Turning an antiviral into an anticancer drug: nanoparticle delivery of acyclovir monophosphate.

Abstract

Anti-herpes simplex virus (HSV) drug acyclovir (ACV) is phosphorylated by the viral thymidine kinase (TK), but not the cellular TK. Phosphorylated ACV inhibits cellular DNA synthesis and kills the infected cells. We hypothesize that ACV monophosphate (ACVP), which is an activated metabolite of ACV, should be efficient in killing cells independent of HSV-TK. If so, ACVP should be a cytotoxic agent if properly delivered to the cancer cells. The Lipid/Calcium/Phosphate (LCP) nanoparticles (NPs) with a membrane/core structure were used to encapsulate ACVP to facilitate the targeted delivery of ACVP to the tumor. The LCP NPs showed entrapment efficiency of ~70%, the nano-scaled particle size and positive zeta potential. Moreover, ACVP-loaded LCP NPs (A-LCP NPs) exhibited concentration-dependent cytotoxicity against H460 cells and increased S-phase arrest. More importantly, a significant reduction of the tumor volume over 4 days following administration (p<0.05-0.005) of A-LCP NPs, suggests excellent in vivo efficacy. Whereas, two free drugs (ACV and ACVP) and blank LCP NPs showed little or no therapeutic effect. It was also found that the high efficacy of A-LCP NPs was associated with the ability to induce dramatic apoptosis of the tumor cells, as well as significantly inhibit tumor cell proliferation and cell cycle progression. In conclusion, with the help of LCP NPs, monophosphorylation modification of ACV can successfully modify an HSV-TK-dependent antiviral drug into an anti-tumor drug.

• Authors: Jing Yao, Yuan Zhang, Srinivas Ramishetti, Yuhua Wang, Leaf Huang
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 170 Issue 3 Pg. 414-20 (Sep 28 2013) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 23791977 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published by Elsevier B.V.

Chemical References

• Antineoplastic Agents
• Antiviral Agents
• Calcium Phosphates
• Lipids
• Viral Proteins
• acyclovir monophosphate
• calcium phosphate
• Thymidine Kinase
• Acyclovir

Topics

• Acyclovir (administration & dosage, analogs & derivatives, chemistry)
• Animals
• Antineoplastic Agents (administration & dosage, chemistry)
• Antiviral Agents (administration & dosage, chemistry)
• Calcium Phosphates (chemistry)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Humans
• Lipids (chemistry)
• Mice
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Neoplasms (drug therapy, pathology)
• Simplexvirus (enzymology)
• Thymidine Kinase (genetics)
• Tumor Burden (drug effects)
• Viral Proteins (genetics)
• Xenograft Model Antitumor Assays