Shuyun Liu 1 , Meng Zhao 1 , Yijie Zhou 1 , Ling Li 2 , Chengshi Wang 1 , Yujia Yuan 1 , Lan Li 1 , Guangneng Liao 3 , William Bresette 4 , Younan Chen 1 , Jingqiu Cheng 1 , Yanrong Lu 1 , Jingping Liu 5
Ischemia-reperfusion (I/R)-induced organ injury is a serious health problem worldwide, and poor recovery of acute phase injury leads to chronic fibrosis and further organ dysfunction. Thus, a more precise approach to enhance tissue repair is needed. By using a renal I/R model, we aimed to evaluate the role of a hydrogel-based dual-drug delivery platform on promoting tissue repair. An injectable, self-assembling peptide/heparin (SAP/Hep) hydrogel was used to co-deliver TNF-α neutralizing antibody (anti-TNF-α) and hepatocyte growth factor (HGF). The microstructure and controlled release properties of KLD2R/Hep hydrogel were analyzed. The effects of the drug-loaded hydrogel (SAP-drug) on renal injury were evaluated in mice with I/R injury. In vitro, the SAP/Hep hydrogel allowed for a faster release of anti-TNF-α with a sustained release of HGF, and both drugs maintained their bioactivities after release. In vivo, combined anti-TNF-α/HGF showed better renal protective potential than anti-TNF-α or HGF alone. SAP-drug (anti-TNF-α/HGF in SAP hydrogel) treatment reduced the level of serum creatinine (Scr), blood urea nitrogen (BUN), tubular apoptosis, renal inflammatory factors, and macrophage infiltration compared to Free-drug (anti-TNF-α/HGF in solution) or SAP alone. Moreover, the SAP-drug group had better efficacy on promoting tubular cell proliferation and dedifferentiation than SAP or Free-drug alone, and thus reduced chronic renal fibrosis in I/R mice. This study highlighted that SAP could sequentially deliver the two drugs to achieve anti-inflammatory and pro-proliferative effects with one injection and thus is a promising delivery platform for tissue repair. STATEMENT OF SIGNIFICANCE: Ischemia-reperfusion (I/R)-induced organ injury is a serious health issue, and delayed tissue repair leads to chronic fibrosis and organ failure. Systemic administration of anti-inflammatory agents or growth factors have shown some benefits on I/R injury, but their therapeutic efficacy was limited by side effects, poor bioavailability, and absent key signals of tissue repair. To address these issues, a hydrogel-based drug co-delivery platform was used to treat I/R injury. This platform could achieve sequential release kinetics with faster rate of anti-TNF-ɑ and slower rate of HGF, and effectively promoted tissue repair by targeting inflammation and proliferation in mice with renal I/R. This nanoscale delivery platform represents a promising strategy for solid organs (heart, liver and kidney) regeneration after I/R.