title: 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.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ramishetti
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry; D002130:Calcium Phosphates / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects; D014764:Viral Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002130:Calcium Phosphates; D008055:Lipids; D014764:Viral Proteins; C026145:acyclovir monophosphate; C020243:calcium phosphate; D013937:Thymidine Kinase; D000212:Acyclovir
keywords: 1, 2-dioleoyl-3-trimethylammonium-propane chloride salt; 1,2-distearoryl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000) ammonium salt; A-LCP NPs; ACV; ACVP; ACVP-loaded LCP nanoparticles; Acyclovir; Acyclovir monophosphate; CaP; Calcium phosphate; DOPA; DOTAP; DSPE–PEG; DSPE–PEG–AA; DSPE–PEG–anisamide; Dioleoylphosphatydic acid; EPR; Enhanced permeability and retention effect; GCV; Ganciclovir; HE; HSV-TK; Hematoxylin and Eosin; Herpes simplex virus thymidine kinase; LCP; Lipid/Calcium/Phosphate; NPs; Nanoparticles; PCNA; Proliferating cell nuclear antigen; RES; Reticuloendothelial system; TEM; TUNEL; TdT-mediated dUTP Nick-End Labeling; Transmission electron microscope; Tumor therapy; nanoparticles