A dendritic, redox-responsive, supramolecular (Dr.S) system for lysis-triggered delivery for drug-resistant renal cancer. Issue 62 (13th October 2020)

• Record Type: Journal Article
• Authors: Yuan, Yichu; Jin, Piaopiao; Wang, Yueming; Zhao, Xinyu; Hu, Qida; Wu, Wangteng; Huang, Jiwei; Zhang, Nan
• Is Part Of: RSC advances. Volume 10:Issue 62(2020)
• Page Start: 37826
• Page End: 37833
• Publication Date: 2020-10-13
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d0ra06444k
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Aiming to improve the drug loading capacity of dendritic nanoparticles and enhance delivery efficacy in drug-resistant cancer, we developed and optimized a more advanced dendritic, redox-responsive, supramolecular (Dr.S) system for intravenous RAD001 administration. Abstract : Purpose : Aiming to improve the drug loading capacity of dendritic nanoparticles and enhance delivery efficacy in drug-resistant cancer, we developed and optimized a more advanced dendritic, redox-responsive, supramolecular (Dr.S) system for intravenous RAD001 administration. Materials and methods : The Dr.S system was engineered by linking 3 rd generation polyamidoamine dendrimers (G3 PAMAM) with 8-arm polyethylene glycol (PEG) to encapsulate a molecular targeted agent RAD001. The drug-loading capacity was measured by ultraviolet-visible spectrophotometry. In vitro release behavior was determined with a two-compartment model, and the in vivo distribution pattern was tracked by Cy5.5 fluorescence. The therapeutic effect of Dr.S/RAD001 was evaluated in RAD001-resistant cancer cells and tumor-bearing nude mice, respectively. Results : The Dr.S system encapsulating RAD001 with a loading efficiency of 10.6% formed a core–shell structure, by shifting hydrophobic PAMAM/RAD001 components towards inner space and exposing the hydrophilic PEG on the surface. The Dr.S/RAD001 system could respond to a lysis-mimicking reduction stimulus, and functionally release cargoes to facilitate tumor accumulation and cellular internalization. These features contributed to the enhanced anti-tumor activity of RAD001 in renal cancers in vitro and in vivo . The Dr.S/RAD001 system also reversed acquired RAD001-resistance by a 60-fold increase in tumor accumulation of the therapeutics. Conclusion : The functional Dr.S/RAD001 system enables lysis-triggered release of RAD001 to achieve better tumor accumulation, which helps overcome acquired drug resistance in renal cancers.