A thermosensitive liposome prepared with a Cu2+ gradient demonstrates improved pharmacokinetics, drug delivery and antitumor efficacy

作者：Tagami Tatsuaki; May Jonathan P; Ernsting Mark J; Li Shyh Dar^*

来源：Journal of Controlled Release, 2012, 161(1): 142-149.

DOI：10.1016/j.jconrel.2012.03.023

• Thermosensitive liposomes
• Triggered drug release
• Tumor-targeted drug delivery
• Mild hyperthermia
• Brij78
• Copper gradient for drug loading

Here we report the development of an enhanced thermosensitive formulation composed of DPPC and Brij78, loaded with doxorubicin (DOX) using a Cu2+ gradient and post-inserted with an additional amount of Brij78. This optimal formulation (HaT-II: Hyperthermia-activated cytoToxic) displayed significantly improved stability in serum at 37 degrees C, and enhanced drug release rates at 41-42 degrees C, compared to LTSL (lyso-lipid temperature sensitive liposomes, DPPC/MSPC/DSPE-PEG(2000)=86/10/4, pH gradient drug loading). HaT-II released 100% DOX within 15-40 s at 40-42 degrees C, with only 5% drug leakage at 37 degrees C after 30 min in serum, while LTSL lost 30% of its drug content at 37 degrees C and exhibited similar to 2-fold decreased release rate constants at 41-42 degrees C under the same conditions. The pharmacokinetics of DOX was significantly improved in non-heated HaT-II treated healthy mice with 2.5-fold increased area under the curve and 2-fold prolonged circulation half life compared to LTSL. This led to 2-fold improved drug delivery to the heated tumor by HaT-II (similar to 20% injected dose/g tissue), relative to LTSL and significantly enhanced antitumor efficacy with complete inhibition of tumor growth after a single dose of HaT-II. Finally, HaT-II exhibited little toxicity in mice, inducing no body weight loss and no abnormality in the blood chemistry (10 mg DOX/kg).

• 出版日期2012-7-10