Faculty of Medicine, Lomonosov Moscow State University, Leninskiye Gory 1, 119991 Moscow, Russia.
Faculty of Chemical and Pharmaceutical Technologies and Biomedical Drugs, D. Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, 125047 Moscow, Russia.
Molecules. 2021 Feb 5;26(4):831. doi: 10.3390/molecules26040831.
Targeted delivery of doxorubicin still poses a challenge with regards to the quantities reaching the target site as well as the specificity of the uptake. In the present approach, two colloidal nanocarrier systems, NanoCore-6.4 and NanoCore-7.4, loaded with doxorubicin and characterized by different drug release behaviors were evaluated in vitro and in vivo. The nanoparticles utilize a specific surface design to modulate the lipid corona by attracting blood-borne apolipoproteins involved in the endogenous transport of chylomicrons across the blood-brain barrier. When applying this strategy, the fine balance between drug release and carrier accumulation is responsible for targeted delivery. Drug release experiments in an aqueous medium resulted in a difference in drug release of approximately 20%, while a 10% difference was found in human serum. This difference affected the partitioning of doxorubicin in human blood and was reflected by the outcome of the pharmacokinetic study in rats. For the fast-releasing formulation NanoCore-6.4, the AUC was significantly lower (2999.1 ng × h/mL) than the one of NanoCore-7.4 (3589.5 ng × h/mL). A compartmental analysis using the physiologically-based nanocarrier biopharmaceutics model indicated a significant difference in the release behavior and targeting capability. A fraction of approximately 7.310-7.615% of NanoCore-7.4 was available for drug targeting, while for NanoCore-6.4 only 5.740-6.057% of the injected doxorubicin was accumulated. Although the targeting capabilities indicate bioequivalent behavior, they provide evidence for the quality-by-design approach followed in formulation development.
阿霉素的靶向递送仍然存在一些挑战，比如到达靶部位的数量以及摄取的特异性。在本研究中，我们评估了两种载阿霉素的胶体纳米载体系统（NanoCore-6.4 和 NanoCore-7.4），它们具有不同的药物释放行为，并在体外和体内进行了研究。这些纳米颗粒利用特定的表面设计来调节脂质包膜，通过吸引与乳糜微粒内源性转运穿过血脑屏障有关的血液载脂蛋白。当应用这种策略时，药物释放和载体积累之间的精细平衡决定了靶向递送的效果。在水介质中的药物释放实验导致药物释放差异约为 20%，而在人血清中发现差异为 10%。这种差异影响了阿霉素在人血液中的分配，并反映在大鼠的药代动力学研究结果中。对于快速释放制剂 NanoCore-6.4，AUC 明显较低（2999.1ng×h/mL），而 NanoCore-7.4 的 AUC 较高（3589.5ng×h/mL）。使用基于生理的纳米载体生物药剂学模型进行的房室分析表明，两种制剂在释放行为和靶向能力方面存在显著差异。大约 7.310-7.615%的 NanoCore-7.4 可用于药物靶向，而 NanoCore-6.4 中只有 5.740-6.057%的注射阿霉素被积累。尽管靶向能力表明具有生物等效性，但它们为制剂开发中遵循的质量源于设计方法提供了证据。
