Akhtar Saghir, Babiker Fawzi, Al-Kouh Aisha, F Benter Ibrahim
College of Medicine, QU Health, Qatar University, Doha, Qatar.
Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
Biomol Biomed. 2025 Mar 7;25(4):914-924. doi: 10.17305/bb.2024.10735.
Polyamidoamine (PAMAM) dendrimer nanoparticles are efficient drug delivery vectors with potential clinical applications in nanomedicine. However, PAMAMs can compromise heart function, and strategies to mitigate cardiotoxicity would be beneficial. In this study, we investigated whether the adjunct use of three key cardioprotective agents could prevent cardiac injury induced by a seventh-generation cationic PAMAM dendrimer (G7). Isolated rat hearts were subjected to ischemia and reperfusion (I/R) injury in the presence or absence of G7 or the cardioprotective agents Losartan, epidermal growth factor (EGF), or S-nitroso-N-acetylpenicillamine (SNAP). I/R injury significantly compromised cardiac function, in terms of left ventricular (LV) hemodynamics, contractility, and vascular dynamics, which were markedly improved (P < 0.05) by the administration of Losartan, EGF, or SNAP alone, confirming their cardioprotective effects. The administration of G7 significantly worsened cardiac function recovery following I/R (P < 0.05). G7-induced impairments in cardiac and vascular dynamics were significantly improved by co-administration of Losartan, EGF, or SNAP. Treatment with G7 also significantly increased cardiac enzyme levels and infarct size, both of which were markedly reduced upon co-infusion of Losartan, EGF, or SNAP (P < 0.05). Thus, G7 deteriorates the recovery of cardiac function in isolated hearts subjected to I/R injury, which can be rescued by co-administration of Losartan, EGF, or SNAP. These findings enhance our understanding of PAMAM dendrimer nanotoxicology in the mammalian heart and suggest that the adjunct use of cardioprotective agents is an effective strategy for mitigating the cardiotoxicity of these dendrimers and potentially other drug delivery systems.
聚酰胺 - 胺（PAMAM）树枝状大分子纳米颗粒是高效的药物递送载体，在纳米医学中具有潜在的临床应用价值。然而，PAMAMs会损害心脏功能，减轻心脏毒性的策略将是有益的。在本研究中，我们调查了三种关键心脏保护剂的辅助使用是否可以预防由第七代阳离子PAMAM树枝状大分子（G7）引起的心脏损伤。在有或没有G7或心脏保护剂氯沙坦、表皮生长因子（EGF）或S - 亚硝基 - N - 乙酰青霉胺（SNAP）的情况下，对离体大鼠心脏进行缺血再灌注（I/R）损伤。就左心室（LV）血流动力学、收缩性和血管动力学而言，I/R损伤显著损害了心脏功能，单独给予氯沙坦、EGF或SNAP可显著改善这些指标（P < 0.05），证实了它们的心脏保护作用。G7的给药显著恶化了I/R后心脏功能的恢复（P < 0.05）。氯沙坦、EGF或SNAP的共同给药显著改善了G7诱导的心脏和血管动力学损伤。G7治疗还显著提高了心脏酶水平和梗死面积，在共同输注氯沙坦、EGF或SNAP后，这两者均显著降低（P < 0.05）。因此，G7会使遭受I/R损伤的离体心脏的心脏功能恢复恶化，而氯沙坦、EGF或SNAP的共同给药可以挽救这种情况。这些发现增强了我们对PAMAM树枝状大分子在哺乳动物心脏中的纳米毒理学的理解，并表明心脏保护剂的辅助使用是减轻这些树枝状大分子以及潜在其他药物递送系统心脏毒性的有效策略。
