Investigation of Basolateral Targeting Micelles for Drug Delivery Applications in Polycystic Kidney Disease

被引:2
作者
Huang, Yi [1 ]
Osouli, Ali [1 ]
Pham, Jessica [2 ,3 ]
Mancino, Valeria [2 ,3 ]
O'Grady, Colette [1 ]
Khan, Taranatee [1 ]
Chaudhuri, Baishali [1 ]
Pastor-Soler, Nuria M. [2 ,3 ]
Hallows, Kenneth R. [2 ,3 ]
Chung, Eun Ji [1 ,2 ,4 ,5 ,6 ,7 ]
机构
[1] Univ Southern Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA
[2] Univ Southern Calif, Keck Sch Med, Div Nephrol & Hypertens, Dept Med, Los Angeles, CA 90033 USA
[3] Univ Southern Calif, USC UKRO Kidney Res Ctr, Keck Sch Med, Los Angeles, CA 90033 USA
[4] Univ Southern Calif, Keck Sch Med, Dept Surg, Div Vasc Surg & Endovascular Therapy, Los Angeles, CA 90033 USA
[5] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA
[6] Univ Southern Calif, Dept Chem Engn & Mat Sci, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90089 USA
[7] Univ Southern Calif, Bridge Inst, Los Angeles, CA 90089 USA
关键词
BARDOXOLONE METHYL; NANOPARTICLES; PRAVASTATIN; TOLVAPTAN; DESIGN; MODELS;
D O I
10.1021/acs.biomac.3c01397
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC20) on renal proximal tubule cells derived from Pkd1(flox/-):TSLargeT mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their in vitro therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections in vivo, RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice (Pkd1(fl/fl);Pax8-rtTA;Tet-O-Cre) with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.
引用
收藏
页码:2749 / 2761
页数:13
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