Targeting of Cancer Cells with Ferrimagnetic Ferritin Cage Nanoparticles

Uchida, Masaki; Flenniken, Michelle L.; Allen, Mark; Willits, Deborah A.; Crowley, Bridgid E.; Brumfield, Susan K.; Willis, Ann F.; Jackiw, Larissa; Jutila, Mark A.; Young, Mark; Douglas, Trevor

doi:10.1021/ja0655690

Cited by 366 publications

(394 citation statements)

References 49 publications

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“…1,2 Moreover, protein-protein interactions are also integral to the generation of cellular selfassembled nano-structures, and establishing how they control self-assembly could lead not only to fundamental understanding but also to the eventual rational design of novel structures for a myriad of applications such as the templation of inorganic nano-materials and for encapsulated reaction chemistry. [3][4][5][6][7][8] Although protein-protein interactions are intriguing medicinal targets, they have only recently been pursued for drug development studies somewhat owing to the discovery that although they often involve large, buried surface area, they can be inhibited using low molecular weight small molecules that target ''hot spot'' residues where the binding energy is concentrated. 9,10 Alanine shaving, where individual side changes are conceptually shaved to a methyl residuum and where the stabilities of the resulting mutants are determined with respect to wild type, is the most common method to identify hot spot residues.…”

Section: Introductionmentioning

confidence: 99%

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

Zhang

Chee

et al. 2011

Protein Science

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DNA-binding protein from starved cells (DPS), a mini-ferritin capable of self-assembling into a 12-meric nano-cage, was chosen as the basis for an alanine-shaving mutagenesis study to investigate the importance of key amino acid residues, located at symmetry-related protein-protein interfaces, in controlling protein stability and self-assembly. Nine mutants were designed through simple inspection, synthesized, and subjected to transmission electron microscopy, circular dichroism, size exclusion chromatography, and ''virtual alanine scanning'' computational analysis. The data indicate that many of these residues may be hot spot residues. Most remarkably, two residues, R83 and R133, were observed to shift the oligomerization state to~50% dimer. Based on the hypothesis that these two residues constitute a ''hot strip,'' located at the ferritin-like threefold axis, the double mutant was generated which completely shuts down detectable formation of 12-mer in solution, favoring a cooperatively folded dimer. The fact that this effect logically builds upon the single mutants emphasizes that complex self-assembly has the potential to be manipulated rationally. This study should have an impact on the fundamental understanding of the assembly of DPS protein cages specifically and protein quaternary structure in general. In addition, as there is much interest in applying these and similar systems to the templation of nano-materials and drug delivery, the ability to control this ferritin's oligomerization state and stability could prove especially valuable.

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Section: Introductionmentioning

confidence: 99%

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

Zhang

Chee

et al. 2011

Protein Science

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“…In particular, natural HFn nanocarriers are expected to possess an outstanding biocompatibility and safety profile, because they exist naturally in the human body and are composed of nontoxic elements that therefore would not activate inflammatory or immunological responses (25). In addition, HFn can be produced economically in Escherichia coli and can be purified easily by exploiting their heat-resistant property (17,26). The production and purification characteristics of the HFn nanocarriers are effective for scale-up of the manufacturing process with robust and reproducible procedures.…”

mentioning

confidence: 99%

H-ferritin–nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection

Liang

Fan

Zhou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

417

438

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An ideal nanocarrier for efficient drug delivery must be able to target specific cells and carry high doses of therapeutic drugs and should also exhibit optimized physicochemical properties and biocompatibility. However, it is a tremendous challenge to engineer all of the above characteristics into a single carrier particle. Here, we show that natural H-ferritin (HFn) nanocages can carry high doses of doxorubicin (Dox) for tumor-specific targeting and killing without any targeting ligand functionalization or property modulation. Doxloaded HFn (HFn-Dox) specifically bound and subsequently internalized into tumor cells via interaction with overexpressed transferrin receptor 1 and released Dox in the lysosomes. In vivo in the mouse, HFn-Dox exhibited more than 10-fold higher intratumoral drug concentration than free Dox and significantly inhibited tumor growth after a single-dose injection. Importantly, HFn-Dox displayed an excellent safety profile that significantly reduced healthy organ drug exposure and improved the maximum tolerated dose by fourfold compared with free Dox. Moreover, because the HFn nanocarrier has well-defined morphology and does not need any ligand modification or property modulation it can be easily produced with high purity and yield, which are requirements for drugs used in clinical trials. Thus, these unique properties make the HFn nanocage an ideal vehicle for efficient anticancer drug delivery.

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“…For example, magnetic Fe 3 O 4 75) 41,[84][85][86][87] for magnetic resonance imaging, 32,46) and even as the core of a magnonic device. 88) In analogy, Co(O)OH 89) 91) Many metal hydroxide NPs can be grown from the respective metal ion without an oxidizer.…”

Section: Apoferritinmentioning

confidence: 99%

Nanoscale device architectures derived from biological assemblies: The case of tobacco mosaic virus and (apo)ferritin

Calò

Eiben

Okuda

et al. 2016

Jpn. J. Appl. Phys.

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Virus particles and proteins are excellent examples of naturally occurring structures with well-defined nanoscale architectures, for example, cages and tubes. These structures can be employed in a bottom-up assembly strategy to fabricate repetitive patterns of hybrid organic–inorganic materials. In this paper, we review methods of assembly that make use of protein and virus scaffolds to fabricate patterned nanostructures with very high spatial control. We chose (apo)ferritin and tobacco mosaic virus (TMV) as model examples that have already been applied successfully in nanobiotechnology. Their interior space and their exterior surfaces can be mineralized with inorganic layers or nanoparticles. Furthermore, their native assembly abilities can be exploited to generate periodic architectures for integration in electrical and magnetic devices. We introduce the state of the art and describe recent advances in biomineralization techniques, patterning and device production with (apo)ferritin and TMV.

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Targeting of Cancer Cells with Ferrimagnetic Ferritin Cage Nanoparticles

Cited by 366 publications

References 49 publications

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

H-ferritin–nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection

Nanoscale device architectures derived from biological assemblies: The case of tobacco mosaic virus and (apo)ferritin

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