Atypical Renal Clearance of Nanoparticles Larger Than the Kidney Filtration Threshold

Adhipandito, Christophorus Fideluno; Cheung, Siu Hung; Lin, Yu; Wu, Si Han

doi:10.3390/ijms222011182

Cited by 54 publications

(30 citation statements)

References 87 publications

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“…A potential reason for this could be a slow release of 111 In from the formulation due to kinetic instability of the DTPA chelator, which was expected from the measured slow in vitro release from HPG in plasma (Figure S10). Another contributing factor could be that HPG, while being small enough to extravasate through the fenestrated endothelium in the kidney, is too large to escape through the pores between podocytes and becomes entrapped in the glomerular basement membrane . Tumor uptake was visible after 3 h and increased over the course of the study.…”

Section: Resultsmentioning

confidence: 99%

Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting

et al. 2023

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Aptamers are promising targeting agents for imaging and therapy of numerous diseases, including cancer. However, a significant shortcoming of aptamers is their poor stability and fast excretion, limiting their application in vivo. Common strategies to overcome these challenges is to chemically modify aptamers in order to increase their stability and/or to apply formulation technologies such as conjugating them to polymers or nanocarriers in order to increase their circulation half-life. This is expected to result in improved cellular uptake or retention to passively targeted nanomedicines. Herein, we report a modular conjugation strategy based on click chemistry between functionalized tetrazines and trans -cyclooctene (TCO), for the modification of high molecular weight hyperbranched polyglycerol (HPG) with sgc8 aptamer, fluorescent dyes, and 111 In. Our data indicate strong affinity of sgc8 against a range of solid tumor-derived cell lines that have previously not been tested with this aptamer. Nevertheless, nonspecific uptake of scrambled ssDNA-functionalized HPG in cells highlights inherent challenges of aptamer-targeted probes that remain to be solved for clinical translation. We validate HPG-sgc8 as a nontoxic nanoprobe with high affinity against MDA-MB-468 breast and A431 lung cancer cells and show significantly increased plasma stability compared to free sgc8. In vivo quantitative SPECT/CT imaging indicates EPR-mediated tumor uptake of HPG-sgc8 and nontargeted or scrambled ssDNA-conjugated HPG but no statistically significant difference between these formulations in terms of total tumor uptake or retention. Our study emphasizes the need for stringent controls and quantification in the evaluation of aptamer-targeted probes. For this purpose, our versatile synthesis strategy provides a simple approach for the design and evaluation of long-circulating aptamer-conjugated nanoformulations.

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Section: Resultsmentioning

confidence: 99%

Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting

et al. 2023

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“…The current hNPs did not have significant selectivity to tumors than other major organs. Previous studies showed that small molecules or nanoparticles with diameter smaller than ~ 6 nm were mainly cleared through kidney [ 37 , 38 ]. The improved tumor accumulation of hNPs than free dye was probably due to the increased size, which diminished renal clearance and leaved more drugs available in blood circulation.…”

Section: Resultsmentioning

confidence: 99%

Doxorubicin and CpG loaded liposomal spherical nucleic acid for enhanced Cancer treatment

Deng

et al. 2022

J Nanobiotechnol

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Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8+ and CD4+ T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect. Graphical Abstract

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“…PEGylation, covalently attaching polyethylene glycol (PEG) chains to peptides, proteins, or nanoparticles, is expected to improve water solubility, non-immunization by decreasing macrophage clearance, non-filtration by increasing the molecular mass, and enzymatic non-degradation by interfering with enzymes [ 86 ]. Compounds with a diameter of less than 6–8 nm are subject to filtration and excretion by kidneys from the blood stream into urine [ 87 ]. Compounds of approximately 500 Da to approximately 1500 Da, such as glucuronic acid conjugates, are subject to secretion by the liver into bile over biliary epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

Tashima

2022

Antibodies

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Innumerable people worldwide die of cancer every year, although pharmaceutical therapy has actualized many benefits in human health. For background, anti-cancer drug development is difficult due to the multifactorial pathogenesis and complicated pathology of cancers. Cancer cells excrete hydrophobic low-molecular anti-cancer drugs by overexpressed efflux transporters such as multiple drug resistance 1 (MDR1) at the apical membrane. Mutation-driven drug resistance is also developed in cancer. Moreover, the poor distribution of drug to cancer cells is a serious problem, because patients suffer from off-target side effects. Thus, highly selective and effective drug delivery into solid cancer cells across the membrane should be established. It is known that substances (10–100 nm in diameter) such as monoclonal antibodies (mAbs) (approximately 14.2 nm in diameter) or nanoparticles spontaneously gather in solid tumor stroma or parenchyma through the capillary endothelial fenestration, ranging from 200–2000 nm, in neovasculatures due to the enhanced permeability and retention (EPR) effect. Furthermore, cancer antigens, such as HER2, Nectin-4, or TROP2, highly selectively expressed on the surface of cancer cells act as a receptor for receptor-mediated endocytosis (RME) using mAbs against such antigens. Thus, antibody–drug conjugates (ADCs) are promising anti-cancer pharmaceutical agents that fulfill accurate distribution due to the EPR effect and due to antibody–antigen binding and membrane permeability owing to RME. In this review, I introduce the implementation and possibility of highly selective anti-cancer drug delivery into solid cancer cells based on the EPR effect and RME using anti-cancer antigens ADCs with payloads through suitable linkers.

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Atypical Renal Clearance of Nanoparticles Larger Than the Kidney Filtration Threshold

Cited by 54 publications

References 87 publications

Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting

Quantitative Evaluation of a Multimodal Aptamer-Targeted Long-Circulating Polymer for Tumor Targeting

Doxorubicin and CpG loaded liposomal spherical nucleic acid for enhanced Cancer treatment

Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

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