Chaperonin–Dendrimer Conjugates for siRNA Delivery

Nussbaumer, Martin G.; Duskey, Jason Thomas; Rother, Martin; Renggli, Kasper; Chami, Mohamed; Bruns, Nico

doi:10.1002/advs.201600046

Cited by 28 publications

(29 citation statements)

References 60 publications

(55 reference statements)

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“…Prodrugs based on HA and protein-drug complexes were able to assemble into nanoparticles and improve drug delivery. It is well known that as materials, especially hydrophobic or lipid compounds (particles) 28 , 29 , enter the blood or are exposed to physiological fluids, various proteins associate with the materials and form protein coronas 30 . Inspired by this mechanism, we speculated that a HA-PTX prodrug can interact with MATT/CN complexes and aggregate into nanoparticles.…”

Section: Discussionmentioning

confidence: 99%

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Zhao

Zhu

et al. 2018

Theranostics

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Treatment for metastatic cancer is a great challenge throughout the world. Commonly, directed inhibition of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells can reduce metastasis. Here, a novel nanoplatform (HPMC NPs) assembled from hyaluronic acid (HA)-paclitaxel (PTX) prodrug and marimastat (MATT)/β-casein (CN) complexes was established to cure a 4T1 metastatic cancer model via targeting CD44 and intracellular, rather than extracellular, MMPs.Methods: HPMC NPs were prepared by assembling the complexes and prodrug under ultrasonic treatment, which the interaction between them was evaluated by förster resonance energy transfer, circular dichroism and fluorescence spectra. The developed nanoplatform was characterized via dynamic light scattering and transmission electron microscopy, and was evaluated in terms of MMP-sensitive release and stability. Subsequently, the cellular uptake, trafficking, and in vitro invasion were studied by flow cytometry, confocal laser microscopy and transwell assay. MMP expression and activity was determined by western blotting and gelatin zymography. Finally, the studies of biodistribution and antitumor efficacy in vivo were performed in a mouse 4T1 tumor breast model, followed by in vivo safety study in normal mouse.Results: The interaction between the prodrug and complexes is strong with a high affinity, resulting in the assembly of these two components into hybrid nanoparticles (250 nm). Compared with extracellular incubation with MATT, HPMC NP treatment markedly reduced the expression (100%) and activity (50%) of MMPs in 4T1 cells and in the tumor. HPMC NPs exhibited 1.4-fold tumor accumulation, inhibited tumor-growth by >8-fold in volume with efficient apoptosis and proliferation, and suppressed metastasis (>5-fold) and angiogenesis (>3-fold). Overall, HPMC NPs were efficient in metastatic cancer therapy. Conclusions: According to the assembly of polymer prodrug and protein-drug complexes, this study offers a new strategy for constructing nanoparticles for targeted drug delivery, biomedical imaging, and combinatorial treatment. Importantly, via inhibition of intracellular MMPs, metastasis and angiogenesis can be potently blocked, benefiting the rational design of nanomedicine for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Zhao

Zhu

et al. 2018

Theranostics

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“…221 Generation four Poly(amidoamine) dendrimer, which has about 4.5 nm diameter, has successfully encapsulated inside of thermosome to use the protein cage for siRNA delivery vehicle and gold nanoparticles have been synthesized on the interior. 222,223 Similarly, a semiconducting polymer poly(2-methoxy-5-propyloxy sulfonate phenylene vinylene) (MPS-PPV) has been encapsulated inside of a vault cage, while the MPS-PPV could not enter the cavity if vault subunit proteins were covalently cross-linked together prior to the polymer loading. This result indicates that the MPS-PPV can diffuse into the cage through inter subunit pores.…”

Section: Encapsulation Within Protein Cagesmentioning

confidence: 99%

Protein cage assembly across multiple length scales

2018

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Within the materials science community, proteins with cage-like architectures are being developed as versatile nanoscale platforms for use in protein nanotechnology. Much effort has been focused on the functionalization of protein cages with biological and non-biological moieties to bring about new properties of not only individual protein cages, but collective bulk-scale assemblies of protein cages. In this review, we report on the current understanding of protein cage assembly, both of the cages themselves from individual subunits, and the assembly of the individual protein cages into higher order structures. We start by discussing the key properties of natural protein cages (for example: size, shape and structure) followed by a review of some of the mechanisms of protein cage assembly and the factors that influence it. We then explore the current approaches for functionalizing protein cages, on the interior or exterior surfaces of the capsids. Lastly, we explore the emerging area of higher order assemblies created from individual protein cages and their potential for new and exciting collective properties.

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“…Different strategies have been used to improve the properties of PAMAM as a non-viral mediated gene delivery agent. Conjugation of group II chaperonin thermosome (THS) in PAMAM-G4 was tested by the group of Nussbaumer [ 82 ]. This compound was considered to be a new architecture for gene delivery, carrying KIF11- and GAPDH-silencing interfering RNAS (siRNAS) to cancer cells with good results, significantly inhibiting the proliferation of those cells.…”

Section: Biomedical Applicationsmentioning

confidence: 99%

New Advances in General Biomedical Applications of PAMAM Dendrimers

et al. 2018

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Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named ‘starburst polymers’. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.

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Chaperonin–Dendrimer Conjugates for siRNA Delivery

Cited by 28 publications

References 60 publications

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis

Protein cage assembly across multiple length scales

New Advances in General Biomedical Applications of PAMAM Dendrimers

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