Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells

Bellini, Melissa; Mazzucchelli, Serena; Galbiati, Elisabetta; Sommaruga, Silvia; Fiandra, Luisa; Truffi, Marta; Rizzuto, Maria Antonietta; Colombo, Miriam; Tortora, Paolo; Corsi, Fabio; Prosperi, Davide

doi:10.1016/j.jconrel.2014.10.002

Cited by 104 publications

(146 citation statements)

References 42 publications

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Section: Extended Abstractmentioning

confidence: 99%

“…As an ideal DOX nanocarrier, we used H-Ferritin (HFn) nanocages, owing to its affinity for transferrin receptor 1 (TfR-1), which is constitutively overexpressed in cancer cells [4]. HFn-DOX complex was recently demonstrated to overcome chemoresistance by actively promoting DOX nuclear translocation in vitro [4].4T1-L tumor bearing mice were treated with placebo, DOX, liposomal-DOX (pl-DOX) or HFn-DOX under our LDNM setting. The progression of tumor volume was monitored in vivo demonstrating that HFn-DOX could decrease tumor growth, while DOX displayed a tumor progression similar to the control.…”

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confidence: 99%

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Metronomic Nanocaged Doxorubicin Prevents Chemoresistance and Cardiotoxicity in Breast Cancer

Mazzucchelli¹,

Truffi²,

Bellini³

et al. 2017

Proceedings of the 2nd World Congress on Recent Advances in Nanotechnology

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Extended AbstractLow-dose metronomic (LDM) chemotherapy is based on frequent administration of a lower dose of drugs, without the need of extensive interruptions [1]. LDM affects the vasculature growth and repair [1] and stimulates the host immune system against the tumor [2], while it has not activity against tumor cells. Nanotechnology could improve the effectiveness of LDM chemotherapy, by taking advantage of the unique targeting efficiency of engineered nanocarriers [3].In the present work, we propose a new concept of low dose "nanometronomic" (LDNM) chemotherapy, using doxorubicin (DOX) as pilot drug. As an ideal DOX nanocarrier, we used H-Ferritin (HFn) nanocages, owing to its affinity for transferrin receptor 1 (TfR-1), which is constitutively overexpressed in cancer cells [4]. HFn-DOX complex was recently demonstrated to overcome chemoresistance by actively promoting DOX nuclear translocation in vitro [4].4T1-L tumor bearing mice were treated with placebo, DOX, liposomal-DOX (pl-DOX) or HFn-DOX under our LDNM setting. The progression of tumor volume was monitored in vivo demonstrating that HFn-DOX could decrease tumor growth, while DOX displayed a tumor progression similar to the control. An even better effect was achieved with pl-DOX, which was indeed able to arrest the tumor development. Moreover, we find that HFn-DOX antitumor effect is attributable to multiple nanodrug actions beyond cell killing, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Otherwise, although an even better reduction of tumor progression was achieved with pl-DOX a fivefold increase in MDR1positive cells has been displayed, suggesting that liposomal DOX is not suitable in view of a protracted metronomic treatment, due to the onset of chemoresistance. [5]. Multiparametric assessment of heart tissues, has been performed to investigate the cardiotoxicity of the metronomic HFn-DOX treatment [6]. Histological evaluations of cardiomyocyte crosssections from mice treated with HFn-DOX, pl-DOX, DOX or non-treated was coupled with ultrastructural assessment of morphological alterations in mitochondria number, surface area and cristae depletion. Pathological alterations were detected in DOX and pl-DOX samples suggesting a strong cellular damage response compared to HFn-DOX samples. Therefore, the absence of obvious alterations in heart samples from mice treated with HFn-DOX strongly supports the lack of cardiotoxicity in LDNM HFn-DOX treatment, even compared to pl-DOX, which is currently considered the most safe anthracycline therapy in terms of cardiotoxicity. DOX and pl-DOX ultrastructural cardiac alterations were also associated to functional ones, such as the decrease in mitochodrial membrane potential and the reduction in the reactive oxygen species (ROS) quencher, GSH, confirming mitochondrial dysfunction induced by treatment with DOX and pl-DOX only.In summary, this study provides robust evidence that LDNM monotherapy with HFn-DOX is expected to remodel the therapeutic outcome of advanced metastatic BC co...

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Section: Extended Abstractmentioning

confidence: 99%

mentioning

confidence: 99%

Metronomic Nanocaged Doxorubicin Prevents Chemoresistance and Cardiotoxicity in Breast Cancer

Mazzucchelli¹,

Truffi²,

Bellini³

et al. 2017

Proceedings of the 2nd World Congress on Recent Advances in Nanotechnology

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“…A key structural attribute of Fn is the ability to disassemble at acidic pH and reassemble at neutral pH with perfect shape memory [28]. In addition to the disassembly/reassembly mechanism, ferritins are also thermodynamically stable, can bind different metal ions [26] and are tolerant of genetic fusions [20] making Fn a highly multifunctional PNP capable of a number diagnostic and biosensing applications.…”

Section: Enzyme-derived Pnpsmentioning

confidence: 99%

“…Chemical conjugation methods are often used to attach inorganic, non-proteinaceous components such as chemical dyes for imaging [28,35], targeting ligands for drug delivery [36], and peptides for immune activation [37]. Typically, well-characterized chemistries can be employed to couple substances to reactive side chains that are either surface exposed or genetically incorporated into the protein monomer backbone.…”

Section: Functionalization Of Protein Nanoparticlesmentioning

confidence: 99%

Protein nanoparticles as multifunctional biocatalysts and health assessment sensors

Raeeszadeh‐Sarmazdeh

Hartzell

Price

et al. 2016

Current Opinion in Chemical Engineering

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The use of protein nanoparticles for biosensing, biocatalysis and drug delivery has exploded in the last few years. The ability of protein nanoparticles to self-assemble into predictable, monodisperse structures is of tremendous value. The unique properties of protein nanoparticles such as high stability, and biocompatibility, along with the potential to modify them led to development of novel bioengineering tools. Together, the ability to control the interior loading and external functionalities of protein nanoparticles makes them intriguing nanodevices. This review will focus on a number of recent examples of protein nanoparticles that have been engineered towards imparting the particles with biocatalytic or biosensing functionality.

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“…When expressed artificially in iron-free conditions, the yielded AFn is hollow, comprising a cavity that can be loaded with different species. 15 The characteristics such as good biocompatibility, non-immunogenicity, and unique nanostructure were the important reasons for choosing ferritin nanocage as a drug carrier. It has been observed that in strong acidic environments (pH 2.0), the ferritin cage disassembles into discrete subunits, while at pH 7.4 these subunits once again self-assemble through non-covalent interactions and restore the cage-like structure.…”

Section: Introductionmentioning

confidence: 99%

Construction of magnetic-carbon-quantum-dots-probe-labeled apoferritin nanocages for bioimaging and targeted therapy

Yao¹,

Su²,

Zeng³

et al. 2016

IJN

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Carbon dots (CDs) are one of the most highlighted carbon-based materials for biological applications, such as optical imaging nanoprobes, which are used for labeling cells in cancer treatment mainly due to their biocompatibility and unique optical properties. In this study, gadolinium (Gd)-complex-containing CDs were obtained through a one-step microwave method to develop multimodal nanoprobes integrating the advantages of optical and magnetic imaging. The obtained Gd-CDs exhibited highly fluorescent properties with excellent water solubility and biological compatibility. Natural apoferritin (AFn) nanocages, an excellent drug delivery carrier, are hollow in structure, with their pH-dependent, unfolding–refolding process at pH 2.0 and 7.4. The chemotherapeutic drug doxorubicin (DOX) can be highly effective and encapsulated into AFn cavity. A widely used tumor-targeting molecule, folic acid (FA), functionalized the surface of AFn to obtain an active tumor targeting effect on MCF-7 cells and malignant tumors in mice models. In this study, an AFn nanocarrier encapsulating high concentration of DOX labeled with magnetic and fluorescent Gd-CDs probe was developed. Gd-CDs exhibited a unique green photoluminescence and almost no toxicity compared with free GdCl 3 . Furthermore, Gd-doped CDs significantly increased the circulation time and decreased the toxicity of Gd 3+ in in vitro and in vivo magnetic resonance imaging, which demonstrated that the AFn nanocages labeled with Gd-CD compounds could serve as an excellent T 1 contrast agent for magnetic resonance imaging. The self-assembling multifunctional Gd-CDs/AFn (DOX)/FA nanoparticles have a great potential for cancer theranostic applications.

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Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells

Cited by 104 publications

References 42 publications

Metronomic Nanocaged Doxorubicin Prevents Chemoresistance and Cardiotoxicity in Breast Cancer

Metronomic Nanocaged Doxorubicin Prevents Chemoresistance and Cardiotoxicity in Breast Cancer

Protein nanoparticles as multifunctional biocatalysts and health assessment sensors

Construction of magnetic-carbon-quantum-dots-probe-labeled apoferritin nanocages for bioimaging and targeted therapy

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