Nephritis, a chronic inflammatory kidney disease, is a leading cause of mortality in lupus patients. Current therapy for lupus nephritis includes corticosteroids, such as dexamethasone (Dex), which are often associated with significant toxicity that results from systemic exposure to the drugs and off target effects. To address this problem, we propose to develop kidney-targeted corticosteroid therapy, which will allow sufficient Dex concentration in the kidney for inflammation resolution, while limiting systemic exposure to corticosteroids. Our long-term goal is to develop novel therapies for lupus. The objective of this application is to demonstrate that molecularly targeted copolymer-conjugated Dex will provide safe but effective therapy for lupus by targeted delivery and local retention of the anti-inflammatory drug Dex to the kidney. Our central hypothesis is that molecularly targeted copolymer conjugated Dex will be nephrotropic to lupus-affected kidneys with limited systemic distribution and will ameliorate renal dysfunction and increase lifespan of lupusprone mice. This hypothesis is based upon our initial studies showing that copolymer conjugated Dex shows enhanced uptake by the inflamed kidney, particularly in the proximal tubule epithelial cells. Furthermore, we have strong preliminary data that demonstrate that copolymer conjugated Dex reduces nephritis and extends lifespan in lupus mice without inducing loss of bone mineral density. However, some side effects remain and thus further refinement of this kidney targeted therapy is needed to maximize therapeutic benefits and eliminate residual off target effects. However, our lack of knowledge about the cellular mechanisms involved in renal uptake of copolymer conjugated Dex hampers our progress toward this goal. Therefore, we propose in vitro and in vivo studies to determine the mechanisms involved in cellular uptake and processing of copolymer conjugated Dex in the kidney. We will also use peptides to more effectively target copolymer conjugated Dex to the proximal tubule epithelial cells and to promote more efficient cellular uptake. The impact of peptide targeting on the safety and efficacy of copolymer conjugated Dex will also be examined.

Public Health Relevance

There is a need for improved therapy for nephritis, the leading cause of renal failure and mortality in lupus patients. Current therapy involves corticosteroids, which cause major toxicity due to systemic exposure. Our development of kidney-targeted corticosteroid therapy, which effectively treat nephritis while limiting systemic exposure to corticosteroids, represents a major leap forward in the treatment of lupus nephritis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
United States
Zip Code
Soni, Kruti S; Lei, Fan; Desale, Swapnil S et al. (2017) Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. J Control Release 264:276-287
Karuturi, Bala V K; Tallapaka, Shailendra B; Yeapuri, Pravin et al. (2017) Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diamet Mol Pharm 14:1469-1481
Fan, Wei; Zhang, Wenting; Jia, Yinnong et al. (2017) Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers. Mol Pharm 14:1405-1417
Chen, Shixuan; Ge, Liangpeng; Mueller, Aubrey et al. (2017) Twisting electrospun nanofiber fine strips into functional sutures for sustained co-delivery of gentamicin and silver. Nanomedicine 13:1435-1445
Chen, Shixuan; Ge, Liangpeng; Gombart, Adrian F et al. (2017) Nanofiber-based sutures induce endogenous antimicrobial peptide. Nanomedicine (Lond) 12:2597-2609
Jiang, Jiang; Chen, Shixuan; Wang, Hongjun et al. (2017) CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. Acta Biomater :
Shrishrimal, Shashank; Kosmacek, Elizabeth A; Chatterjee, Arpita et al. (2017) The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. Antioxidants (Basel) 6:
Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830
Smolsky, Joseph; Kaur, Sukhwinder; Hayashi, Chihiro et al. (2017) Surface-Enhanced Raman Scattering-Based Immunoassay Technologies for Detection of Disease Biomarkers. Biosensors (Basel) 7:
Lakshmanan, Imayavaramban; Salfity, Shereen; Seshacharyulu, Parthasarathy et al. (2017) MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53. Clin Cancer Res 23:3906-3917

Showing the most recent 10 out of 74 publications