Liposomal Encapsulation of Ganciclovir Enhances the Efficacy of Herpes Simplex Virus Type 1 Thymidine Kinase Suicide Gene Therapy against Hepatic Tumors in Rats

Abstract

Suicide gene therapy based on ganciclovir (GCV) metabolism by transgene herpes simplex thymidine kinase (HSV-1 TK) has been used to selectively kill proliferating cells in clinical settings such as cancer, vascular restenosis, and immunological disorders. We investigated whether encapsulation of ganciclovir (GCV) into liposomes would improve its efficacy, especially against hepatic tumors. Large unilamellar liposomes containing GCV were prepared by reversed-phase evaporation. Pharmacokinetic studies in rats showed that, compared with free GCV, the intravenous injection of liposome-encapsulated GCV (lip-GCV) led to a faster decrease in GCV plasma concentrations, but higher liver-blood ratios. After treatment of syngeneic HSV-1 TK+ liver metastases in rats, histologically active tumors were found in 95% of the transplanted lesions when physiological saline had been given and in 50% when free GCV had been given at 90.2 microM/kg twice daily. This dose is known to be insufficient for the eradication of HSV-1 TK+ tumors. In contrast, only 5% viable tumors were found in rats receiving lip-GCV at this same concentration. Average tumor volumes were 19 +/- 15, 7 +/- 9, and <1 mm3 for the control, free GCV, and lip-GCV groups, respectively. GCV-related toxicity was no longer observed. The results demonstrate that liposomal encapsulation of GCV is feasible and significantly enhances its efficacy against HSV-1 TK+ hepatic tumors.

The efficacy of retroviral herpes simplex virus thymidine kinase gene transfer and ganciclovir treatment on the inhibition of melanoma growth in vitro and in vivo

“…The tumors induced by nontransduced B16BL6tk -cells in vivo and treated with GCV showed slower growth than the same tumors without GCV treatment. Although some studies have shown that at the doses needed to eliminate the tumor, GCV causes leukopenia, immunosuppression and diarrhea (Engelmann et al 1999), and some treatment-related mortality (Caruso et al 1993), in our model GCV treatment did not cause such symptoms in the animals. Even though GCV did not show any side effects, we tested another purine analog, ACV, which is thought to be less toxic.…”

Prodrug activation enzymes in cancer gene therapy

“…Although GCV is a prodrug, the doses required for tumor eradication have proven toxic to normal tissues in some animal studies. Studies using HSV‐TK gene therapy in rodents have found that 150 mg GCV/kg body weight/day was required for complete tumor elimination36; but that five treatments with this dose produced leukopenia and immunosuppression37, diarrhea37, and some treatment‐related mortality36. HSV‐TK expression in rats bearing colorectal liver metastases and in tumor‐free rats caused severe hepatic dysfunction upon GCV administration38.…”

Interfacial Interactions of Hydrophobic Peptides with Lipid Bilayers

“…3. Changes in the thermotropic behavior of DPPC followed by TMA-DPH fluorescence polarization induced by (a) decanoyl-YIGSR NH 2 and (b) cholesteryl succinoyl-YIGSR NH 2 . , DPPC-liposomes; ᭡, DPPC-liposomespeptide.…”

“…Several approaches (liposomes, nanoparticles, implants, etc.) have been assayed to improve stability, overcome solubility, and modify the therapeutic index of well-known drugs (1)(2)(3).…”

“…We previously found (12) that these hydrophobic derivatives of the parent sequence YIGSR 2 behave as amphiphilic compounds and are able to spread on water surfaces forming monomolecular layers and 2 Abbreviations used: Y, tyrosine; I, isoleucine; G, glycine; S, serine; R, arginine; DSC, differential scanning calorimetry; CF, carboxyfluorescein; DPPC, dipalmitoylphosphatidylcholine; NBD-PE, N -(7-nitrobenz-2-oxa-1,3-diazol-4-yl) phosphatidylethanolamine; Rh-PE, L-α-phosphatidylethanolamine-Nlissamine-rhodamine B sulfonyl); TLC, thin-layer chromatography; Nle, norleucine; DMSO, dimethyl sulfoxide; PL phospholipid; DPH, 1, 6-diphenyl-1,3,5-hexatriene; TMA-DPH, trimethylammonium 1,6-diphenyl-1,3,5-hexatriene; ANS, 1-anilinonaphthalene-8-sulfonate; NGPE, N -glutaryl phosphatidylethanolamine; DSPE-PEG, diestearoylphosphatidylethanolamine polyethylene glycol; DSPE-PEG-COOH diestearoylphosphatidylethanoaminepolyethylene glycol-carboxylate; MES, 2-(N -morpholino)ethanesulfonic acid; MLV, multilamelar vesicles; EDC, N -(3-dimethylaminopropyl)-Nethylcarbodiimide; NHSS, N -hydroxysulfosuccinimide.…”