Nanomedicines for kidney diseases

Nanomedicines have been the subject of great interest for the treatment, diagnosis, and research of disease; however, few specifically address kidney disorders. Nanotechnology can confer significant benefits to medicine, such as the targeted delivery of drugs to specific tissues. Nanomedicines in the clinic have increased drug solubility, reduced off-target side effects, and provided novel diagnostic tools. There is an increasing cohort of nanomaterials that may have implications for kidney disease. Here, we review nanomaterial properties that are potentially applicable to kidney research and therapy, and we highlight clinical areas of need that may benefit from kidney nanomedicines. Nanomedicines have been the subject of great interest for the treatment, diagnosis, and research of disease; however, few specifically address kidney disorders. Nanotechnology can confer significant benefits to medicine, such as the targeted delivery of drugs to specific tissues. Nanomedicines in the clinic have increased drug solubility, reduced off-target side effects, and provided novel diagnostic tools. There is an increasing cohort of nanomaterials that may have implications for kidney disease. Here, we review nanomaterial properties that are potentially applicable to kidney research and therapy, and we highlight clinical areas of need that may benefit from kidney nanomedicines. Nanomaterials can loosely be defined as engineered macromolecules in the size range of 1 to 1000 nm.1Duncan R. Gaspar R. Nanomedicine (s) under the microscope.Mol Pharm. 2011; 8: 2101-2141Crossref PubMed Scopus (753) Google Scholar The types of materials involved are broad and can include lipids, modified biomacromolecules, polymers, metals, semiconductors, and others. Many nanomaterials have unique physical properties conferred by their size. One of the most common uses of nanoparticles (NPs) is in the delivery and controlled release of therapeutic molecules. Nanomaterials have been engineered to incorporate small molecule drugs as well as macromolecules such as nucleic acids, proteins, and peptides. One advantage of encapsulating therapeutic drugs in NPs includes the suspension of otherwise insoluble drugs.2Singh R. Lillard J.W. Nanoparticle-based targeted drug delivery.Exp Mol Pathol. 2009; 86: 215-223Crossref PubMed Scopus (1901) Google Scholar Perhaps the greatest promise of nanomedicines for drug delivery applications is the ability to control drug pharmacokinetics.1Duncan R. Gaspar R. Nanomedicine (s) under the microscope.Mol Pharm. 2011; 8: 2101-2141Crossref PubMed Scopus (753) Google Scholar Many potentially therapeutic molecules exhibit poor pharmacokinetics, especially with respect to the kidneys. Many small molecule therapies are cleared from the body renally, but their persistence in the kidneys is too brief to achieve a therapeutic effect. Compounds that are cleared by hepatobiliary mechanisms may have even less exposure to the kidneys. The targeting of NPs to specific organs, tissues, and cells in the body would allow for the reduction of off-target side effects of drugs that produce toxicities when administered conventionally. The physical targeting of drugs may also enable a reduction in the total administered dose, as more payload is available at the disease site instead of healthy organs.3Wang A.Z. Langer R. Farokhzad O.C. Nanoparticle delivery of cancer drugs.Annu Rev Med. 2012; 63: 185-198Crossref PubMed Scopus (1229) Google Scholar Targeting is often achieved through the use of molecular recognition entities such as antibodies, peptides, nucleic acids, or small molecules, which may be attached to or coat NPs.3Wang A.Z. Langer R. Farokhzad O.C. Nanoparticle delivery of cancer drugs.Annu Rev Med. 2012; 63: 185-198Crossref PubMed Scopus (1229) Google Scholar Nanomaterials incorporating therapeutic molecules can be engineered to control the rate of drug release. Nanomedicines can be administered in a depot format, allowing timed-release and single-dose administrations to achieve an optimal therapeutic index.4Peer D. Karp J.M. Hong S. et al.Nanocarriers as an emerging platform for cancer therapy.Nat Nanotechnol. 2007; 2: 751-760Crossref PubMed Scopus (6912) Google Scholar Also, NPs may protect encapsulated molecules from degradation in the body.3Wang A.Z. Langer R. Farokhzad O.C. Nanoparticle delivery of cancer drugs.Annu Rev Med. 2012; 63: 185-198Crossref PubMed Scopus (1229) Google Scholar This strategy can be combined with encapsulation or conjugation of therapeutic or imaging payloads to design a functional material. NPs can also have other desirable therapeutic properties. Among these is the potential for photothermal therapy, often in oncology applications. Nanomaterials composed of certain metals including gold and silver can produce an increase in local temperature because of light-induced plasmon resonance—a physical property that can only be exploited at nanoscale dimensions.5El-Sayed I.H. Huang X. El-Sayed M.A. Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles.Cancer Lett. 2006; 239: 129-135Abstract Full Text Full Text PDF PubMed Scopus (1184) Google Scholar Such plasmonic nanomaterials are often targeted by molecular recognition entities to specific tissues before exposure to light, producing a temperature elevation to kill the targeted cells. Another potential therapeutic use of nanomaterials is the selective sequestration and removal of toxic substances, often through the use of magnetic nanomaterials.6Hu C.-M.J. Fang R.H. Copp J. et al.A biomimetic nanosponge that absorbs pore-forming toxins.Nat Nanotechnol. 2013; 8: 336-340Crossref PubMed Scopus (510) Google Scholar The intrinsic properties of certain nanomaterials, most often metallic, may facilitate applications in medical diagnostics. NPs are often considered as contrast agents for magnetic resonance imaging (MRI) and computed tomography because of intrinsic paramagnetic or electron-dense material properties, or the ability to encapsulate radiometals.7Popovtzer R. Agrawal A. Kotov N.A. et al.Targeted gold nanoparticles enable molecular CT imaging of cancer.Nano Lett. 2008; 8: 4593-4596Crossref PubMed Scopus (668) Google Scholar, 8Na H.B. Song I.C. Hyeon T. Inorganic nanoparticles for MRI contrast agents.Adv Mater. 2009; 21: 2133-2148Crossref Scopus (1506) Google Scholar, 9Ananta J.S. Godin B. Sethi R. et al.Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T1 contrast.Nat Nanotechnol. 2010; 5: 815-821Crossref PubMed Scopus (344) Google Scholar Such materials have the potential to prevent renal toxicity of conventional contrast agents. Other diagnostic functions of NPs can stem from properties specific to nanoscale materials, such as gold NPs developed to detect cancer facilitated by the signal enhancement afforded by plasmon resonance effects.10El-Sayed I.H. Huang X. El-Sayed M.A. Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer.Nano Lett. 2005; 5: 829-834Crossref PubMed Scopus (1762) Google Scholar ‘Theranostics’ are technologies, often involving nanomaterials, with both diagnostic and therapeutic capabilities. Some examples pair the two capabilities, allowing the technology to monitor or control the administration of therapy.11Xie J. Lee S. Chen X. Nanoparticle-based theranostic agents.Adv Drug Deliv Rev. 2010; 62: 1064-1079Crossref PubMed Scopus (1119) Google Scholar An important application of nanotechnologies in the biomedical sciences is in the development of new research tools. Nanotechnologies are being developed to monitor analytes and processes in tissue culture and in vivo, including blood flow, renal filtration, and cardiovascular function.12Pankhurst Q.A. Connolly J. Jones S. et al.Applications of magnetic nanoparticles in biomedicine.J Phys D Appl Phys. 2003; 36: R167Crossref Scopus (5427) Google Scholar Examples of a commercially available nanomaterial are quantum dots, which are semiconductor nanocrystals that emit bright fluorescence due to the quantum confinement effect.13Michalet X. Pinaud F.F. Bentolila L.A. et al.Quantum dots for live cells, in vivo imaging, and diagnostics.Science. 2005; 307: 538-544Crossref PubMed Scopus (7045) Google Scholar The fluorescence output of quantum dots is relatively photostable and depends on tunable properties such as NP size and chemical composition, facilitating multicolor imaging capabilities. The localization of nanomaterials to specific sites in the body can be modulated by changing particle size and surface chemistry, including the attachment of molecular recognition entities14Williams R.M. Shah J. Ng B.D. et al.Mesoscale nanoparticles selectively target the renal proximal tubule epithelium.Nano Lett. 2015; 15: 2358-2364Crossref PubMed Scopus (95) Google Scholar (Figure 1). Depending on these factors, NPs can be targeted to specific parts of the nephron, may be filtered by the kidneys, or may avoid the kidneys entirely. Currently, the overwhelming majority of nanomaterials synthesized and intravenously administered to animals are known to accumulate in the liver and spleen.14Williams R.M. Shah J. Ng B.D. et al.Mesoscale nanoparticles selectively target the renal proximal tubule epithelium.Nano Lett. 2015; 15: 2358-2364Crossref PubMed Scopus (95) Google Scholar NPs smaller than 200 nm in diameter can extravasate through fenestrations in the liver endothelium. In addition, NPs can be taken up by macrophages that migrate to the liver, lymph nodes, and spleen, or by macrophages resident to liver sinusoids (Kupffer cells).15Owens D.E. Peppas N.A. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles.Int J Pharm. 2006; 307: 93-102Crossref PubMed Scopus (2821) Google Scholar Macrophage uptake is mediated in part by NP opsonization—the binding to serum proteins—which marks them for phagocytosis as part of the complement activation cascade.15Owens D.E. Peppas N.A. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles.Int J Pharm. 2006; 307: 93-102Crossref PubMed Scopus (2821) Google Scholar This process can be avoided to some degree by reducing the likelihood of opsonization of the NP by altering its surface chemistry. This is often done by attaching polyethylene glycol to the NP.14Williams R.M. Shah J. Ng B.D. et al.Mesoscale nanoparticles selectively target the renal proximal tubule epithelium.Nano Lett. 2015; 15: 2358-2364Crossref PubMed Scopus (95) Google Scholar, 15Owens D.E. Peppas N.A. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles.Int J Pharm. 2006; 307: 93-102Crossref PubMed Scopus (2821) Google Scholar Microparticles, which are above the nanoscale size range (>1000 nm), can accumulate in the lungs by retention in alveolar capillaries.16Azarmi S. Roa W.H. Lobenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases.Adv Drug Deliv Rev. 2008; 60: 863-875Crossref PubMed Scopus (354) Google Scholar Methods for targeting NPs to tissues and disease sites in the body other than the kidneys have been reviewed extensively elsewhere.17Schroeder A. Heller D.A. Winslow M.M. et al.Treating metastatic cancer with nanotechnology.Nat Rev Cancer. 2012; 12: 39-50Crossref Scopus (890) Google Scholar, 18Steichen S.D. Caldorera-Moore M. Peppas N.A. A review of current nanoparticle and targeting moieties for the delivery of cancer therapeutics.Eur J Pharm Sci. 2013; 48: 416-427Crossref PubMed Scopus (591) Google Scholar NP size, chemistry, and payload can be modified extensively to modulate their pharmacologic properties.15Owens D.E. Peppas N.A. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles.Int J Pharm. 2006; 307: 93-102Crossref PubMed Scopus (2821) Google Scholar, 19Medintz I.L. Mattoussi H. Clapp A.R. Potential clinical applications of quantum dots.Int J Nanomedicine. 2008; 3: 151PubMed Google Scholar Many nanomaterials exhibit renal clearance. This is a highly desirable pharmacokinetic property for elimination of potentially toxic metal nanomaterials, such as those used for diagnostic imaging.20Liu J. Yu M. Zhou C. et al.Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology.Materials Today. 2013; 16: 477-486Crossref Scopus (246) Google Scholar To be cleared by renal filtration, NPs must be small enough to pass through the glomerular endothelial fenestrae (∼100 nm) and the podocyte slit diaphragm (∼8-nm pores).20Liu J. Yu M. Zhou C. et al.Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology.Materials Today. 2013; 16: 477-486Crossref Scopus (246) Google Scholar Renal filtration may allow for the imaging of the kidney during the excretion process21Hainfeld J. Slatkin D. Focella T. Smilowitz H.M. Gold nanoparticles: a new X-ray contrast agent.Br J Radiol. 2014; 79: 248-253Crossref Scopus (1123) Google Scholar and to study renal functions.22Choi H.S. Liu W. Misra P. et al.Renal clearance of quantum dots.Nat Biotechnol. 2007; 25: 1165-1170Crossref PubMed Scopus (3387) Google Scholar There are no clinically approved NPs that specifically target the kidney for therapeutic or imaging applications. However, several recent preclinical studies describe nanomaterials that appear to selectively target renal tissues. Various studies describe the targeting of NPs to the glomerulus, portending the targeted treatment and imaging of this part of the kidney.23Zuckerman J.E. Davis M.E. Targeting therapeutics to the glomerulus with nanoparticles.Adv Chronic Kidney Dis. 2013; 20: 500-507Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Within the glomerulus, NPs have been shown to target the glomerular basement membrane and mesangial cells.24Bennett K.M. Zhou H. Sumner J.P. et al.MRI of the basement membrane using charged nanoparticles as contrast agents.Magn Reson Med. 2008; 60: 564-574Crossref PubMed Scopus (80) Google Scholar, 25Choi C.H.J. Zuckerman J.E. Webster P. et al.Targeting kidney mesangium by nanoparticles of defined size.Proc Natl Acad Sci U S A. 2011; 108: 6656-6661Crossref PubMed Scopus (336) Google Scholar, 26Zuckerman J.E. Choi C.H.J. Han H. et al.Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.Proc Natl Acad Sci U S A. 2012; 109: 3137-3142Crossref PubMed Scopus (271) Google Scholar One study describes the localization of polyethylene glycol–coated gold NPs 80 nm in diameter in mesangial cells, although the majority of the particles accumulated in the liver.25Choi C.H.J. Zuckerman J.E. Webster P. et al.Targeting kidney mesangium by nanoparticles of defined size.Proc Natl Acad Sci U S A. 2011; 108: 6656-6661Crossref PubMed Scopus (336) Google Scholar Follow-up work has suggested that similarly sized NPs transporting small interfering RNA (siRNA), composed of cationic polymers, can accumulate and disassemble in the glomerular basement membrane.26Zuckerman J.E. Choi C.H.J. Han H. et al.Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.Proc Natl Acad Sci U S A. 2012; 109: 3137-3142Crossref PubMed Scopus (271) Google Scholar NP surface charge appears to affect glomerular deposition. Cationic ferritin NPs 13 nm in diameter accumulated in the rat glomerular basement membrane, while negatively charged ferritin NPs did not.24Bennett K.M. Zhou H. Sumner J.P. et al.MRI of the basement membrane using charged nanoparticles as contrast agents.Magn Reson Med. 2008; 60: 564-574Crossref PubMed Scopus (80) Google Scholar Additionally, investigators have conjugated specific targeting agents such as antibodies to nanomaterials to increase their glomerular localization (also reviewed in the article by Zuckerman and Davis23Zuckerman J.E. Davis M.E. Targeting therapeutics to the glomerulus with nanoparticles.Adv Chronic Kidney Dis. 2013; 20: 500-507Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). There have been few successful attempts to develop NPs that target the renal tubules. One described strategy is the engineering of NPs small enough to pass through the glomerular filtration barrier, which subsequently could be absorbed by epithelial cells lining the lumen of the nephron.27Sancey L. Kotb S. Truillet C. et al.Long-term in vivo clearance of gadolinium-based AGuIX nanoparticles and their biocompatibility after systemic injection.ACS Nano. 2015; 9: 2477-2488Crossref PubMed Scopus (120) Google Scholar, 28Nair A.V. Keliher E.J. Core A.B. et al.Characterizing the interactions of organic nanoparticles with renal epithelial cells in vivo.ACS Nano. 2015; 9: 3641-3653Crossref PubMed Scopus (45) Google Scholar This strategy is similar to that used for low molecular-weight polymers and proteins.29Dolman M. Harmsen S. Storm G. et al.Drug targeting to the kidney: advances in the active targeting of therapeutics to proximal tubular cells.Adv Drug Deliv Rev. 2010; 62: 1344-1357Crossref PubMed Scopus (114) Google Scholar A second strategy has used biodegradable nanomaterials that pass through glomerular endothelial fenestrations but not the glomerular basement membrane.30Gao S. Hein S. Dagnæs-Hansen F. et al.Megalin-mediated specific uptake of chitosan/siRNA nanoparticles in mouse kidney proximal tubule epithelial cells enables AQP1 gene cilencing.Theranostics. 2014; 4: 1039Crossref PubMed Scopus (67) Google Scholar The hypothesized mechanism of uptake was degradation of the NP at this deposition site and subsequent megalin-mediated uptake of the degradation products by the luminal membrane of proximal tubular epithelial cells. The authors of this review recently found selective targeting of the proximal tubules by large “mesoscale” NPs that were much larger (∼400 nm) than the fenestration of the glomerular basement membrane.14Williams R.M. Shah J. Ng B.D. et al.Mesoscale nanoparticles selectively target the renal proximal tubule epithelium.Nano Lett. 2015; 15: 2358-2364Crossref PubMed Scopus (95) Google Scholar The authors hypothesized a mechanism whereby the NPs transcytosed across peritubular capillaries to be endocytosed by proximal tubule epithelial cells from the basal size of the tubule. These NPs localized in the kidneys with high specificity—up to 7 times greater than any other organ (Figure 2). Many nanotherapeutics have entered clinical trials, and several nanomedicines have achieved Food and Drug Administration approval for use in patients. Several nanomedicines are approved for use in oncology. The first Food and Drug Administration–approved therapeutic NP was Doxil in 1995, a PEGylated liposome-encapsulating doxorubicin designed to reduce cardiotoxicity.31Barenholz Y.C. Doxil—the first FDA-approved nano-drug: lessons learned.J Control Release. 2012; 160: 117-134Crossref PubMed Scopus (2750) Google Scholar Other chemotherapeutic-encapsulating nanoformulations that have progressed to the clinic include daunorubicin (DaunoXome), cytarabine (DepoCyt), and protein-bound paclitaxel (Abraxane).32Lytton-Jean A.K. Kauffman K.J. Kaczmarek J.C. et al.Cancer nanotherapeutics in clinical trials.in: Mirkin C.A. Meade T.J. Hurst Petrosko S. Stegh A.H. Nanotechnology-Based Precision Tools for the Detection and Treatment of Cancer. Springer, Cham, Switzerland2015: 293-322Crossref Scopus (32) Google Scholar NP-based contrast agents have also been approved for use in the clinic. These include Technetium-99m sulfur colloid, a radiopharmaceutical used for sentinel lymph node mapping in breast cancer,33Newman E.A. Newman L.A. Lymphatic mapping techniques and sentinel lymph node biopsy in breast cancer.Surg Clin N Am. 2007; 87: 353-364Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar and ferumoxides (Feridex), a superparamagnetic iron oxide NP for MRI of lymph node and liver metastases.34Choi H.S. Frangioni J.V. Nanoparticles for biomedical imaging: fundamentals of clinical translation.Mol Imaging. 2010; 9: 291PubMed Google Scholar A review listing nanomaterials in clinical trials or already Food and Drug Administration approved has been published recently.32Lytton-Jean A.K. Kauffman K.J. Kaczmarek J.C. et al.Cancer nanotherapeutics in clinical trials.in: Mirkin C.A. Meade T.J. Hurst Petrosko S. Stegh A.H. Nanotechnology-Based Precision Tools for the Detection and Treatment of Cancer. Springer, Cham, Switzerland2015: 293-322Crossref Scopus (32) Google Scholar Given recent technological developments of nanomaterials and new capabilities for interactions with the kidneys, great potential lies in their application for the treatment, diagnosis, and research of kidney diseases (Table 1). We describe potential disease applications below and note recent examples of kidney nanomedicine investigations.Table 1Kidney disease applications of nanotechnologies, suggested and under investigationDiseaseDisease originNanotechnology applicationsHypertensionTubules and renal vasculatureFree radical scavenger,39Ankola D.D. Viswanad B. Bhardwaj V. et al.Development of potent oral nanoparticulate formulation of coenzyme Q10 for treatment of hypertension: can the simple nutritional supplements be used as first line therapeutic agents for prophylaxis/therapy?.Eur J Pharm Biopharm. 2007; 67: 361-369Crossref PubMed Scopus (107) Google Scholar vasodilator,40Ghosh S. Chiang P.C. Wahlstrom J.L. et al.Oral delivery of 1,3-dicyclohexylurea nanosuspension enhances exposure and lowers blood pressure in hypertensive rats.Basic Clin Pharmacol Toxicol. 2008; 102: 453-458Crossref PubMed Scopus (34) Google Scholar siRNA delivery42Lu P. Yuan L. Wang Y. et al.Effect of GPE-AGT nanoparticle shRNA transfection system mediated RNAi on early atherosclerotic lesion.Int J Clin Exp. Pathol. 2012; 5: 698-706PubMed Google ScholarAcute kidney injuryProximal tubuleMRI imaging,35Kobayashi H. Jo S.K. Kawamoto S. et al.Polyamine dendrimer-based MRI contrast agents for functional kidney imaging to diagnose acute renal failure.J Magn Reson Imaging. 2004; 20: 512-518Crossref PubMed Scopus (68) Google Scholar, 36Hauger O. Delalande C. Deminiere C. et al.Nephrotoxic nephritis and obstructive nephropathy: evaluation with MR imaging enhanced with ultrasmall superparamagnetic iron oxide-preliminary findings in a rat model.Radiology. 2000; 217: 819-826Crossref PubMed Scopus (74) Google Scholar free radical scavenger,50Manne N.D. Arvapalli R. Nepal N. et al.Cerium oxide nanoparticles attenuate acute kidney injury induced by intra-abdominal infection in Sprague-Dawley rats.J Nanobiotechnol. 2015; 13: 75Crossref PubMed Scopus (39) Google Scholar thrombin inhibitor delivery51Chen J. Vemuri C. Palekar R.U. et al.Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury.Am J Physiol Renal Physiol. 2015; 308: F765-F773Crossref PubMed Scopus (27) Google ScholarChronic kidney diseaseGlomerulus and renal interstitiumsiRNA53Zuckerman J.E. Gale A. Wu P. et al.siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.Nucleic Acid Ther. 2015; 25: 53-64Crossref PubMed Scopus (43) Google Scholar and small molecule delivery, detection in exhaled breath,56Marom O. Nakhoul F. Tisch U. et al.Gold nanoparticle sensors for detecting chronic kidney disease and disease progression.Nanomedicine. 2012; 7: 639-650Crossref PubMed Scopus (81) Google Scholar magnetically assisted hemodialysis,57Stamopoulos D. Bouziotis P. Benaki D. et al.Utilization of nanobiotechnology in haemodialysis: mock-dialysis experiments on homocysteine.Nephrol Dial Transplant. 2008; 23: 3234-3239Crossref PubMed Scopus (19) Google Scholar, 58Stamopoulos D. Manios E. Gogola V. et al.Bare and protein-conjugated Fe(3)O(4) ferromagnetic nanoparticles for utilization in magnetically assisted hemodialysis: biocompatibility with human blood cells.Nanotechnology. 2008; 19: 505101Crossref PubMed Scopus (29) Google Scholar, 61Spinowitz B.S. Kausz A.T. Baptista J. et al.Ferumoxytol for treating iron deficiency anemia in CKD.J Am Soc Nephrol. 2008; 19: 1599-1605Crossref PubMed Scopus (213) Google Scholar, 62Provenzano R. Schiller B. Rao M. et al.Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients.Clin J Am Soc Nephrol. 2009; 4: 386-393Crossref PubMed Scopus (164) Google Scholar resistant infections in peritoneal dialysis59Ortega A. Farah S. Tranque P. et al.Antimicrobial evaluation of quaternary ammonium polyethyleneimine nanoparticles against clinical isolates of pathogenic bacteria.IET Nanobiotechnol. 2015; 9: 342-348Crossref PubMed Scopus (21) Google Scholar, 60Santamaría B. Benito-Martin A. Ucero A.C. et al.A nanoconjugate Apaf-1 inhibitor protects mesothelial cells from cytokine-induced injury.PLoS One. 2009; 4: e6634Crossref PubMed Scopus (30) Google ScholarGlomerular diseasesGlomerulusImmunosuppressive agent delivery65Liao J. Hayashi K. Horikoshi S. et al.Effect of steroid-liposome on immunohistopathology of IgA nephropathy in ddY mice.Nephron. 2001; 89: 194-200Crossref PubMed Scopus (28) Google Scholar, 66Suana A.J. Tuffin G. Frey B.M. et al.Single application of low-dose mycophenolate mofetil-OX7-immunoliposomes ameliorates experimental mesangial proliferative glomerulonephritis.J Pharmacol Exp Ther. 2011; 337: 411-422Crossref PubMed Scopus (29) Google Scholar, 67Asgeirsdottir S.A. Kamps J.A. Bakker H.I. et al.Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium.Mol Pharmacol. 2007; 72: 121-131Crossref PubMed Scopus (71) Google Scholar, 68Shimizu H. Hori Y. Kaname S. et al.siRNA-based therapy ameliorates glomerulonephritis.J Am Soc Nephrol. 2010; 21: 622-633Crossref PubMed Scopus (71) Google ScholarKidney cancerProximal tubulePotential for targeted drug deliveryMRI, magnetic resonance imaging; siRNA, small interfering RNA. Open table in a new tab MRI, magnetic resonance imaging; siRNA, small interfering RNA. NP-based MRI has been used as a strategy to detect early changes that could be consistent with acute kidney injury (AKI). Dendrimer-based nanomaterials for MRI have been shown to detect changes consistent with AKI before a rise in creatinine in mouse models.35Kobayashi H. Jo S.K. Kawamoto S. et al.Polyamine dendrimer-based MRI contrast agents for functional kidney imaging to diagnose acute renal failure.J Magn Reson Imaging. 2004; 20: 512-518Crossref PubMed Scopus (68) Google Scholar A dendrimer is a repetitively branched polymer that takes the form of a sphere. In rat models of renal injury, ultra-small superparamagnetic iron oxide NPs have been used for MRI imaging, allowing the distinction between renal intrinsic disease and obstructive uropathy, as well as to identify the signs of kidney rejection.36Hauger O. Delalande C. Deminiere C. et al.Nephrotoxic nephritis and obstructive nephropathy: evaluation with MR imaging enhanced with ultrasmall superparamagnetic iron oxide-preliminary findings in a rat model.Radiology. 2000; 217: 819-826Crossref PubMed Scopus (74) Google Scholar Silica NPs with fluorescent anti-CD11 also have been used as an imaging tool for inflammation and fibrosis in animal models of obstructive uropathy.37Shirai T. Kohara H. Tabata Y. Inflammation imaging by silica nanoparticles with antibodies orientedly immobilized.J Drug Target. 2012; 20: 535-543Crossref PubMed Scopus (14) Google Scholar Several NP formulations have been used experimentally for the treatment of hypertension as a strategy to overcome problems associated with delivery and bioavailability of specific agents. The free-radical scavenger coenzyme Q10 has shown some potential in the treatment of hypertension by inducing vascular relaxation.38Digiesi V. Cantini F. Oradei A. et al.Coenzyme Q10 in essential hypertension.Mol Aspects Med. 1994; 15: s257-s263Crossref PubMed Scopus (91) Google Scholar Poly(lactic-co-glycolic acid)–formulated NPs containing coenzyme Q10 were found to have greater oral bioavailability and to effectively reduce blood pressure in an animal model of hypertension.39Ankola D.D. Viswanad B. Bhardwaj V. et al.Development of potent oral nanoparticulate formulation of coenzyme Q10 for treatment of hypertension: can the simple nutritional supplements be used as first line therapeutic agents for prophylaxis/therapy?.Eur J Pharm Biopharm. 2007; 67: 361-369Crossref PubMed Scopus (107) Google Scholar Nano-suspensions containing 1,3-Dicyclohexyl urea, a potent inhibitor of the degradation of the vasodilatory eicosanoid epoxyeicosatrienoic acid, were shown to be orally bioavailable and effective in reducing blood pressure in animal models of hypertension.40Ghosh S. Chiang P.C. Wahlstrom J.L. et al.Oral delivery of 1,3-dicyclohexylurea nanosuspension enhances exposure and lowers blood pressure in hypertensive rats.Basic Clin Pharmacol Toxicol. 2008; 102: 453-458Crossref PubMed Scopus (34) Google Scholar NPs loaded with siRNA against angiotensinogen were also shown to effectively reduce blood pressure in rat models of hypertension,41Olearczyk J. Gao S. Eybye M. et al.Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension.Hypertens Res. 2014; 37: 405-412Crossref PubMed Scopus (26) Google Scholar, 42Lu P. Yuan L. Wang Y. et al.Effect of GPE-AGT nanoparticle shRNA transfection system mediated RNAi on early atherosclerotic lesion.Int J Clin Exp. Pathol. 2012; 5: 698-706PubMed Google Scholar and nano-formulated superoxide dismutase has been shown to attenuate angiotensin II-induced hypertension.43Savalia K. Manickam D.S. Rosenbaugh E.G. et al.Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration.Free Radic Biol. Med. 2014; 73: 299-307Crossref PubMed Scopus (20) Google Scholar In addition, nanomedicines have been used to increase the bioavailability of drugs already in use for hypertension, including nebivolol, candesartan, felodipine, olmesartan, and ramipril.44Üstündağ-Okur N. Yurdasiper A. Gündoğdu E. Homan Göçke E. Modification of solid lipid nanoparticles loaded with nebivolol hydrochloride for improvement of oral bioavailability in treatment of hypertension: polyethylene glycol versus chitosan oligosaccharide lactate.J Microencapsul. 2016; 33: 30-42Crossref PubMed Scopus (14) Google Scholar, 45Dudhipala N. Veerabrahma K. Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation.Drug Deliv. 2016; 23: 395-404Crossref PubMed Scopus (95) Google Scholar, 46Shah U. Joshi G. Sawant K. Improvement in antihypertensive and antianginal effects of felodipine by enhanced absorption from PLGA nanoparticles optimized by factorial design.Mater Sci Eng C Mater Biol Appl. 2014; 35: 153-163Crossref PubMed Scopus (48) Google Scholar, 47Gorain B. Choudhury H. Kundu A. et al.Nanoemulsion strategy for olmesartan medoxomil improves oral absorption and extended antihypertensive activity in hypertensive rats.Colloids Surf B Biointerfaces. 2014; 115: 286-294Crossref PubMed Scopus (113) Google Scholar, 48Ekambaram P. Abdul H.S. Formulation and evaluation of solid lipid nanoparticles of ramipril.J Young Pharm. 2011; 3: 216-220Abstract Full Text PDF PubMed Scopus (118) Google Scholar AKI is a complex disease in which a variety of mediators play an important role, including nitric oxide (NO), reactive oxygen species, proinflammatory and profibrotic cytokines, among others.49Bonventre J.V. Yang L. Cellular pathophysiology of ischemic acute kidney injury.J Clin Invest. 2011; 121: 4210-4221Crossref PubMed Scopus (1326) Google Scholar Given the paucity of effective therapies for AKI, the use of NP-based approaches to deliver molecules specifically to the kidney to treat AKI is attractive and it is starting to be explored in animal models. Cerium oxide NPs that scavenge reactive oxygen species reduced AKI severity in a rat model of peritonitis-induced AKI.50Manne N.D. Arvapalli R. Nepal N. et al.Cerium oxide nanoparticles attenuate acute kidney injury induced by intra-abdominal infection in Sprague-Dawley rats.J Nanobiotechnol. 2015; 13: 75Crossref PubMed Scopus (39) Google Scholar Treatment with a thrombin-inhibiting NP was shown to improve renal function in mice when administered after induction of AKI.51Chen J. Vemuri C. Palekar R.U. et al.Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury.Am J Physiol Renal Physiol. 2015; 308: F765-F773Crossref PubMed Scopus (27) Google Scholar Further, antiapoptotic peptoid nanoconjugates have also shown efficacy against AKI.52Ucero Á.C. Berzal S. Ocaña-Salceda C. et al.A polymeric nanomedicine diminishes inflammatory events in renal tubular cells.PloS One. 2013; 8: e51992Crossref PubMed Scopus (31) Google Scholar Few studies have explored nanomedicines for the treatment of chronic kidney disease (CKD). Recent investigations have demonstrated the delivery of polycationic cyclodextrin NPs containing siRNA (siRNA/CDP-NPs) to the glomerular mesangium in mice, which could be used for the delivery of siRNA against specific targets.53Zuckerman J.E. Gale A. Wu P. et al.siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.Nucleic Acid Ther. 2015; 25: 53-64Crossref PubMed Scopus (43) Google Scholar Additionally, kidney-specific hepatocyte growth factor gene delivery using a peptide-conjugated poly(ester amine) has shown promise for the reduction of renal fibrosis in a model of obstructive uropathy.54Kim Y.K. Kwon J.T. Jiang H.L. et al.Kidney-specific peptide-conjugated poly(ester amine) for the treatment of kidney fibrosis.J Nanosci Nanotechnol. 2012; 12: 5149-5154Crossref PubMed Scopus (15) Google Scholar In a mouse model of obstructive uropathy, treatment with chitosan/siRNA against cyclooxygenase 2 was associated with reduced severity of tubular injury and inflammation and reduced expression of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6.55Yang C. Nilsson L. Cheema M.U. et al.Chitosan/siRNA nanoparticles targeting cyclooxygenase type 2 attenuate unilateral ureteral obstruction-induced kidney injury in mice.Theranostics. 2015; 5: 110-123Crossref PubMed Scopus (59) Google Scholar NP-based technology also has been tested for the early diagnosis of CKD. Gold NP-based sensors were used to measure differences in exhaled air from early-stage CKD subjects as well as in animal models of CKD.56Marom O. Nakhoul F. Tisch U. et al.Gold nanoparticle sensors for detecting chronic kidney disease and disease progression.Nanomedicine. 2012; 7: 639-650Crossref PubMed Scopus (81) Google Scholar Nanomaterials have the potential to improve dialysis efficacy in patients with end-stage renal disease. The use of magnetically assisted hemodialysis is a potentially promising method. In this modality, ferromagnetic NPs are conjugated to targeting moieties with high affinity for uremic toxins. Experiments using an in vitro system of mock dialysis demonstrated the effective removal of homocysteine with ferromagnetic NPs. This approach could potentially be used for the removal of toxins not adequately removed by conventional hemodialysis.57Stamopoulos D. Bouziotis P. Benaki D. et al.Utilization of nanobiotechnology in haemodialysis: mock-dialysis experiments on homocysteine.Nephrol Dial Transplant. 2008; 23: 3234-3239Crossref PubMed Scopus (19) Google Scholar, 58Stamopoulos D. Manios E. Gogola V. et al.Bare and protein-conjugated Fe(3)O(4) ferromagnetic nanoparticles for utilization in magnetically assisted hemodialysis: biocompatibility with human blood cells.Nanotechnology. 2008; 19: 505101Crossref PubMed Scopus (29) Google Scholar Additionally, polymeric antiapoptotic nanoconjugates may hold promise in the prevention of mesothelial cell injury in peritonitis, and NPs may also reduce resistant infections in peritoneal dialysis.59Ortega A. Farah S. Tranque P. et al.Antimicrobial evaluation of quaternary ammonium polyethyleneimine nanoparticles against clinical isolates of pathogenic bacteria.IET Nanobiotechnol. 2015; 9: 342-348Crossref PubMed Scopus (21) Google Scholar, 60Santamaría B. Benito-Martin A. Ucero A.C. et al.A nanoconjugate Apaf-1 inhibitor protects mesothelial cells from cytokine-induced injury.PLoS One. 2009; 4: e6634Crossref PubMed Scopus (30) Google Scholar The treatment of anemia associated with end-stage renal disease and CKD is also a potential use of NPs in this patient population. Several clinical trials have shown that ferumoxytol, a superparamagnetic iron oxide NP, is more effective in improving iron levels and decreasing side effects as compared with the administration of oral or non-nanoscale iron.61Spinowitz B.S. Kausz A.T. Baptista J. et al.Ferumoxytol for treating iron deficiency anemia in CKD.J Am Soc Nephrol. 2008; 19: 1599-1605Crossref PubMed Scopus (213) Google Scholar, 62Provenzano R. Schiller B. 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In a mouse model of IgA nephropathy, treatment with TRX20-prednisolone–loaded liposomes reduced IgA and C3 deposition to a higher degree as compared with prednisolone alone.65Liao J. Hayashi K. Horikoshi S. et al.Effect of steroid-liposome on immunohistopathology of IgA nephropathy in ddY mice.Nephron. 2001; 89: 194-200Crossref PubMed Scopus (28) Google Scholar In the anti-Thy1 model of acute nephritis, TRX20 liposomes significantly reduced the glomerular cell proliferation characteristic of this model. Mycophenolatemofetil-OX-immunoliposomes have also demonstrated a benefit by reducing the severity of inflammation and extracellular matrix expansion.66Suana A.J. Tuffin G. Frey B.M. et al.Single application of low-dose mycophenolate mofetil-OX7-immunoliposomes ameliorates experimental mesangial proliferative glomerulonephritis.J Pharmacol Exp Ther. 2011; 337: 411-422Crossref PubMed Scopus (29) Google Scholar In a mouse model of antiglomerular basement membrane, E-selectin antibody-targeted immunoliposomes resulted in a significant improvement in renal function and downregulation of proinflammatory genes.67Asgeirsdottir S.A. Kamps J.A. Bakker H.I. et al.Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium.Mol Pharmacol. 2007; 72: 121-131Crossref PubMed Scopus (71) Google Scholar In MRL/lpr mice, a lupus nephritis model, siRNA/cationic polymer micelles reduced glomerular MAPK-1 expression and ameliorated kidney injury.68Shimizu H. Hori Y. Kaname S. et al.siRNA-based therapy ameliorates glomerulonephritis.J Am Soc Nephrol. 2010; 21: 622-633Crossref PubMed Scopus (71) Google Scholar The use of biodegradable polymer NPs as a strategy for the controlled delivery of drugs has shown promise for the treatment of various types of cancer including prostate, breast, hepatocellular carcinoma, colon, lung, and ovaries, among others.17Schroeder A. Heller D.A. Winslow M.M. et al.Treating metastatic cancer with nanotechnology.Nat Rev Cancer. 2012; 12: 39-50Crossref Scopus (890) Google Scholar, 69Devulapally R. Paulmurugan R. Polymer nanoparticles for drug and small silencing RNA delivery to treat cancers of different phenotypes.Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014; 6: 40-60Crossref PubMed Scopus (52) Google Scholar Whether this strategy will also be effective in the treatment of kidney cancer has not been established. However, for the treatment of metastatic urothelial carcinoma, Abraxane (nanoparticle albumin-bound paclitaxel) was shown to be well tolerated and resulted in tumor response in 27.7% of patients, suggesting that this strategy could be an effective second-line therapy.70Ko Y.J. Canil C.M. Mukherjee S.D. et al.Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study.Lancet Oncol. 2013; 14: 769-776Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The nanotechnology field holds great potential for the diagnosis, imaging, and treatment of disease. An increasingly large body of preclinical work has demonstrated the potential for addressing renal diseases. In this review, we have outlined the applications of nanomedicines and highlighted recent work in the targeting of the kidneys. We also summarized the current state of the use of nanomaterials in renal disease treatment and diagnosis, and we pointed out several nephrological areas of need. We expect to see the increasing use of nanomaterials to fill technological gaps in the treatment and diagnosis of kidney diseases.