Lysosomal Proteases

Brix, Klaudia

doi:10.1007/0-387-28957-7_5

Cited by 14 publications

(11 citation statements)

References 51 publications

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“… 45 Endosomal and lysosomal proteases hydrolyze peptide bonds of internalized cargo, facilitating, in the case of protein–drug conjugates, the release of the active form of the cytotoxic agent. 46 , 47 …”

Section: Resultsmentioning

confidence: 99%

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

2020

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In spite of significant progress in the field of targeted anticancer therapy, the FDA has approved only five ADC-based drugs. Hence the search for new targeted anticancer agents is an unfulfilled necessity. Here, we present novel types of protein–drug conjugates (PDCs) that exhibit superior anticancer activities. Instead of a monoclonal antibody, we used fibroblast growth factor 2 (FGF2) as a targeting molecule. FGF2 is a natural ligand of fibroblast growth factor receptor 1 (FGFR1), a transmembrane receptor overproduced in various types of cancers. We synthesized site-specific and stoichiometric-controlled conjugates of FGF2 with a highly potent, hydrophilic derivative of auristatin called auristatin Y. To increase the hydrophilicity and hydrodynamic radius of conjugates, we employed PEG4 and PEG27 molecules as a spacer between the targeting molecule and the cytotoxic payload. All conjugates were selective to FGFR1-positive cell lines, effectively internalized via the FGFR1-dependent pathway, and exhibited a highly cytotoxic effect only on FGFR1-positive cancer cell lines.

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Section: Resultsmentioning

confidence: 99%

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

2020

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“…We found greater than 2-fold variation in BG microglial lysosome content, supporting the conclusion that microglial functional status varies across BG nuclei. The ability of individual lysosomes to process substrates and influence diverse aspects of cell function depends on abundance of lysosomal membrane proteins and matrix proteases, which can vary across cell types and subcellular locations (Brix, 2005; Gowrishankar et al, 2015; Johnson et al, 2016). Analysis of additional lysosomal membrane and matrix proteins will be needed to determine whether regional differences in BG microglial lysosome content are accompanied by differences in lysosome “maturational state.”…”

Section: Discussionmentioning

confidence: 99%

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Biase

Schuebel

Fusfeld

et al. 2017

Neuron

347

348

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SUMMARY Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei. Region-specific phenotypes of BG microglia emerged during the second postnatal week and were re-established following genetic or pharmacological microglial ablation and repopulation in the adult, indicating that local cues play an ongoing role in shaping microglial diversity. These findings demonstrate that microglia in the healthy brain exhibit a spectrum of distinct functional states and provide a critical foundation for defining microglial contributions to BG circuit function.

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“…To ensure full biodegradability, we crosslinked the PASK building blocks with poly(L-glutamic acid) (PGA) (E), a homo amino acid polymer often used for its biocompatibility and degradability by lysosomal proteases. 32,33,34 We further assessed the capacities of the obtained PASKE particles as a non-invasive molecular imaging tool of thrombosis and we tested their capacities to cross an inflamed endothelium.…”

mentioning

confidence: 99%

Low-Fouling and Biodegradable Protein-Based Particles for Thrombus Imaging

et al. 2018

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Nanomedicine holds great promise for vascular disease diagnosis and specific therapy, yet rapid sequestration by the mononuclear phagocytic system limits the efficacy of particle-based agents. The use of low-fouling polymers, such as poly(ethylene glycol), efficiently reduces this immune recognition, but these nondegradable polymers can accumulate in the human body and may cause adverse effects after prolonged use. Thus, new particle formulations combining stealth, low immunogenicity and biocompatible features are required to enable clinical use. Here, a low-fouling particle platform is described using exclusively protein material. A recombinant protein with superior hydrophilic characteristics provided by the amino acid repeat proline, alanine, and serine (PAS) is designed and cross-linked into particles with lysine (K) and polyglutamic acid (E) using mesoporous silica templating. The obtained PASKE particles have low-fouling behavior, have a prolonged circulation time compared to albumin-based particles, and are rapidly degraded in the cell's lysosomal compartment. When labeled with near-infrared fluorescent molecules and functionalized with an anti-glycoprotein IIb/IIIa single-chain antibody targeting activated platelets, the particles show potential as a noninvasive molecular imaging tool in a mouse model of carotid artery thrombosis. The PASKE particles constitute a promising biodegradable and versatile platform for molecular imaging of vascular diseases.

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Lysosomal Proteases

Cited by 14 publications

References 51 publications

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Low-Fouling and Biodegradable Protein-Based Particles for Thrombus Imaging

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