Construction of multifunctional targeted nano-prodrugs based on PAMAM dendrimers for tumor therapy

• Published in: European polymer journal 2023-11, Vol.200, p.112486, Article 112486
• Main Authors: Gu, Yuan, Cai, Yanjun, Kou, Yige, Cheng, Erzhuo, Bi, Hanjie, Hu, Min, Wu, Songyao, Jiang, Yong, Zhang, Jingxi, Wu, Qingting, Li, Yunyi, Yang, Bin
• Format: Article
• Language: English
• Subjects: Nano-prodrug; PAMAM dendrimer; pH-responsive; Resveratrol; Targeted tumor therapy
• ISSN: 0014-3057; 1873-1945
• DOI: 10.1016/j.eurpolymj.2023.112486

A multifunctional tumor-targeting nano-prodrug based on PAMAM dendritic polymers with the conjugation of RGDyC-PEG-PAMAM-PBA and resveratrol via pH-responsive boronate ester bonds was developed, which can improve drug utilization and supply efficient treatment of tumor both in vitro and in vivo. [Display omitted] •A PAMAM dendrimer-based nano-prodrug based on the bonding of Resveratrol and phenylboronic acid through the pH-responsive boronate ester was constructed.•Through the modification of PAMAM with peptides containing the RGDyC sequence and PEGylation, the targeted delivery of nano-prodrug to tumor could be realized to improve drug utilization and efficient treatment.•This method is expected to construct a more general strategy for the PAMAM dendrimer-based nanosystem in the field of tumor therapy. Nanomaterial-based drug delivery systems have demonstrated powerful applications in tumor therapy. PAMAM dendrimers by virtue of multivalent modification and biocompatible components were widely used to construction multifunctional targeted chemotherapeutics. In this report, we present a PAMAM dendrimer-based nano-prodrug delivery system for targeted tumor therapy. The RGDyC-PEG-PAMAM-PBA-Res (RPPPR) nano-prodrug was characterized by 1H NMR, zetasizer, and TEM, the drug loading and pH-sensitive drug release behaviors were investigated. In vitro cell viability assay revealed that the group treated with the nano-prodrug exhibited lower cell viability compared to the control group as concentration increased, confirming the nano-prodrug’s effectiveness in treating tumors. In vitro studies on cellular uptake of the nano-prodrug demonstrated that RPPPR had a high targeting ability, primarily attributed to the RGD-mediated target effect. Relevant data from our hemolysis assay indicated that the nano-prodrug maintained good blood compatibility within the concentration range of 0.1 to 0.3 mg/mL. In vivo experiments focusing on tumor therapy showed that RPPPR suppressed tumor growth and promoted tumor apoptosis. H&E staining, TUNEL assay, and immunohistochemistry results further validated the enhanced therapeutic effect. Importantly, no toxicity was observed in the vital organs such as the heart, liver, lung, kidneys, or spleen. These results suggest the superior antitumor efficacy of RPPPR compared to Resveratrol alone, and thus may be useful for tumor therapy. It is expected to explore new directions to establish a general strategy with dendritic prodrugs for syner