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Turning an antiviral into an anticancer drug: nanoparticle delivery of acyclovir monophosphate
Jing Yao1, Yuan Zhang, Srinivas Ramishetti
1Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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.
Insights
Acyclovir monophosphate (ACVP) shows anti-tumor potential by killing cancer cells independently of viral thymidine kinase. Lipid/Calcium/Phosphate nanoparticles effectively deliver ACVP, demonstrating significant tumor reduction in vivo.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cancer Therapeutics
Background:
- Acyclovir (ACV), an anti-herpes simplex virus (HSV) drug, requires viral thymidine kinase (TK) for activation.
- Activated acyclovir inhibits DNA synthesis, leading to infected cell death.
- This study explores acyclovir monophosphate (ACVP) as a potential anti-cancer agent, independent of HSV-TK.
Purpose of the Study:
- To investigate the potential of acyclovir monophosphate (ACVP) as a cytotoxic agent against cancer cells.
- To develop a targeted delivery system for ACVP using Lipid/Calcium/Phosphate (LCP) nanoparticles.
- To evaluate the in vitro and in vivo anti-tumor efficacy of ACVP-loaded LCP nanoparticles (A-LCP NPs).
Main Methods:
- Encapsulation of ACVP into LCP nanoparticles with a membrane/core structure.
- Characterization of LCP nanoparticles for entrapment efficiency, particle size, and zeta potential.
- Assessment of A-LCP NPs' cytotoxicity, S-phase arrest, apoptosis induction, and tumor volume reduction in vivo.
Main Results:
- LCP nanoparticles exhibited ~70% entrapment efficiency, nano-scale size, and positive zeta potential.
- A-LCP NPs demonstrated concentration-dependent cytotoxicity and induced S-phase arrest in H460 cells.
- Significant tumor volume reduction was observed with A-LCP NPs administration, indicating excellent in vivo efficacy.
Conclusions:
- ACVP can be repurposed as an anti-tumor drug, bypassing the need for viral thymidine kinase.
- LCP nanoparticles facilitate effective targeted delivery of ACVP to tumor cells.
- ACVP-loaded LCP nanoparticles show promising therapeutic potential for cancer treatment by inducing apoptosis and inhibiting proliferation.
