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.
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.
|Macha, M A; Rachagani, S; Pai, P et al. (2015) MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 34:1698-708|
|Macha, Muzafar A; Seshacharyulu, Parthasarathy; Krishn, Shiv Ram et al. (2014) MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. Curr Pharm Des 20:5287-97|
|Gutti, Tanuja L; Knibbe, Jaclyn S; Makarov, Edward et al. (2014) Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. Am J Pathol 184:101-9|
|Yi, Xiang; Manickam, Devika S; Brynskikh, Anna et al. (2014) Agile delivery of protein therapeutics to CNS. J Control Release 190:637-63|
|Alakhova, Daria Y; Kabanov, Alexander V (2014) Pluronics and MDR reversal: an update. Mol Pharm 11:2566-78|
|Savalia, Krupa; Manickam, Devika S; Rosenbaugh, Erin G et al. (2014) Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration. Free Radic Biol Med 73:299-307|
|Shi, Wen; Ogbomo, Sunny M; Wagh, Nilesh K et al. (2014) The influence of linker length on the properties of cathepsin S cleavable (177)Lu-labeled HPMA copolymers for pancreatic cancer imaging. Biomaterials 35:5760-70|
|Gupta, Suprit; Batra, Surinder; Jain, Maneesh (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol 1141:147-57|
|Nukolova, Natalia V; Oberoi, Hardeep S; Zhao, Yi et al. (2013) LHRH-targeted nanogels as a delivery system for cisplatin to ovarian cancer. Mol Pharm 10:3913-21|
|Zhou, Zhengyuan; Wagh, Nilesh K; Ogbomo, Sunny M et al. (2013) Synthesis and in vitro and in vivo evaluation of hypoxia-enhanced 111In-bombesin conjugates for prostate cancer imaging. J Nucl Med 54:1605-12|
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