Kee Patrick H, Abruzzo Todd A, Smith Denise A B, Kopechek Jonathan A, Wang Boyu, Huang Shaoling L, MacDonald Robert C, Holland Christy K, McPherson David D
Division of Cardiology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
J Liposome Res. 2008;18(4):263-77. doi: 10.1080/08982100802354558.
development of encapsulated therapeutics that could be released upon ultrasound exposure has strong implications for enhancing drug effects at the target site. We have developed echogenic liposomes (ELIP) suitable for ultrasound imaging of blood flow and ultrasound-mediated intravascular drug release. Papaverine was chosen as the test drug because its clinical application requires high concentration in the target vascular bed but low concentration in the systemic circulation.
the procedure for preparation of standard ELIP was modified by including Papaverine hydrochloride in the lipid hydration solution, followed by three freeze-thaw cycles to increase encapsulation of the drug. Sizing and encapsulation pharmacokinetics were performed using a Coulter counter and a phosphodiesterase activity assay. Stability of Papaverine-loaded ELIP (PELIP) was monitored with a clinical diagnostic ultrasound scanner equipped with a linear array transducer at a center frequency of 4.5 MHz by assessing the mean digital intensity within a region of interest over time. The stability of PELIP was compared to those of standard ELIP and Optison.
relative to standard ELIP, PELIP were larger (median diameter = 1.88 +/- 0.10 microm for PELIP vs 1.08 +/- 0.15 microm for ELIP) and had lower Mean Gray Scale Values (MGSV) (92 +/- 24.8 for PELIP compared to 142.3 +/- 10.7 for ELIP at lipid concentrations of 50 microg/ml). The maximum loading efficiency and mean encapsulated concentration were 24% +/- 7% and 2.1 +/- 0.7 mg/ml, respectively. Papaverine retained its phosphodiesterase inhibitory activity when associated with PELIP. Furthermore, a fraction of this activity remained latent until released by dissolution of liposomal membranes with detergent. The stability of both PELIP and standard ELIP were similar, but both are greater than that of Optison.
our results suggest that PELIP have desirable physical, biochemical, biological, and acoustic characteristics for potential in vivo administration and ultrasound-controlled drug delivery.
开发可在超声照射下释放的封装治疗剂对于增强靶部位的药物效果具有重要意义。我们已开发出适用于血流超声成像和超声介导的血管内药物释放的回声脂质体（ELIP）。选择罂粟碱作为测试药物，因为其临床应用需要在靶血管床中具有高浓度，但在体循环中具有低浓度。
通过在脂质水合溶液中加入盐酸罂粟碱来修改标准ELIP的制备程序，然后进行三个冻融循环以增加药物的包封率。使用库尔特计数器和磷酸二酯酶活性测定法进行粒径测定和包封药代动力学研究。通过在配备有中心频率为4.5MHz的线性阵列换能器的临床诊断超声扫描仪上评估感兴趣区域内的平均数字强度随时间的变化，监测载罂粟碱ELIP（PELIP）的稳定性。将PELIP的稳定性与标准ELIP和Optison的稳定性进行比较。
相对于标准ELIP，PELIP更大（PELIP的中位直径=1.88±0.10μm，而ELIP为1.08±0.15μm），并且具有较低的平均灰度值（MGSV）（在脂质浓度为50μg/ml时，PELIP为92±24.8，而ELIP为142.3±10.7）。最大负载效率和平均包封浓度分别为24%±7%和2.1±0.7mg/ml。罂粟碱与PELIP结合时保留其磷酸二酯酶抑制活性。此外，该活性的一部分保持潜伏状态，直到用去污剂溶解脂质体膜而释放。PELIP和标准ELIP的稳定性相似，但两者均大于Optison。
我们的结果表明，PELIP具有理想的物理、生化、生物学和声学特性，可用于体内给药和超声控制药物递送。
