Drug Delivery and Formulation, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada.
J Control Release. 2012 Jul 10;161(1):142-9. doi: 10.1016/j.jconrel.2012.03.023. Epub 2012 Apr 4.
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 °C, and enhanced drug release rates at 41-42 °C, compared to LTSL (lyso-lipid temperature sensitive liposomes, DPPC/MSPC/DSPE-PEG₂₀₀₀=86/10/4, pH gradient drug loading). HaT-II released 100% DOX within 15-40s at 40-42 °C, with only 5% drug leakage at 37 °C after 30 min in serum, while LTSL lost 30% of its drug content at 37 °C and exhibited 2-fold decreased release rate constants at 41-42 °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 (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).
在这里，我们报告了一种由 DPPC 和 Brij78 组成的增强型热敏制剂的开发，该制剂使用 Cu²⁺梯度装载阿霉素（DOX），并在其基础上额外插入了一定量的 Brij78。与 LTSL（溶酶体脂质温度敏感脂质体，DPPC/MSPC/DSPE-PEG₂₀₀₀=86/10/4，pH 梯度药物加载）相比，这种最佳制剂（HaT-II：热激活细胞毒性）在 37°C 的血清中表现出明显更高的稳定性，并且在 41-42°C 时具有更高的药物释放率。HaT-II 在 40-42°C 下 15-40 秒内释放 100%的 DOX，而在 37°C 下 30 分钟后仅 5%的药物泄漏，而 LTSL 在 37°C 下损失了 30%的药物含量，并且在相同条件下在 41-42°C 下释放率常数降低了约 2 倍。在非加热的 HaT-II 处理的健康小鼠中，DOX 的药代动力学得到了显著改善，与 LTSL 相比，曲线下面积增加了 2.5 倍，循环半衰期延长了 2 倍。这使得 HaT-II 向加热肿瘤的药物输送提高了 2 倍（~20%注射剂量/g 组织），与 LTSL 相比，显著提高了抗肿瘤疗效，单次 HaT-II 治疗后完全抑制了肿瘤生长。最后，HaT-II 在小鼠中表现出较小的毒性，未引起体重减轻，血液化学也没有异常（10 mg DOX/kg）。
