| Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease for which there currently is no cure. Lupus nephritis (LN), affecting 50% of SLE patients, is initiated by precipitation of immune complex within the glomeruli. Activation of the complement cascade and recruitment of inflammatory cells into renal sites occurs resulting in renal dysfunction, and potentially renal failure. Currently, glucocorticoids (GCs) are still being used as the standard therapy due to their high potency and fast onset. However, the major concern for GCs is their severe systemic side effects due to their wide tissue distribution after systemic administration. Therefore, this thesis focused on solving this problem by incorporating a nephrotropism and retention features on dexamethasone using macromolecular prodrug approaches. Firstly, the feasibility of a macromolecular prodrug approach in LN treatment was tested by evaluating the efficiency of an HPMA copolymer-based dexamethasone prodrug (P-Dex) in the prevention of LN, and the potential side effects related to GCs treatment. We demonstrated that monthly administration of P-Dex not only superiorly prevented LN, but also displayed reduced toxicity, as compared to dose equivalent Dex given by daily administration. These effects are, at least partially, attributed to its reduced glomerular capillary permselectivity and enhanced uptake by activated kidney cells including the proximal tubule epithelial cells. We then further explored the efficiency of P-Dex in treating established LN to extend the life-span of the animals. The results showed that P-Dex is more effective and less toxic in treating LN than free dexamethasone in (NZB X NZW)F1 mice by attenuating the renal inflammatory response to immune complexes. Finally, to further reduce the off target side effects as observed in the P-Dex treatment, we tried to explore the feasibility of other polymer (i.e. PEG)-based prodrug micelle system for dexamethasone delivery. Two different prodrugs were successfully developed with different PEG MW and different linkage chemistry. The in vitro characterization study demonstrated that the prodrugs were both able to spontaneously form micelles in aqueous solution. The in vitro release study and preliminary in vivo evaluation indicated that acid-labile PEG-di-NHNDex might be able to provide sustainable treatment for LN, whereas PEG-tri-ODex formed via an ester-linkage at the C21-hydroxyl group of dexamethasone may not be optional due to the rapid activation. Collectively, we have successfully demonstrated the potential of macromolecular dexamethasone prodrugs for improved treatment of LN. By introducing nephrotropism and retention mechanisms to small molecular drug, these prodrug systems may provide a superior and sustainable prophylactic and therapeutic efficacy for LN, and also reduce free drug-associated off-target effects. In summary, macromolecular prodrug approaches have great potential to be used as a new clinical strategy for the prevention and treatment of LN. |
