Kidney Week

Abstract: FR-PO189

Nano-carrier Based Approach to Target the Inflamed Kidney Endothelium

Session Information

• AKI: Mechanisms
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Bishop, Boaz Yehuda, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Boaz Yehuda Bishop, MD

• Sharma, Swagat Hasmukhbhai, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Swagat Hasmukhbhai Sharma, PhD

• Yuk, Simseok A., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Simseok A. Yuk, PhD

• Almunif, Sultan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Sultan Almunif

• Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Susan E. Quaggin, MD, FASN

• Tiwari, Ratnakar, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Ratnakar Tiwari, PhD

• Scott, Evan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Evan Scott, PhD

• Kapitsinou, Pinelopi P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Pinelopi P. Kapitsinou, MD

Background

Previous studies have demonstrated that endothelial cell (EC) derived mechanisms are sufficient to suppress EC activation of leukocyte adhesion molecules and subsequent inflammation promoting repair from acute kidney injury (AKI). Nevertheless, there are significant challenges for the translation of these findings into the clinical domain, in part because drugs and drug carriers have no natural endothelial affinity. Therefore, precise EC drug delivery is a potential strategy to advance the development of novel therapeutics in AKI. Here, we developed nanocarriers for enhanced drug delivery to inflamed kidney endothelium.

Methods

PEG-b-PPS micelles (MC) were decorated with two different high affinity peptides selected for targeting of inflamed kidney endothelium.
The first peptide (CYNTTTHRC) was reported to bind specifically to inflamed endothelial cells (IEC) and is homologue to Scube 1 & 2, previously associated with ischemia reperfusion injury (IRI). The second peptide ,(CLPVASC), was reported to bind specifically to kidneys. Average MC diameter (25nm) with PDI<0.1 were assessed by DLS. MC morphology, characterized by MALDI-TOF MS, cryoTEM and by SAX, remained consistent when dual peptides were added. For in vivo studies, we used a unilateral IRI rodent model induced by 30 minutes clamping of renal pedicle.

Results

Using imaging with In vivo imaging system (IVIS) analysis showed a significantly increased uptake of the targeted MC to the ischemic kidney compared to contralateral (non-inflamed) kidney (by 3.4-fold, p<0.0001). The uptake was also significantly increased compared to non-targeted MC while at the same time, there was significantly reduced off-target uptake by other major organs such as liver, heart and lungs (n=8, p<0.0001).

Conclusion

Our work has shown that peptide-based targeting can enhance the delivery of MCs to the post-ischemic kidney. This represents a significant technological advance enabling improved targeted delivery of novel kidney therapeutics.

Funding

• NIDDK Support