Polymeric Nanovectors Incorporated with Ganciclovir and HSV-tk Encoding Plasmid for Gene-Directed Enzyme Prodrug Therapy

Abstract

In the area of gene-directed enzyme prodrug therapy (GDEPT), using herpes simplex virus thymidine kinase (HSV-tk) paired with prodrug ganciclovir (GCV) for cancer treatment has been extensively studied. It is a process involved with two steps whereby the gene (HSV-tk) is first delivered to malignant cells. Afterward, non-toxic GCV is administered to that site and activated to cytotoxic ganciclovir triphosphate by HSV-tk enzyme expressed exogenously. In this study, we presented a one-step approach that both gene and prodrug were delivered at the same time by incorporating them with polymeric micellar nanovectors. GCV was employed as an initiator in the ring-opening polymerization of ε-caprolactone (ε-CL) to synthesize hydrophobic GCV-poly(caprolactone) (GCV–PCL), which was furthered grafted with hydrophilic chitosan to obtain amphiphilic polymer (GCV–PCL–chitosan) for the fabrication of self-assembled micellar nanoparticles. The synthesized amphiphilic polymer was characterized using Fourier transform infrared spectroscopy and proton nuclear magnetic resonance. Micellar prodrug nanoparticles were analyzed by dynamic light scattering, zeta potential, critical micelle concentration, and transmission electron microscopy. Polymeric prodrug micelles with optimal features incorporated with HSV-tk encoding plasmids were cultivated with HT29 colorectal cancer cells and anticancer effectiveness was determined. Our results showed that prodrug GCV and HSV-tk cDNA encoded plasmid incorporated in GCV–PCL–chitosan polymeric nanocarriers could be delivered in a one-step manner to HT-29 cells and triggered high cytotoxicity.

Chimeric antigen receptor T cells for acute myeloid leukemia

“…Simultaneously, uncontrolled CAR T‐cell activation must be prevented as it can lead to CRS, neurological complications and, potentially, tissue damage. This can be achieved with engineering prodrugs in form of nanovectors such as ganciclovir which triggers CAR T‐cell apoptosis via HSV‐tk activation upon administration 51–53 in order to control CAR T‐cell growth in the patient. In leukemia blasts, IDO1, an enzyme that converts tyrosine into kynurenine, has been identified as a marker that negatively correlates with overall survival.…”

HSV: The scout and assault for digestive system tumors

“…Notably, hrR3 contains the herpes simplex virus thymidine kinase (HSV-TK) suicide gene, an HSV-1 product that converts GCV into the toxic metabolite triphosphate-GCV (GCV-TP) and increases cytotoxicity (Yi et al, 2018). As a result, using this approach in the field of gene-directed enzyme pre-drug therapy (GDEPT) for the treatment of colorectal cancer and other digestive system tumors is feasible (Zhou et al, 2016;Luo et al, 2018;Sawdon et al, 2021;Zhou et al, 2022). The HSV-TK gene must first be delivered to the site of the lesion, followed by the administration of GCV as a prodrug to malignant cells to generate the toxic activation response described above, which will rapidly kill tumor cells.…”

“…The HSV-TK gene must first be delivered to the site of the lesion, followed by the administration of GCV as a prodrug to malignant cells to generate the toxic activation response described above, which will rapidly kill tumor cells. This two-step approach was replaced by a one-step approach employing polymeric micellar nanocarriers that bind the gene and the prodrug simultaneously for simple and efficient delivery of the suicide gene and the prodrug, resulting in high toxicity in colorectal cancer HT-29 cells in vitro (Sawdon et al, 2021).…”