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 Pkd1flox/-: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 (Pkd1fl/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.