Tumor-specific delivery of gemcitabine with activatable liposomes

JOURNAL OF CONTROLLED RELEASE

卷:309

Article

Tucci, Samantha T.¹  Kheirolomoom, Azadeh^1,2  Ingham, Elizabeth S.¹  Mahakian, Lisa M.¹  Tam, Sarah M.¹  Foiret, Josquin²  Hubbard, Neil E.³  Borowsky, Alexander D.³  Baikoghli, Mo⁴  Cheng, R. Holland⁴  Ferrara, Katherine W.² 

[1] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA

[2] Stanford Univ, Dept Radiol, 3165 Porter Dr, Palo Alto, CA 94304 USA

[3] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA

[4] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA

关键词: Gemcitabine;    Temperature-sensitive liposome;    Ultrasound;    Pancreatic ductal adenocarcinoma;    Breast cancer;   

DOI  :  10.1016/j.jconrel.2019.07.014

来源: Elsevier

【 摘 要 】

Gemcitabine delivery to pancreatic ductal adenocarcinoma is limited by poor pharmacokinetics, dense fibrosis and hypo-vascularization. Activatable liposomes, with drug release resulting from local heating, enhance serum stability and circulation, and the released drug retains the ability to diffuse within the tumor. A limitation of liposomal gemcitabine has been the low loading efficiency. To address this limitation, we used the superior solubilizing potential of copper (II) gluconate to form a complex with gemcitabine at copper:gemcitabine (1:4). Thermosensitive liposomes composed of DPPC:DSPC:DSPE-PEG2k (80:15:5, mole%) then reached 12 wt% loading, 4-fold greater than previously reported values. Cryo transmission electron microscopy confirmed the presence of a liquid crystalline gemcitabine-copper mixture. The optimized gemcitabine liposomes released 60% and 80% of the gemcitabine within 1 and 5 min, respectively, at 42 degrees C. Liposomal encapsulation resulted in a circulation half-life of similar to 2 h in vivo (compared to reported circulation of 16 min for free gemcitabine in mice), and free drug was not detected within the plasma. The resulting gemcitabine liposomes were efficacious against both murine breast cancer and pancreatic cancer in vitro. Three repeated treatments of activatable gemcitabine liposomes plus ultrasound hyperthermia regressed or eliminated tumors in the neu deletion model of murine breast cancer with limited toxicity, enhancing survival when compared to treatment with gemcitabine alone. With 5% of the free gemcitabine dose (5 rather than 100 mg/kg), tumor growth was suppressed to the same degree as gemcitabine. Additionally, in a more aggressive tumor model of murine pancreatic cancer, liposomal gemcitabine combined with local hyperthermia induced cell death and regions of apoptosis and necrosis.

【 授权许可】

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