In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil® and Caelyx®. Notably, these included differences in vesicular population aspect ratios and particle number. Among the tested products, only SinaDoxosome, in addition to the presence of unilamellar vesicles with entrapped doxorubicin crystals, contained empty circular disks. Differences were also found in complement responses, which may be related to some morphological differences. This study has demonstrated an integrated biophysical and immunological toolbox for improved analysis and detection of physical differences among vesicular populations that may modulate their clinical performance. Combined, these approaches may help better product selection for infusion to the patients as well as for improved design and characterization of future vesicular NBCDs with enhanced clinical performance and safety.

中文翻译：

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聚乙二醇化脂质体阿霉素产品Doxil®，Caelyx®，DOXOrubicin和SinaDoxosome的形态，大小和补体激活的综合评估

为了提高患者的利益和安全性，需要有关非生物复合药物（NBCD）特异性的综合法规指南，例如阿霉素包封的脂质体及其后续版本。在这里，我们通过低温透射电子显微镜，动态光散射和纳米颗粒跟踪分析，将Doxil®及其欧洲类似物Caelyx®与两个后续产品DOXOrubicin（由美国食品和药物管理局批准）和SinaDoxosome（在伊朗生产）进行了比较。 ，并评估它们在激活人血清中补体系统中的潜力。我们发现被测脂质体产品之间，甚至被测批次的Doxil®和Caelyx®之间都存在细微的理化差异。值得注意的是，这些包括水泡种群长宽比和颗粒数量的差异。在测试的产品中，除了存在带有被困阿霉素晶体的单层囊泡之外，只有SinaDoxosome包含空的圆盘。在补体反应中也发现差异，这可能与某些形态上的差异有关。这项研究表明了一个集成的生物物理和免疫工具箱，用于改进分析和检测囊泡人群之间可能调节其临床表现的物理差异。结合起来，这些方法可能有助于更好的产品选择，以便为患者输液，以及改善未来囊泡NBCD的设计和表征，并增强临床性能和安全性。在补体反应中也发现差异，这可能与某些形态上的差异有关。这项研究表明了一个集成的生物物理和免疫工具箱，用于改进分析和检测囊泡人群之间可能调节其临床表现的物理差异。结合起来，这些方法可能有助于更好的产品选择，以便为患者输液，以及改善未来囊泡NBCD的设计和表征，并增强临床性能和安全性。在补体反应中也发现差异，这可能与某些形态学差异有关。这项研究表明了一个集成的生物物理和免疫工具箱，用于改进分析和检测囊泡人群之间可能调节其临床表现的物理差异。结合起来，这些方法可能有助于更好的产品选择，以便为患者输液，以及改善未来囊泡NBCD的设计和表征，并增强临床性能和安全性。