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Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice., (© 2024. The Author(s).)

Nanomaterials are the subject of a range of biomedical, commercial, and environmental investigations involving measurements in living cells and tissues. Accurate quantification of nanomaterials, at the tissue, cell, and organelle levels, is often difficult, however, in part due to their inhomogeneity. Here, we propose a method that uses the distinct optical properties of a heterogeneous nanomaterial preparation in order to improve quantification at the single-cell and organelle level. We developed "hyperspectral counting", which employs diffraction-limited imaging via hyperspectral microscopy of a diverse set of fluorescent nanomaterials to estimate particle number counts in live cells and subcellular structures. A mathematical model was developed, and Monte Carlo simulations were employed, to improve the accuracy of these estimates, enabling quantification with single-cell and single-endosome resolution. We applied this nanometrology technique with single-walled carbon nanotubes and identified an upper limit of the rate of uptake into cells─approximately 3,000 nanotubes endocytosed within 30 min. In contrast, conventional region-of-interest counting results in a 230% undercount. The method identified significant heterogeneity and a broad non-Gaussian distribution of carbon nanotube uptake within cells. For example, while a particular cell contained an average of 1 nanotube per endosome, the heterogeneous distribution resulted in over 7 nanotubes localizing within some endosomes, substantially changing the accounting of subcellular nanoparticle concentration distributions. This work presents a method to quantify the cellular and subcellular concentrations of a heterogeneous carbon nanotube reference material, with implications for the nanotoxicology, drug/gene delivery, and nanosensor fields.

We developed an innovative therapy for ischemic acute kidney injury with discerning kidney-targeted delivery of a selective Toll-like receptor 9 (TLR9) antagonist in mice subjected to renal ischemia reperfusion injury. Our previous studies showed that mice deficient in renal proximal tubular TLR9 were protected against renal ischemia reperfusion injury demonstrating a critical role for renal proximal tubular TLR9 in generating ischemic acute kidney injury. Herein, we used 300-400 nm polymer-based mesoscale nanoparticles that localize to the renal tubules after intravenous injection. Mice were subjected to sham surgery or 30 minutes renal ischemia and reperfusion injury after receiving mesoscale nanoparticles encapsulated with a selective TLR9 antagonist (unmethylated CpG oligonucleotide ODN2088) or mesoscale nanoparticles encapsulating a negative control oligonucleotide. Mice treated with the encapsulated TLR9 antagonist either six hours before renal ischemia, at the time of reperfusion or 1.5 hours after reperfusion were protected against ischemic acute kidney injury. The ODN2088-encapsulated nanoparticles attenuated renal tubular necrosis, inflammation, decreased proinflammatory cytokine synthesis. neutrophil and macrophage infiltration and apoptosis, decreased DNA fragmentation and caspase 3/8 activation when compared to the negative control nanoparticle treated mice. Taken together, our studies further suggest that renal proximal tubular TLR9 activation exacerbates ischemic acute kidney injury by promoting renal tubular inflammation, apoptosis and necrosis after ischemia reperfusion. Thus, our studies suggest a potential promising therapy for ischemic acute kidney injury with selective kidney tubular targeting of TLR9 using mesoscale nanoparticle-based drug delivery., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and drug-induced phospholipidosis. Current methods cannot monitor endolysosomal lipid content in vivo, hindering preclinical drug development and research into the mechanisms linking endolysosomal lipid accumulation to disease progression. We developed a single-walled carbon nanotube-based optical reporter that noninvasively measures endolysosomal lipid accumulation via bandgap modulation of its intrinsic near-infrared emission. The reporter detected lipid accumulation in Niemann-Pick disease, atherosclerosis, and NAFLD models in vivo. By applying the reporter to the study of NAFLD, we found that elevated lipid quantities in hepatic macrophages caused by a high-fat diet persist long after reverting to a normal diet. The reporter dynamically monitored endolysosomal lipid accumulation in vivo over time scales ranging from minutes to weeks, indicating its potential to accelerate preclinical research and drug development processes., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Direct targeting to the kidneys is a promising strategy to improve drug therapeutic index for the treatment of kidney diseases. We sought to investigate the renal selectivity and safety of kidney-targeted mesoscale nanoparticle technology. We found that direct intravenous administration of these particles resulted in 26-fold renal selectivity and localized negligibly in the liver or other organs. The nanoparticles targeted the renal proximal tubular epithelial cells, as evidenced by intravital microscopy and ex vivo imaging. Mice treated with the nanoparticles exhibited no negative systemic consequences, immune reaction, liver impairment, or renal impairment. The localization of material selectively to the renal tubules is uncommon, and this work portends the development of renal-targeted drugs for the treatment of kidney diseases., (© 2017 American Heart Association, Inc.)

Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu. This results in tumour growth inhibition and radiosensitization despite the use of a sevenfold lower dose of BYL719 compared with oral administration. Furthermore, the nanoparticles abrogate acute and chronic metabolic side effects normally observed after BYL719 treatment. These findings offer a novel strategy that could potentially enhance the efficacy of PI3Kα inhibitors while mitigating dose-limiting toxicity in patients with head and neck squamous cell carcinomas.

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., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor., (Copyright © 2016, American Association for the Advancement of Science.)

The cellular uptake and expulsion rates of length-fractionated single-walled carbon nanotubes (SWNT) from 130 to 660 nm in NIH-3T3 cells were measured via single particle tracking of their intrinsic photoluminescence. We develop a quantitative model to correlate endocytosis rate with nanoparticle geometry that accurately describes this data set and also literature results for Au nanoparticles. The model asserts that nanoparticles cluster on the cell membrane to form a size sufficient to generate a large enough enthalpic contribution via receptor ligand interactions to overcome the elastic energy and entropic barriers associated with vesicle formation. Interestingly, the endocytosis rate constant of SWNT (10(-3) min(-1)) is found to be nearly 1000 times that of Au nanoparticles (10(-6) min(-1)) but the recycling (exocytosis) rate constants are similar in magnitude (10(-4) to 10(-3) min(-1)) for poly(d,l-lactide-co-glycolide), SWNT, and Au nanoparticles across distinct cell lines. The total uptake of both SWNT and Au nanoparticles is maximal at a common radius of 25 nm when scaled using an effective capture dimension for membrane diffusion. The ability to understand and predict the cellular uptake of nanoparticles quantitatively should find utility in designing nanosystems with controlled toxicity, efficacy, and functionality.