ABSTRACT The overall goal of this project is to develop a highly effective and safe nanomedicine for systemic lupuserythematosus (SLE) or lupus. Among many medications used in clinical management of lupus, glucocorticoid(GC) is most widely used because of their high anti-inflammatory potency. But their notorious toxicities havehampered the long-term clinical application. To reduce their side effects, we have conjugated dexamethasone(Dex, a potent GC) to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and found that the Dex prodrugis nephrotropic in a mouse model of lupus nephritis (NZB/W F1). Prophylactic and treatment of establishedlupus nephritis with a monthly P-Dex injection (i.v.) are much more effective in prevention and reduction ofalbuminuria than dose equivalent daily free Dex treatment. The P-Dex treatment did not elicit osteoporosis,but other GC side effects (e.g. adrenal gland atrophy) remained. To further address this challenge, we recentlydesigned a novel prodrug nanomedicine by conjugating Dex to polyethylene glycol (PEG). The resultingamphiphilic PEG-Dex self-assembles into micelles. When tested in the NZB/W F1 mice, it demonstratedpotent therapeutic efficacy, similar to P-Dex, but did not show any classical GC side effects. Based on theseexciting preliminary data, we hypothesize that due to their different structural design, P-Dex and PEG-Dexhave very different pharmacokinetic/biodistribution (PK/BD) profiles and patterns of interaction with the cellularcomponents of the immune system, leading to distinct subcellular distribution/activation patterns, similartherapeutic potency, but different safety profiles. We also speculate that the original structural design of ourlead candidate, PEG-Dex micelle may not always work as well in other lupus models due to the heterogeneityand comorbidities of lupus disease, which would necessitate further structure optimization. To validate thesehypotheses, we propose first to perform a head-to-head comparative PK/BD study of PEG-Dex and P-Dex.We will also analyze the PK/BD profiles of the free Dex released from the two prodrug nanomedicine. Thesestudies may partially explain why PEG-Dex micelle has lower toxicity than P-Dex and will illustrate its workingmechanism from the PK/BD aspect. Second, we will perform in vitro and in vivo cellular studies to compareand analyze the interaction of P-Dex and PEG-Dex with various cellular components of the immune systemand their impact on the biological functions of the prodrug nanomedicine. The results from this study willfurther explain why PEG-Dex shows much better safety profile than P-Dex on the cellular and molecular levels.Third, we will validate PEG-Dex micelle's efficacy and safety in NZM2410, MRL/lpr and CIA mice because ofthe heterogeneity and comorbidities of lupus disease recapitulated in these models. Based on theexperimental feedback, the structure of PEG-Dex micelle will be optimized and the resulting final drugcandidate will be evaluated in NZB/W F1 mice for 1 year to confirm its long-term efficacy and safety inpreparation for its clinical translation.
|Effective start/end date||5/26/16 → 4/30/21|
- National Institutes of Health: $376,250.00