Campara Benedetta, Khurana Nitish, De Nadai Andrea, Yellepeddi Venkata, Watt Kevin, Pasut Gianfranco, Ghandehari Hamidreza
Department Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy.
Utah Center for Nanomedicine, University of Utah, Salt Lake City, UT, USA.
Pharm Res. 2025 Jun 5. doi: 10.1007/s11095-025-03879-3.
Extracorporeal membrane oxygenation (ECMO) is a life-saving cardiopulmonary bypass technology for critically ill patients. Patients treated with ECMO receive multiple drugs to treat critical illnesses, prevent infections, and maintain sedation. However, inaccurate dosing information of some of the administered drugs is a significant cause of ECMO related mortality. Hydrophobic drugs tend to adsorb on the surface of ECMO circuit components leading to suboptimal dosing and therapeutic failure. Modifying the drugs can be exploited as a strategy to reduce drug adsorption in ECMO circuits. Propofol (Diprivan®) is a widely used anesthetic in ECMO patients that is known to substantially adsorb to ECMO circuit components due to its hydrophobicity. The objective of this work was to evaluate the PEGylation of propofol as a strategy to reduce its adsorption to the ECMO circuit. Poly(ethylene glycol) (PEG) was covalently conjugated to propofol with varying PEG lengths, i.e., 3 monomers of PEG (PEG), 5 monomers of PEG (PEG) and 2 kDa molecular weight PEG (PEG). The conjugates were synthesized, characterized, and compared for their water solubility, ability to spontaneously form micelles, and in reducing adsorption to hydrophobic materials in an in vitro ECMO mimic assay. Further, the conjugates were tested for their anesthetic activity in a C57BL/6 mouse model. We demonstrated that PEG-Propofol and PEG-Propofol had improved water solubility and significantly reduced the adsorption of propofol. PEG-Propofol also demonstrated a similar anesthetic activity (520 ± 109 secs) to free propofol (485 ± 103 secs). Our results demonstrate that PEG-Propofol is a promising anesthetic for administration to patients on ECMO.
体外膜肺氧合（ECMO）是一种用于危重症患者的挽救生命的体外循环技术。接受ECMO治疗的患者会使用多种药物来治疗危重症、预防感染并维持镇静状态。然而，一些所用药物的给药信息不准确是导致ECMO相关死亡率的重要原因。疏水性药物倾向于吸附在ECMO回路组件表面，导致给药剂量不足和治疗失败。对药物进行修饰可作为一种减少药物在ECMO回路中吸附的策略。丙泊酚（得普利麻®）是ECMO患者中广泛使用的麻醉剂，由于其疏水性，已知会大量吸附到ECMO回路组件上。这项工作的目的是评估丙泊酚聚乙二醇化作为减少其在ECMO回路上吸附的策略。聚乙二醇（PEG）与丙泊酚共价偶联，PEG长度不同，即3个PEG单体（PEG）、5个PEG单体（PEG）和分子量为2 kDa的PEG（PEG）。合成并表征了这些偶联物，并在体外ECMO模拟试验中比较了它们的水溶性、自发形成胶束的能力以及减少对疏水材料吸附的能力。此外，在C57BL/6小鼠模型中测试了这些偶联物的麻醉活性。我们证明PEG - 丙泊酚和PEG - 丙泊酚具有改善的水溶性，并显著降低了丙泊酚的吸附。PEG - 丙泊酚还表现出与游离丙泊酚相似的麻醉活性（520±109秒对485±103秒）。我们的结果表明，PEG - 丙泊酚是一种有前景的用于ECMO患者给药的麻醉剂。
