Low density lipoprotein receptor targeted doxorubicin/DNA-Gold Nanorods as a chemo- and thermo-dual therapy for prostate cancer

Nan Zhang, Shasha Li, Haiying Hua, Dan Liu, Lili Song, Pengchao Sun, Weiwei Huang, Yafang Tang, Yongxing Zhao
International Journal of Pharmaceutics 2016 November 20, 513 (1-2): 376-386
As drug vehicles and therapeutics, Gold Nanorods (GNRs) have various merits such as easy preparation and modification, passive accumulation to tumor tissues, effective intracellular delivery of therapeutics, and thermal responses to laser radiation. Doxorubicin (DOX) has been the standard chemotherapy for cancer. To enhance the anti-cancer efficacy, chemotherapy and thermotherapy were combined in the present study. To load sufficient DOX, DOX was first intercalated into DNA double strands and then absorbed to GNRs. PEG (polyethylene glycol) was used to modify DOX/DNA-GNRs to prolong circulation in vivo and to enhance its stability. Low density lipoprotein receptor (LDLR) targeted peptide-RLT (R) was also bound to DOX/DNA-GNRs to increase their specificity to LDLR over-expressed cancer cells. DNA-GNRs-PEG/R was successfully prepared with high in vitro stability in this study and DOX was loaded sufficiently to obtain DOX/DNA-GNRs-PEG/R. DOX/DNA-GNRs-PEG/R with near infrared (NIR) laser treatment showed higher inhibition to MCF-7 cells and PC-3 cells and both DOX/DNA-GNRs-PEG/R with/without NIR laser treatment were more potent than free DOX. Cell uptake experiment indicated that DOX loaded in DNA-GNRs-PEG/R was taken by PC-3 cells much faster than free DOX. With DOX/DNA-GNRs-PEG/R, the apoptosis rate and necrosis rate of PC-3 cells increased 1.7 and 6.4 folds respectively compared to free DOX. Additional NIR laser treatment caused significantly increases in PC-3 cell necrosis. DOX/DNA-GNRs-PEG/R+laser also enhanced the inhibition of S phase of PC-3 cells by DOX. ROS (reactive oxygen species) assay showed that DOX/DNA-GNRs-PEG/R produced much more ROS than free DOX. With additional laser treatment, further increase in ROS was detected. Prostate cancer model was achieved by injecting PC-3 cells into nude mice and the results showed that more DNA-GNRs-PEG/R was observed in tumor cells and higher tumor inhibition rate was achieved in vivo with R modification. Conclusively, all results consistently indicated that DNA-GNRs-PEG/R was able to increase in vitro and in vivo anti-cancer efficacy of DOX. With additional NIR laser treatment, GNRs produced heat and further enhanced the anti-cancer effect achieved by DOX/DNA-GNRs-PEG/R. Therefore, the chemo- and thermo-dual therapy could be a potential combined therapy for more efficient anti-cancer treatment in clinical applications.

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