Development of a cationic polyethyleneimine-poly(lactic-<i>co</i>-glycolic acid) nanoparticle system for enhanced intracellular delivery of biologics

Tracey, Shannon R.; Smyth, Peter; Herron, Una M.; Burrows, James F.; Porter, Andrew J.; Barelle, Caroline J.; Scott, Christopher J.

doi:10.1039/d3ra06050k

Cited by 5 publications

(3 citation statements)

References 57 publications

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“…vNARs have been reported to possess inherent stability against a range of factors including variations in pH, temperature and exposure to proteases ( Dooley et al, 2003 ; Dooley and Flajnik, 2005 ; Flajnik et al, 2011 ; Griffiths et al, 2013 ; Tracey et al, 2023 ). This stability may be of particular benefit in targeting CTSS, located within acidic lysosomal compartments.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, these domains have been shown to present as protruding, extended paratopes, with a predisposition to bind cryptic target epitopes, inaccessible to conventional biologics, yielding both specific and tight binders ( Nuttall et al, 2002 ; 2003 ; Stanfield et al, 2004 ; Muller et al, 2012 ; Barelle and Porter, 2015 ; Kovaleva et al, 2017 ). Alongside this, borne out of the harsh environment presented by shark sera, is a remarkable inherent stability, allowing retention of molecular integrity in the face of changes in temperature and pH, the presence of organic solvents and enzymatic activity ( Dooley et al, 2003 ; Dooley and Flajnik, 2005 ; Flajnik et al, 2011 ; Griffiths et al, 2013 ; Tracey et al, 2023 ). Furthermore, vNARs can be expressed in a cost-effective manner in non-mammalian cells at scale.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy

Smyth,

Ferguson,

Burrows

et al. 2023

Front. Pharmacol.

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Aberrant activity of the cysteine protease Cathepsin S (CTSS) has been implicated across a wide range of pathologies. Notably in cancer, CTSS has been shown to promote tumour progression, primarily through facilitating invasion and migration of tumour cells and augmenting angiogenesis. Whilst an attractive therapeutic target, more efficacious CTSS inhibitors are required. Here, we investigated the potential application of Variable New Antigen Receptors (vNARs) as a novel inhibitory strategy. A panel of potential vNAR binders were identified following a phage display panning process against human recombinant proCTSS. These were subsequently expressed, purified and binding affinity confirmed by ELISA and SPR based approaches. Selected lead clones were taken forward and were shown to inhibit CTSS activity in recombinant enzyme activity assays. Further assessment demonstrated that our lead clones functioned by a novel inhibitory mechanism, by preventing the activation of proCTSS to the mature enzyme. Moreover, using an intrabody approach, we exhibited the ability to express these clones intracellularly and inhibit CTSS activity whilst lead clones were also noted to impede cell invasion in a tumour cell invasion assay. Collectively, these findings illustrate a novel mechanistic approach for inhibiting CTSS activity, with anti-CTSS vNAR clones possessing therapeutic potential in combating deleterious CTSS activity. Furthermore, this study exemplifies the potential of vNARs in targeting intracellular proteins, opening a range of previously “undruggable” targets for biologic-based therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy

Smyth,

Ferguson,

Burrows

et al. 2023

Front. Pharmacol.

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show abstract

“…This activation can occur via the NPs' interaction with cellular components that trigger the inflammasome pathway [58,85,86]. Moreover, inherent properties of cationic NPs can lead to the rupture of cell membranes [20,83,87,88]. This disruption can act as a danger signal, alerting the immune system to potential threats by releasing intracellular contents that are recognized as damageassociated molecular patterns (DAMPs).…”

Section: How Particle Size and Positive Charge Drive The Immune Respo...mentioning

confidence: 99%

Emerging Cationic Nanovaccines

Carmona-Ribeiro,

Pérez-Betancourt

2024

Preprint

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Nanovaccines are able to deliver antigen(s) and immunomodulator(s) directly to antigen-presenting cells (APCs) of the lymphatic system. Positive charges improve their uptake by APCs and often drive a Th-1 biased immune response so necessary against infectious diseases caused by intracellular pathogens and cancers. However, cationic compounds often display a dose-dependent toxicity so that systematic evaluation of cytotoxicity against cells in culture is required. After the rapid evolution of nanovaccines against SARS-Covid 2, mRNA vaccines gained much strength and have been designed against several infectious diseases, often relying on cationic components for mRNA protection. Once established the limiting concentration for the cationic compound, cationic nanovaccines perform well eliciting the desired Th-1 improved immune response in most cases. Other valuable approach found in the literature has been the construction of biocompatible nanoparticles (NPs) carrying cationic lipids, polymers or surfactants so that minimization of the concentration for the cationic component led to absence of toxicity. Against cancer, recent constructions of nanovaccines in situ after cancer cell disruption in the presence of adjuvants led to systemic presentation of multiple tumoral antigens yielding, in many instances, prevention of metastasis appearance and conversion of tumors non treatable by immunotherapy into treatable ones.

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US/PA/MR multimodal imaging-guided multifunctional genetically engineered bio-targeted synergistic agent for tumor therapy

Ren,

Wang,

Tang

et al. 2024

J Nanobiotechnol

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Development of a cationic polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticle system for enhanced intracellular delivery of biologics

Abstract: Cationic PEI-PLGA nanoparticles are shown as a superior delivery platform, displaying enhanced intracellular delivery of biologics.

Cited by 5 publications

References 57 publications

Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy

Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy

Emerging Cationic Nanovaccines

US/PA/MR multimodal imaging-guided multifunctional genetically engineered bio-targeted synergistic agent for tumor therapy

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