Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates

Grabowska, Anna; Kircheis, Ralf; Kumari, Rajendra; Clarke, Paula J.; McKenzie, Andrew J.; Hughes, Jaime; Mayne, Cerys; Desai, Arpan; Sasso, Luana; Watson, Susan A.; Alexander, Cameron

doi:10.1039/c5bm00101c

Cited by 17 publications

(9 citation statements)

References 49 publications

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“…The iron binding protein transferrin (Tf), has been extensively studied as a delivery vector for specific therapeutics which otherwise show limited cellular uptake. [24][25][26][27][28] This is because transferrin plays an essential role in the transport of free iron into cells, its mechanism of uptake is well established, it is constitutively endocytosed and transferrin receptors (TfR) are overexpressed in a number of disease states.…”

Section: Introductionmentioning

confidence: 99%

Switching of Macromolecular Ligand Display by Thermoresponsive Polymers Mediates Endocytosis of Multiconjugate Nanoparticles

et al. 2018

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Ligand-mediated targeting and internalization of plasma membrane receptors is central to cellular function. These types of receptors have accordingly been investigated as targets to facilitate entry of diagnostic and therapeutic constructs into cells. However, there remains a need to characterize how receptor targeting agents on nanoparticles interact at surface receptors and whether it is possible to control these interactions via exogenous stimuli. Here, we describe the switchable display of the iron-transporting protein, transferrin (Tf), at the surface of thermoresponsive polymer-coated gold nanoparticles and show that internalization of the coated nanoparticles into target cells changes across temperature ranges over which transferrin is expected to be sterically "hidden" by an extended polymer chain and then "revealed" by polymer chain collapse. The switching process is dependent on the numbers of transferrin molecules and thermoresponsive polymer chains attached and whether the assay temperature is above or below the transition temperatures of the responsive polymers at the nanoparticle surfaces. Significantly, however, the control of internalization is critically reliant on overall nanoparticle colloidal stability while the thermoresponsive component of the surface undergoes conformational change. The data show that the cell entry function of complex and large biomolecule ligands can be modulated by polymer-induced accessibility change but that a simple "hide and reveal" mechanism for ligand display following polymer chain collapse is insufficient to account for nanoparticle uptake and subsequent intracellular trafficking.

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Section: Introductionmentioning

confidence: 99%

Switching of Macromolecular Ligand Display by Thermoresponsive Polymers Mediates Endocytosis of Multiconjugate Nanoparticles

et al. 2018

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“…7 Recent methods to overcome these limitations include direct local drug delivery, chemical modification, viral vectors, and non-viral vector delivery. [8][9][10][11][12] To deliver siRNA directly into the cytoplasm, Hagstrom et al injected a large quantity of siRNA by vein at the distal end of the mouse limb, then immediately bound this limb by tourniquet to isolate the spread of siRNA to the surrounding tissues. This method was found to have specific gene silencing properties; however, it requires a large amount of siRNA and also caused damage to the body.…”

Section: Wen LImentioning

confidence: 99%

Powering up the molecular therapy of RNA interference by novel nanoparticles

Liao

Li²,

Zhang

et al. 2016

Biomater. Sci.

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RNA interference technology has been widely applied in biomedical therapy in recent years. A type of small RNA molecule - siRNA could regulate the expression of disease related genes by breaking down the integrity of mRNA with high specificity. However, the low efficiency of siRNA delivery to its target seriously hampered the RNAi therapy. Compared with viral-based delivery systems, non-viral-based nanoparticles are more suitable for disease treatment due to reduced cellular toxicity, higher loading capacity, and better biocompatibility. This review article highlights several nanoparticle-based siRNA delivery systems, including liposomes, cationic solid lipid nanoparticles, reconstituted high density lipoprotein, polymeric nanoparticles, cationic cell penetrating peptides, and inorganic nanoparticles. The molecular mechanism of gene silencing, clinical examples, and the limitations of current technology related to nanomaterial sciences, are also discussed.

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“…[52–54] Furthermore, the compositions of mixed polyplex and coacervate systems play major roles in determining nanocarrier structural characteristics. [55–57] Recent reports have studied these effects with mixtures of BCPs comprised of different block constituents. [20, 24] In this work, we build on these efforts to analyze how mixing chemically-identical BCPs of different molecular weights affected nanocarrier structure.…”

Section: Discussionmentioning

confidence: 99%

Efficient tuning of siRNA dose response by combining mixed polymer nanocarriers with simple kinetic modeling

et al. 2017

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Two of the most prominent challenges that limit the clinical success of siRNA therapies are a lack of control over cargo release from the delivery vehicle and an incomplete understanding of the link between gene silencing dynamics and siRNA dosing. Herein, we address these challenges through the formulation of siRNA polyplexes containing light-responsive polymer mixtures, whose varied compositions and triggered release behavior provide enhanced gene silencing and controlled dose responses that can be predicted by simple kinetic models. Through the straightforward mixing of two block copolymers, the level of gene knockdown was easily optimized to achieve the maximum level of GAPDH protein silencing in NIH/3T3 cells (70%) using a single siRNA dose. The kinetic model was used to describe the dynamic changes in mRNA and protein concentrations in response to siRNA treatment. These predictions enabled the application of a second dose of siRNA to maximally suppress gene expression over multiple days, leading to a further 50% reduction in protein levels relative to those measured following a single dose. Furthermore, polyplexes remained dormant in cells until exposed to the photo-stimulus, demonstrating the complete control over siRNA activity as well as the stability of the nanocarriers. Thus, this work demonstrates that pairing advances in biomaterials design with simple kinetic modeling provides new insight into gene silencing dynamics and presents a powerful strategy to control gene expression through siRNA delivery.

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Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates

Abstract: Materials for delivery of oligonucleotides need to be simple to produce and formulate yet effectivein vivoto be considered for clinical applications.

Cited by 17 publications

References 49 publications

Switching of Macromolecular Ligand Display by Thermoresponsive Polymers Mediates Endocytosis of Multiconjugate Nanoparticles

Switching of Macromolecular Ligand Display by Thermoresponsive Polymers Mediates Endocytosis of Multiconjugate Nanoparticles

Powering up the molecular therapy of RNA interference by novel nanoparticles

Efficient tuning of siRNA dose response by combining mixed polymer nanocarriers with simple kinetic modeling

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