Study of Renal Accumulation of Targeted Polycations in Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a global healthcare burden characterized by rapid loss of renal function and high morbidity and mortality. Chemokine receptor CXCR4 participates in the renal infiltration of immune cells following injury and in local inflammatory enhancement. Injured renal tubule cells overexpress CXCR4, which could be used as a target for improved drug delivery in AKI. Plerixafor is a small-molecule CXCR4 antagonist that has shown beneficial effects against AKI and has been previously developed into a polymeric analog (polymeric plerixafor, PP). With the goal of gaining a better understanding of how overall charge and hydrophilicity affect renal accumulation of PP, we have synthesized PP copolymers containing hydroxyl, carboxyl, primary amine, and alkyl moieties using Michael-type addition copolymerization. All synthesized copolymers showed excellent CXCR4-binding and inhibiting ability in vitro and improved cellular uptake in hypoxia-reoxygenation stimulated mouse tubule cells. Analysis of serum protein binding revealed that polymers with hydroxyl group modification showed the least amount of protein binding. Biodistribution of the polymers was tested in a unilateral ischemia reperfusion-induced AKI mouse model. The results showed significant differences in accumulation in the injured kidneys depending on the net charge and hydrophilicity of the polymers. The findings of this study will guide the development of polymeric drug carriers for targeted delivery to injured kidneys for better AKI therapy.

Dual-Responsive Curcumin-Loaded Nanoparticles for the Treatment of Cisplatin-Induced Acute Kidney Injury

“…Nanotechnology-based drug delivery systems have facilitated AKI therapy, such as early prevention, early diagnosis, drug delivery, and gene therapy. − In particular, stimulus-responsive polymeric drug delivery systems have attracted increasing attention for low toxicity, less side effects, prone accumulation into targeted tissues, and response to the disease microenvironment. − Liu et al synthesized a ROS-responsive prodrug based on chitosan-SS31 for AKI therapy. The prodrug presented ROS-responsive drug release leading to an enhanced therapeutic effect of SS31.…”

Insights into Repeated Renal Injury Using RNA-Seq with Two New RPTEC Cell Lines

“…AFB1 generally requires metabolic activation to the 8,9-epoxide to produce toxicity by DNA and protein adducts [38] making liver a primary target organ, although AFB1 adducts have also been documented in the kidneys of rats and mice [39]. Here, only the LgT moRPTECs showed substantial transcriptional changes (1139 DEGs) in response to AFB1 at 72 h. Upregulation of typical toxicity markers like Kim1 (Havcr1), Il6, and Mmp's were observed with only minor increases in the LgT cells after 72 h. However, AFB1-mediated increases by concentration for Cxcr4 [40,41] and Il6 [42] are consistent markers of kidney injury. Such changes could be responsible for the induction of multiple developmental transcription factors [43,44] such as Barx1, Gbx2, Nkx2-9, Tlx3, Tfap2e, and Hoxc12.…”

Nanomedicine in kidney disease

“…Small interfering RNA (siRNA) nanocarriers that also transported CXCR4 antagonists (CXCR4a) successfully reduced inflammation and AKI [31 ▪ ,32 ▪ ]. Surface chemistry optimization of CXCR4a nanoparticles, leads to better kidney targeting [33 ▪ ]. Cell-free DNA (cfDNA) is abundant during AKI and is considered to increase local inflammation.…”