University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA.
J Control Release. 2013 Nov 28;172(1):266-273. doi: 10.1016/j.jconrel.2013.08.019. Epub 2013 Aug 28.
The development of treatment protocols that result in a complete response to chemotherapy has been hampered by free drug toxicity and the low bioavailability of nano-formulated drugs. Here, we explore the application of temperature-sensitive liposomes that have been formulated to enhance stability in circulation. We formed a pH-sensitive complex between doxorubicin (Dox) and copper (CuDox) in the core of lysolipid-containing temperature-sensitive liposomes (LTSLs). The complex remains associated at neutral pH but dissociates to free Dox in lower pH environments. The resulting CuDox-LTSLs were injected intravenously into a syngeneic murine breast cancer model (6 mg Dox/kg body weight) and intravascular release of the drug was triggered by ultrasound. The entire tumor was insonified for 5 min prior to drug administration and 20 min post drug injection. A single-dose administration of CuDox-LTSLs combined with insonation suppressed tumor growth. Moreover, after twice per week treatment over a period of 28 days, a complete response was achieved in which the NDL tumor cells and the tumor interstitium could no longer be detected. All mice treated with ultrasound combined with CuDox-LTSLs survived, and tumor was undetectable 8 months post treatment. Iron and copper-laden macrophages were observed at early time points following treatment with this temperature sensitive formulation. Systemic toxicity indicators, such as cardiac hypertrophy, leukopenia, and weight and hair loss were not detected with CuDox-LTSLs after the 28-day therapy.
由于游离药物毒性和纳米制剂药物的生物利用度低，导致完全响应化疗的治疗方案的发展受到了阻碍。在这里，我们探索了应用经过配方设计以增强在循环中稳定性的温敏脂质体。我们在含有溶酶体的温敏脂质体（LTSL）的核心中形成了阿霉素（Dox）和铜（CuDox）的 pH 敏感复合物。该复合物在中性 pH 下保持结合，但在较低 pH 环境下解离为游离的 Dox。所得的 CuDox-LTSLs 被静脉内注射到同种异体小鼠乳腺癌模型（6mg Dox/kg 体重）中，并通过超声触发血管内药物释放。在给药前和给药后 20 分钟，对整个肿瘤进行 5 分钟的超声照射。单次给予 CuDox-LTSLs 联合超声照射抑制了肿瘤生长。此外，在 28 天内每周两次治疗后，实现了完全缓解，即无法再检测到 NDL 肿瘤细胞和肿瘤间质。接受超声联合 CuDox-LTSLs 治疗的所有小鼠均存活，并且在治疗后 8 个月肿瘤无法检测到。在用这种温敏制剂治疗后早期观察到载铁和载铜的巨噬细胞。在 28 天的治疗后，未检测到 CuDox-LTSLs 引起的心脏肥大、白细胞减少、体重减轻和脱发等系统性毒性指标。
