Nekoueifard Effat, Radmanesh Fatemeh, Moghadam Ebrahim Saeedian, Maghsoudian Samane, Kheimeh Abolfazl, Pooyan Paria, Abandansari Hamid Sadeghi, Baharvand Hossein, Dinarvand Rassoul
Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Int J Pharm. 2025 Aug 20;681:125852. doi: 10.1016/j.ijpharm.2025.125852. Epub 2025 Jun 16.
Recent studies have extensively investigated the use of nanocarriers for targeted drug delivery to cancerous tumors, demonstrating promising outcomes. However, their clinical application reveals significant limitations that necessitate substantial revisions for improved efficacy. Addressing issues such as low cell internalization and limited circulation time can improve their therapeutic efficiency. To enhance circulation time, stealth nanocarriers are preferred, while bioadhesive nanoparticles demonstrate higher cell internalization. In this research, pH-responsive PEGylated polyamidoamine (PAMAM) nanoassemblies were prepared. 2-propionic-3-methylmaleic anhydride (CDM) was used as pH sensitive linkage for the cleavable attachment of poly ethylene glycol (PEG) chains on the surface of PAMAM dendrimers. The obtained PEG-CDM-PAMAM nanoassemblies (PCPNAs) engineered to intelligently address these challenges. The design of PCPNAs enables pH-triggered detachment of PEG chains from the surface at the tumor site, resulting in the exposure of protonated, positively charged residual PAMAM nanoassemblies. Cellular studies revealed enhanced cellular uptake of doxorubicin loaded PCPNAs (DPCPNAs) compared to control PEG-PAMAM nanoassemblies (CPPNAs), pH-insensitive nanoparticles, with similar structures. Therefore, it presents a solution to one of the problems of current nanocarriers characterized by limited cellular internalization. DPCPNAs not only demonstrate enhanced efficacy in reducing tumor volume in 4 T1 tumor-bearing mice but also elevate cancer cell death and growth suppression compared to free doxorubicin. Moreover, toxicological and histopathological evaluations of vital tissues confirmed the biocompatibility of this drug delivery system. The feature of charge switchability resulted in favorable outcomes for DPCPNAs in both in vitro and in vivo experiments.
最近的研究广泛调查了纳米载体用于向癌性肿瘤进行靶向药物递送的情况，显示出了有前景的结果。然而，它们的临床应用揭示了显著的局限性，这需要进行大量修订以提高疗效。解决诸如低细胞内化和有限循环时间等问题可以提高它们的治疗效率。为了延长循环时间，隐形纳米载体是首选，而生物粘附性纳米颗粒表现出更高的细胞内化。在本研究中，制备了pH响应性聚乙二醇化聚酰胺-胺（PAMAM）纳米组装体。2-丙酸-3-甲基马来酸酐（CDM）用作pH敏感连接基团，用于在PAMAM树枝状大分子表面可裂解地连接聚乙二醇（PEG）链。所获得的PEG-CDM-PAMAM纳米组装体（PCPNAs）经过设计，能够智能地应对这些挑战。PCPNAs的设计使得PEG链在肿瘤部位能够由pH触发从表面脱离，从而导致质子化的、带正电荷的残余PAMAM纳米组装体暴露出来。细胞研究表明，与具有相似结构的对照PEG-PAMAM纳米组装体（CPPNAs）、pH不敏感纳米颗粒相比，载有多柔比星的PCPNAs（DPCPNAs）的细胞摄取增强。因此，它为当前纳米载体以细胞内化有限为特征的问题之一提供了解决方案。DPCPNAs不仅在减少4T1荷瘤小鼠肿瘤体积方面显示出增强的疗效，而且与游离多柔比星相比，还提高了癌细胞死亡和生长抑制。此外，对重要组织的毒理学和组织病理学评估证实了这种药物递送系统的生物相容性。电荷可切换特性使得DPCPNAs在体外和体内实验中都取得了良好的结果。
