Antitumor activity of tripterine via cell-penetrating peptide-coated nanostructured lipid carriers in a prostate cancer model.
BACKGROUND
The purpose of this study was to evaluate the antitumor effect of cell-penetrating peptide-coated tripterine-loaded nanostructured lipid carriers (CT-NLC) on prostate tumor cells in vitro and in vivo.


METHODS
CT-NLC were developed to improve the hydrophilicity of tripterine. The antiproliferative effects of CT-NLC, tripterine-loaded nanostructured lipid carriers (T-NLC), and free tripterine in a human prostatic carcinoma cell line (PC-3) and a mouse prostate carcinoma cell line (RM-1) were evaluated using an MTT assay. The advantage of CT-NLC over T-NLC and free tripterine with regard to antitumor activity in vivo was evaluated in a prostate tumor-bearing mouse model. The induced tumor necrosis factor-alpha and interleukin-6 cytokine content was investigated by enzyme-linked immunosorbent assay to determine the effect of CT-NLC, T-NLC, and free tripterine on immune responses. Histologic and TUNEL assays were carried out to investigate the mechanisms of tumor necrosis and apoptosis.


RESULTS
CT-NLC, T-NLC, and free tripterine showed high antiproliferative activity in a dose-dependent manner, with an IC50 of 0.60, 0.81, and 1.02 μg/mL in the PC-3 cell line and 0.41, 0.54, and 0.89 μg/mL in the RM-1 cell line after 36 hours. In vivo, the tumor inhibition rates for cyclophosphamide, high-dose (4 mg/kg) and low-dose (2 mg/kg) tripterine, high-dose (4 mg/kg) and low-dose (2 mg/kg) T-NLC, high-dose (4 mg/kg) and low-dose (2 mg/kg) CT-NLC were 76.51%, 37.07%, 29.53%, 63.56%, 48.25%, 72.68%, and 54.50%, respectively, showing a dose-dependent pattern. The induced tumor necrosis factor-alpha and interleukin-6 cytokine content after treatment with CT-NLC and T-NLC was significantly higher than that of high-dose tripterine. Moreover, CT-NLC showed the expected advantage of inducing necrosis and apoptosis in prostate tumor cells.


CONCLUSIONS
CT-NLC noticeably enhanced antitumor activity in vitro and in vivo and showed dramatically improved cytotoxicity in normal cells in comparison with free tripterine. In summary, CT-NLC could be used as a promising drug delivery system for the treatment of prostate cancer.
Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
Ling
L
Yuan
Congyan
C
Liu
Yan
Y
Chen
Zhenhai
Z
Zhang
Lei
L
Zhou
Ding
D
Qu
D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000097:blood; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000737:chemistry* / Q000633:toxicity; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; C508600:IL6 protein, human; D015850:Interleukin-6; D008055:Lipids; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C050414:celastrol
antitumor activity; cell-penetrating peptide; nanostructured lipid carriers; prostate cancer; tripterine