Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy

Falvo, Elisabetta; Arcovito, Alessandro; Conti, Giamaica; Cipolla, Giuseppe; Pitea, Martina; Morea, Veronica; Damiani, Verena; Sala, Gianluca; Fracasso, Giulio; Ceci, Pierpaolo

doi:10.3390/pharmaceutics12100992

Cited by 16 publications

(28 citation statements)

References 30 publications

(42 reference statements)

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“…HFn has raised great interest in the drug delivery field and it is widely used at a preclinical level [43,44]. Several antitumor drugs currently in clinical practice have been nanoformulated in HFn nanocages to increase their therapeutic efficacy and reduce side effects [16].…”

Section: Discussionmentioning

confidence: 99%

Combined Method to Remove Endotoxins from Protein Nanocages for Drug Delivery Applications: The Case of Human Ferritin

et al. 2021

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Protein nanocages represent an emerging candidate among nanoscaled delivery systems. Indeed, they display unique features that proved to be very interesting from the nanotechnological point of view such as uniform structure, stability in biological fluids, suitability for surface modification to insert targeting moieties and loading with different drugs and dyes. However, one of the main concerns regards the production as recombinant proteins in E. coli, which leads to a product with high endotoxin contamination, resulting in nanocage immunogenicity and pyrogenicity. Indeed, a main challenge in the development of protein-based nanoparticles is finding effective procedures to remove endotoxins without affecting protein stability, since every intravenous injectable formulation that should be assessed in preclinical and clinical phase studies should display endotoxins concentration below the admitted limit of 5 EU/kg. Different strategies could be employed to achieve such a result, either by using affinity chromatography or detergents. However, these strategies are not applicable to protein nanocages as such and require implementations. Here we propose a combined protocol to remove bacterial endotoxins from nanocages of human H-ferritin, which is one of the most studied and most promising protein-based drug delivery systems. This protocol couples the affinity purification with the Endotrap HD resin to a treatment with Triton X-114. Exploiting this protocol, we were able to obtain excellent levels of purity maintaining good protein recovery rates, without affecting nanocage interactions with target cells. Indeed, binding assay and confocal microscopy experiments confirm that purified H-ferritin retains its capability to specifically recognize cancer cells. This procedure allowed to obtain injectable formulations, which is preliminary to move to a clinical trial.

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Section: Discussionmentioning

confidence: 99%

Combined Method to Remove Endotoxins from Protein Nanocages for Drug Delivery Applications: The Case of Human Ferritin

et al. 2021

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“…When it enters the tumor microenvironment, MMP makes the MMP-cleavable peptide fragments, so that PASE polypeptide is detached from the surface of ferritin and the ferritin activity is restored. Then, the treatment in vivo showed significant efficacy, eradicating several highly aggressive human tumors, such as pancreatic, triple-negative breast and liver cancer [34,35].…”

Section: Tumor Targeting Modification On Ferritinmentioning

confidence: 99%

“…When it enters t tumor microenvironment, MMP makes the MMP-cleavable peptide fragments, so th PASE polypeptide is detached from the surface of ferritin and the ferritin activity is stored. Then, the treatment in vivo showed significant efficacy, eradicating several high aggressive human tumors, such as pancreatic, triple-negative breast and liver canc [34,35]. In order to enhance the targeting ability of ferritin, peptides have been developed target receptors specifically expressed on the surface of different types of tumor cells.…”

Section: Tumor Targeting Modification On Ferritinmentioning

confidence: 99%

Bioengineered Ferritin Nanocarriers for Cancer Therapy

Sun

Hong

Gong

et al. 2021

IJMS

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Ferritin naturally exists in most organisms and can specifically recognize the transferrin 1 receptor (TfR1), which is generally highly expressed on various types of tumor cells. The pH dependent reversible assembling and disassembling property of ferritin renders it as a suitable candidate for encapsulating a variety of anticancer drugs and imaging probes. Ferritins external surface is chemically and genetically modifiable which can serve as attachment site for tumor specific targeting peptides or moieties. Moreover, the biological origin of these protein cages makes it a biocompatible nanocarrier that stabilizes and protects the enclosed particles from the external environment without provoking any toxic or immunogenic responses. Recent studies, further establish ferritin as a multifunctional nanocarrier for targeted cancer chemotherapy and phototherapy. In this review, we introduce the favorable characteristics of ferritin drug carriers, the specific targeted surface modification and a multifunctional nanocarriers combined chemotherapy with phototherapy for tumor treatment. Taken together, ferritin is a potential ideal base of engineered nanoparticles for tumor therapy and still needs to explore more on its way.

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“…At the tumor site, the PASE-linked MP sequence is selectively cleaved off by matrix metalloproteases 2 and 9 of the tumor microenvironment, leading to HFt unmasking, and hence to binding to TfR1, selective internalization in the cancer cells, and tumor killing. The HFt-MP-PASE protein (also called The-05) incorporating doxorubicin, mitoxantrone and the potent noncamptothecin topoisomerase I inhibitor Genz-644282 was proved to be efficacious against several tumor models of different origin [Fracasso et al, 2016;Damiani et al, 2017;Falvo et al, 2020;Falvo et al, 2021].…”

Section: Introductionmentioning

confidence: 99%

Nose-to-brain selective drug delivery to glioma via ferritin-based nanovectors reduces tumor growth and improves survival rate

Colotti,

Marrocco,

Falvo

et al. 2023

Preprint

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Gliomas are among the most fatal tumors, and the available therapeutic options are very limited. Additionally, the blood-brain barrier (BBB) prevents most drugs from entering the brain. We designed and produced a ferritin-based stimuli-sensitive nanocarrier with high biocompatibility and water solubility. It can incorporate high amounts of the potent topoisomerase 1 inhibitor Genz-644282. Here, we show that this nanocarrier, named The-0504, can cross the BBB and specifically deliver the payload to gliomas that express high amounts of the ferritin/transferrin receptor TfR1 (CD71). Intranasal or intravenous administration of The-0504 both reduce tumor growth and improve the survival rate of glioma-bearing mice. However, nose-to-brain administration is a simpler and less invasive route that may spare most of the healthy tissues compared to intravenous injections. For this reason, the data reported here could pave the way towards a new, safe, and direct ferritin-based drug delivery method for brain diseases, especially brain tumors.

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Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy

Cited by 16 publications

References 30 publications

Combined Method to Remove Endotoxins from Protein Nanocages for Drug Delivery Applications: The Case of Human Ferritin

Combined Method to Remove Endotoxins from Protein Nanocages for Drug Delivery Applications: The Case of Human Ferritin

Bioengineered Ferritin Nanocarriers for Cancer Therapy

Nose-to-brain selective drug delivery to glioma via ferritin-based nanovectors reduces tumor growth and improves survival rate

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