University of California, Davis, Department of Biomedical Engineering, Davis, CA 95616, USA.
University of California, Davis, Department of Biomedical Engineering, Davis, CA 95616, USA; Stanford University, Department of Radiology, 3165 Porter Drive, Palo Alto, CA 94304, USA.
J Control Release. 2019 Sep 10;309:277-288. doi: 10.1016/j.jconrel.2019.07.014. Epub 2019 Jul 10.
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 °C. Liposomal encapsulation resulted in a circulation half-life of ~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.
吉西他滨向胰腺导管腺癌的递药受到药代动力学不佳、致密纤维化和低血管化的限制。可激活的脂质体，通过局部加热导致药物释放，增强了血清稳定性和循环，并使释放的药物保留在肿瘤内扩散的能力。脂质体吉西他滨的一个局限性是载药量低。为了解决这个限制，我们使用了葡萄糖酸铜的优越溶解能力，使吉西他滨与葡萄糖酸铜形成 1:4 的复合物。由 DPPC:DSPC:DSPE-PEG2k（80:15:5，摩尔%）组成的热敏脂质体的载药量达到 12wt%，是以前报道值的 4 倍。低温透射电子显微镜证实存在液态晶相吉西他滨-铜混合物。优化的吉西他滨脂质体在 42°C 下分别在 1 和 5 分钟内释放 60%和 80%的吉西他滨。脂质体包封导致体内循环半衰期约为 2 小时（相比之下，报道的游离吉西他滨在小鼠体内的循环时间为 16 分钟），并且在血浆中未检测到游离药物。所得吉西他滨脂质体在体外对小鼠乳腺癌和胰腺癌均有效。在 neu 缺失的小鼠乳腺癌模型中，三次重复的激活吉西他滨脂质体加超声热疗治疗，在毒性有限的情况下使肿瘤消退或消除，与单独使用吉西他滨相比，提高了存活率。用 5%的游离吉西他滨剂量（5 而不是 100mg/kg），肿瘤生长抑制程度与吉西他滨相同。此外，在更具侵袭性的小鼠胰腺癌肿瘤模型中，脂质体吉西他滨联合局部热疗诱导细胞死亡和凋亡和坏死区域。
