Gene therapy utilizing
lipid-based delivery systems holds tremendous promise for the treatment of
cancer. However, due to the potential adverse inflammatory and/or immune effects upon systemic administration, treatments thus far have been predominantly limited to intratumoral or regional treatment. Previous studies from our group have demonstrated the antitumor efficacy of systemically administered,
folate-targeted,
lipid-
protamine-
DNA complexes (LPD-
PEG-Folate) against
breast cancer using an immunodeficient xenogenic murine model. In the current study, the antitumor efficacy of LPD-
PEG-Folate in a syngeneic, immune competent, murine model of
breast cancer was examined. In this model, the potential inflammatory or immune responses and their effects on systemic delivery can be addressed. The 410.4 murine breast
adenocarcinoma cell line was initially evaluated in vitro for its interactions with LPD-
PEG-Folate and control LPD-PEG formulations. Utilizing fluorescently labeled formulations and fluorescence-activated cell sorting (FACS) analysis, a 1.6-fold enhancement of binding and internalization of LPD-
PEG-Folate over LPD-PEG formulations was observed, suggestive of specific receptor interaction. Increased binding was manifested as 5-26-fold increases in
luciferase gene expression in 410.4 cell transfection when comparing LPD-
PEG-Folate to LPD-PEG. Moreover, in vivo treatment of 410.4
breast tumors in BALB/c mice with i.v. injected LPD-
PEG-Folate delivering the HSV-1
thymidine kinase (TK) gene, in combination with
gancyclovir treatment, resulted in a significant reduction in mean
tumor volume (260.1 mm3) compared to the LPD-PEG-TK (914.1 mm3), as well as the vehicle (749.7 mm3) and untreated (825.3 mm3) control groups (day 25, P<.019). In addition to a reduced
tumor volume, LPD-
PEG-Folate-TK treatment also increased median survival from 25 days in the nontargeted LPD-PEG-TK groups to 31 days (P=.0011), which correlated with the termination of treatment. Together, these results demonstrate that in the context of a fully functional immune system, LPD-
PEG-Folate-TK treatment possesses significant specific antitumor efficacy and the potential for further preclinical development.