# Nanotechnology, Nanomedicine, and the Kidney
## 5 Nanotechnology for Renal Therapy
### Drug Delivery
#### 5.1.5 Nanoparticles  
In renal targeting with nanoparticles, particle size can be used to generally determine the target compartment of the kidney. Particles small enough to pass the glomerular filtration (5-7 nm) barrier can be used to target the tubular area, where they are reabsorbed. Particles sized 30-150 nm cannot extravasate into the primary urine and remain in circulation [75]. Maximum glomerular accumulation has been described with a particle size of 80 nm. There are exceptions. For example, ultra-small particles (~2 nm) are too small to pass the glycocalyx and be removed via the liver. Mesoscale nanoparticles (MNP) (~400 nm) were found in proximal tubular cells, seemingly transported there by endocytosis because at that size, they are larger than the endothelial fenestration. [PERSON] et al., used an LMW polycationic chitosan and formed nanoparticles with polyanionic siRNA duplexes of an approximate 450 nm size. When they injected the LMW chitosan nanoparticles loaded with siRNA duplexes specific for water channel aquaporin 1 (AQP1) into mice, they were able to target more than 50% of the proximal tubule epithelial cells (PTECs). Targeting of PTECs was mediated via Megalin, and targeted PTECs showed a reduced expression of AQP1. This proof of principle experiment demonstrated the potential of LMW chitosan siRNA duplex nanoparticles [76]. In a very recent study, [PERSON] et al., demonstrated that a chitosan nanoparticle could be used for the oral delivery of the drug candidate metformin to treat polycystic kidney disease [77]. Metformin is approved for the treatment of type 2 diabetes. Recent clinical trials demonstrated that it also reduces the cyst growth in polycystic kidney disease, but that 8-fold higher doses caused discomfort in a high number of patients, and some developed an intolerance. [PERSON] loaded metformin into chitosan nanoparticles (~145 nm diameter) to accelerate the intestine transmembrane transport and enable rapid drug uptake. They found that chitosan-encapsulated metformin showed a higher bioavailability and that mice treated with oral chitosan-metformin had a lower cyst burden than mice treated with free metformin. Blood urea, nitrogen and creatinine levels were similar to untreated mice demonstrating the absence of nephrotoxicity. This study highlights the potential of chitosan encapsulation for drugs with low oral bioavailability and a potential treatment for polycystic kidney disease. Nanoparticles can also be used to monitor the progression of renal disease, as [PERSON] et al., demonstrated in murine experimental Adriamycinin Nephrosis, a model for human Focal Segmental Glomerulosclerosis, the main cause of adult and pediatric nephrotic syndrome [78]. The doxorubicin-derivate Adriamycininduces a podocyte injury, leading to proteinuria and, subsequently, glomerulosclerosis. [PERSON] constructed a sensor by combining an amino headgroup gold nanoparticle (Ami-AuNP) with three fluorophore proteins. The fluorophores fluorescein isothiocyanate-modified bovine serum albumin (BSA-FITC), cyanine dye Cy5-modified \(\beta\)-lactoglobulin (\(\beta\)-Lac-Cy5), and rhodamine B-modifiedpeanut agglutinin (PNA-RhB) were electrostatically linked to Ami-AuNP. While bound to Ami-AuNP, the fluorescence of the fluorophore proteins was quenched. When protein is present in the urine, the urinary proteins compete for binding with Ami-AuNP, and the fluorophore proteins are no longer quenched and emit light. Using wavelength combinations of the three fluorescence proteins, the authors were able to correlate disease stages with specific light signals [78]. [PERSON] and colleagues generated MNP by conjugating poly(lactic-co-glycolic acid) with polyethylene glycol (PLGA-PEG). In addition, they generated fluorescent MNP by the addition of 3,3'-diethylthiadicarbocyanine iodide (DEDC) to PLGA-PEG. They then injected the MNP intravenously and detected the nanoparticles after 30 min in the kidney, where they persisted for 72 h. Renal or systemic toxicity was not observed.