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Selective Trafficking of Light Chain-Conjugated Nanoparticles to the Kidney and Renal Cell Carcinoma.

ABSTRACT: Specific delivery platforms for drugs to the kidney and diagnostic agents to renal cell carcinoma (RCC) constitute urgent but unfulfilled clinical needs. To address these challenges, we engineered nanocarriers that interact selectively for the first time with proximal tubule epithelial cells (PTECs) in the kidney and with RCC through the interplay between lambda light chains (LCs) attached to PEGylated polylactic-co-glycolic acid (PLGA) nanoparticles and the membrane protein megalin. Systemic administration of these light chain-conjugated nanoparticles (LC-NPs) to mice resulted in their specific retention by megalin-expressing PTECs for seven days. Repetitive dosing of LC-NPs demonstrated no renal toxicity. LC-NPs also localized selectively to megalin-expressing RCC tumors in mice. Moreover, we confirmed that both the primary tumor and lymph node metastases of human RCC express megalin, reinforcing the potential of LC-NPs for clinical use. Thus, LC-NPs can contribute potentially to improving the management of both non-oncologic and oncologic renal disorders.

SUBMITTER: Ordikhani F

PROVIDER: S-EPMC7685247 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprised of ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, while sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evident by a rise in serum creatinine and cystatin C, and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy post-sepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NFkB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, loss of FtL did not influence sepsis pathogenesis.

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Selective Trafficking of Light Chain-Conjugated Nanoparticles to the Kidney and Renal Cell Carcinoma.

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