Development of liver-specific ribavirin-loaded nanoparticles with reduced cytotoxicity

Abstract

Ribavirin is widely used in several types of combination chemotherapy for the treatment of chronic hepatitis C. In order to deliver ribavirin to the liver and reduce its side effects, we previously prepared ribavirin monophosphate (RMP)-loaded nanoparticles consisting of a mixture of poly(D,L-lactic acid), arabinogalactan-poly(L-lysine) conjugate, and iron (III) ions. In this study, the nanoparticles were developed in the absence of poly(L-lysine) to avoid cytotoxicity. The nanoparticles were successfully prepared from a mixture of poly(D,L-lactic acid) with terminal amino group(s) and arabinogalactan-poly(L-glutamic acid) conjugate. RMP was stably loaded in the nanoparticles and was gradually released from the nanoparticles under physiological conditions. Furthermore, high accumulation of the nanoparticles in hepatic cells was observed in vitro and in vivo. The nanoparticles also exhibited significantly lower cytotoxicity than that exhibited by those containing poly(L-lysine). Thus, the nanoparticles are expected to be useful in liver-specific ribavirin delivery with low cytotoxicity for the treatment of chronic hepatitis C.

Keywords:

• nanoparticles
• liver targeting
• controlled release
• biodegradable polymers
• drug delivery

Public Interest Statement

Chronic hepatitis mainly results from infection of hepatocytes with the hepatitis virus and is the major risk factor for the development of cirrhosis and hepatocellular carcinoma. Ribavirin exhibits anti-viral activity in hepatocytes infected with the hepatitis C virus and hepatitis E virus. Although ribavirin is essential to many of the beneficial effects of hepatitis treatments, clinical application of ribavirin is restricted because of ribavirin-induced hemolytic anemia. In order to avoid the side effects of ribavirin and improve its therapeutic effects, we have developed biodegradable nanoparticles as ribavirin carriers to accumulate ribavirin in the hepatocytes. The nanoparticles in our previous report showed high accumulation and long retention times of ribavirin in the livers of mice. However, there was concern that the nanoparticles caused tissue or cell injury because the nanoparticles were formed from cytotoxic polymers. In this study, we successfully developed novel liver-specific ribavirin-loaded nanoparticles without these cytotoxic polymers.

Competing interests

The authors declare no competing interest.

Acknowledgements

The authors thank Sayuri Ohuchi and Fumie Hashimoto for their technical assistance with the experiments.

Additional information

Notes on contributors

Kohei Kaneko

The research activities of our group are focused on delivery systems for drugs. We have directed substantial effort toward the development of carriers for low-molecular-mass drugs, peptides and poly(oligo)nucleotides (genes and siRNA), including polymeric solid particles, synthetic polymers, and lipid emulsions, to expand the utility of drugs for various clinical applications. As reported in this manuscript, we take a special interest in solid particles made from biodegradable polymers such as poly(lactic acid). Using our unique techniques of preparation, the particles, which have multiple functions such as stable drug retention, accumulation at the target lesion, sustained release of drugs at the target lesion, and further biological activity in vivo, have been developed. Our team has also clarified that the particles could be used in combination with various drugs such as steroids, prostaglandins, an immunosuppressive drug, anticancer drugs, and poly(oligo)nucleotides.