. (C) Release profile of CsA from CsANP-LTP. The data are shown as mean ± SD. Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; SD, standard deviation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4321639&req=5

f2-ijn-10-903: Physicochemical characterization and in vitro CsA release profile of engineered nanoparticles.Notes: (A) Average zeta size distribution. (B) Scanning electron microscope images (magnification 30,000×, voltage 15 kV). The data are shown as the mean ± SD. (C) Release profile of CsA from CsANP-LTP. The data are shown as mean ± SD. Abbreviations: CsA, cyclosporine A; CsANP, cyclosporine A nanoparticles; CsANP-LTP, CsANP conjugated with liver-targeting peptide; SD, standard deviation.
Mentions: The physicochemical properties of the non-PEGylated, PEGylated nontargeted (CsANP), and PEGylated liver-targeted CsA-encapsulated PLGA nanoparticles (CsANP-LTP) were analyzed using DLS and SEM. The size distribution of all the prepared nanoparticles was homogenous and appropriate for both in vitro and in vivo studies. Generally, the clinically applicable size of nanomedicines is less than 250 nm, as this size tends to have a similar range of properties based on physiological and anatomical consequences.33 Our non-PEGylated nanoparticles, CsANP, AND CsANP-LTP particles had an average size of 188 nm with a polydispersity index (PDI) value of 0.088, 212 nm with a PDI value of 0.125, and 229 nm with a PDI value of 0.912, respectively (Figure 2A). These results were further supported by SEM images, which showed evenly-dispersed morphology (Figure 2B). In order to evaluate the surface properties of the nanoparticles, we again utilized DLS analysis to measure the ζ potential. The ζ potential values were found to vary depending upon the surface modification of nanoparticles. The non-PEGylated nanoparticles possessed the highest negative charge, at −32.5 mV, followed by the CsANP (−17.4 mV) and CsANP-LTP (−8.2 mV) (Table 1). The reduction in the negative charge on CsANP or CsANP-LTP indirectly indicates the decreased number of carboxyl groups and addition of amine groups on the surface of the nanoparticles which contribute toward the net surface charge. Targeted nanoparticles with LTP possessed increased ζ potential values on average, owing to the additional positive charge amino acids in the peptide.

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