An Apoferritin‐based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib

Kuruppu, Anchala I.; Zhang, Lei; Collins, Hilary M.; Turyanska, Lyudmila; Thomas, Neil R.; Bradshaw, Tracey D.

doi:10.1002/adhm.201500389

Cited by 60 publications

(57 citation statements)

References 38 publications

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“…We ascribe the observed difference to the increased polarity of GW 608, which hinders encapsulation into AFt with a negatively charged cavity. 24 We note, that encapsulation following one-step addition of the full quantity of test agent reported in the literature 25,26 resulted in reduced drug loading values, comparable to those published.…”

Section: Introductionsupporting

confidence: 77%

“…Hence, GW 608-Lys interacts with the negatively charged AFt interface, leading to enhanced encapsulation. Our step-wise encapsulation strategy and modification of charge and polarity of the agent enabled us to achieve approximately two orders of magnitude greater encapsulation efficiency (386 molecules) per AFt cage compared with that reported for gefitinib, 26 doxorubicin, 8,25 or cisplatin. 27 Improved doxorubicin encapsulation via the reassembly route was recently reported for fusion protein HFt-PAS, achieving 90 molecules per cage 8 ; hence, our encapsulation method offers an advantageous approach for enhanced drug loading.…”

Section: Introductionmentioning

confidence: 85%

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Development of novel apoferritin formulations for antitumour benzothiazoles

et al. 2019

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Background The benzothiazole structure is important in medicinal chemistry, and 5‐fluoro‐2‐(3,4‐dimethoxyphenyl) benzothiazole (GW 610) is of particular interest as it shows outstanding anticancer activity in sensitive breast and colorectal carcinoma cell lines via generation of lethal DNA adducts in sensitive cancer cells. Despite promising activity, poor water solubility limits its applications. The apoferritin (AFt) protein cage has been proposed as a robust and biocompatible drug delivery vehicle. Aims Here, we aim to enhance solubility of GW 610 by developing amino acid prodrug conjugates and utilizing the AFt capsule as drug delivery vessel. Methods and results The potent experimental antitumour agent, GW 610, has been successfully encapsulated within AFt with more than 190 molecules per AFt cage. The AFt‐GW 610 complex exhibits dose‐dependent growth inhibition and is more potent than GW 610 alone in 5/7 cancer cell lines. To enhance both aqueous solubility and encapsulation efficiency, a series of amino acid esters of GW 608 prodrug were synthesized via N,N′‐dicyclohexylcarbodiimide ester coupling to produce molecules with different polarity. A dramatic increase in encapsulation efficiency was achieved, with more than 380 molecules of GW 608‐Lys molecules per AFt cage. Release studies show sustained release of the cargo over 12 hours at physiologically relevant pH. The AFt‐encapsulated amino acid modified GW 608 complexes are sequestered more rapidly and exhibit more potent anticancer activity than unencapsulated agent. Conclusion These results indicate that AFt‐encapsulation of GW 610 prodrug provides a biocompatible delivery option for this potent, selective experimental antitumour agent and for amino acid‐modified GW 608. Of particular interest is the encapsulation efficiency and in vitro antitumour activity of AFt‐GW 608‐Lys, which warrants further preclinical evaluation.

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Section: Introductionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 85%

Development of novel apoferritin formulations for antitumour benzothiazoles

et al. 2019

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“…Ferritin has been shown to be a successful nanocarrier for small molecule drugs. Anti‐cancer drugs such as carboplatin and cisplatin have been loaded into ferritin,, as well as gefitinib, an epidermal growth factor tyrosine kinase inhibitor . Doxorubicin loaded into ferritin cages showed improved circulation time, less cardiotoxicity, and greater accumulation at the tumor site .…”

Section: Ferritins For Targeting and Deliverymentioning

confidence: 99%

“…The NP can be generated in situ in the ferritin cage, or the protein can be disassembled and reassembled around a NP of appropriate size and shape. Ferritins have also served as nanocontainers for a variety of small molecules, including drugs and fluorescent dyes . Due to the relative ease of functionalizing proteins through genetic or chemical means, ferritin is an excellent delivery vehicle once a cargo is encapsulated.…”

Section: Introductionmentioning

confidence: 99%

Ferritin: Versatile Host, Nanoreactor, and Delivery Agent

Pulsipher

Dmochowski

2016

Israel Journal of Chemistry

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The ferritin family of proteins can be thought of as natural, nano‐sized containers. Their native function is to oxidize and store iron as a hydrated ferric oxide mineral, which can be removed to give apoferritin. The hollow interior (D=5–8 nm) provides an excellent template for inorganic nanoparticle (NP) synthesis. In addition to preparing new cores in situ, apoferritins can be disassembled and reassembled around a NP of interest. Ferritin encapsulation increases NP biocompatibility and allows site‐specific functionalization. We and others have prepared many NP‐filled ferritins, as well as ferritins loaded with small molecules of interest. Uniquely, apoferritin serves as a model for a general anesthetic‐protein binding site, which has led to the discovery of the first fluorescent general anesthetic and improved understanding of anesthetic mechanisms. Finally, ferritin conjugates have exciting applications for targeted delivery, which we have explored in the vascular endothelium.

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“…Cada estrutura de AFt é composta por 24 subunidades polipeptídicas montadas em uma estrutura proteica esférica de tamanho uniforme (Figura 26) que são facilmente moduladas a partir de variações entre condições ácidas e alcalinas, permitindo a liberação controlada de substâncias [147]. Possuindo canais de 0,3 -0,4 nm com diâmetro interno de 8 nm [148], uma das principais propriedades estruturais é sua grande cavidade interior, projetada para armazenar até 4000 átomos de ferro que transitam por meio de seis canais hidrofílicos responsáveis pelo transporte de prótons. Em procariotos e A AFt é internalizada nas células por endocitose mediada pelo receptor de transferrina 1 (TfR1) que é altamente expresso nas membranas celulares em muitos tipos de câncer [153].…”

Section: Apoferritina Como Carreador Molecularunclassified

Planejamento molecular, atividade tripanossomicida e anticancerígena de inibidores covalentes reversíveis de cisteíno proteases

Junior¹,

Carlos²

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Cysteine proteases (CP) activity has been related to different pathologies, such as leishmaniasis, Chagas disease and some types of cancer. Due to the homology between cysteine proteases expressed by these cellular systems, it was investigated here the importance of these enzymes for the development and establishment of these diseases based on the in vitro biological activity of novel reversible cysteine protease inhibitors. In general, inhibitors had a significant inhibitory activity of cysteine proteases in all assays, with a maximum inhibition of 42 % for Neq0554 concerning the CP activity expressed by Leishmania spp. and 76 % to CP activity expressed by pancreatic cancer cells. Different profiles of biological activity were observed between the cellular systems, but all substances had significant CP activity suppression, in cytostatic levels after the inhibition of CPA. When the inhibitors were tested against Leishmania spp., the cell growth was suppressed by at least 67 %, with maximum inhibition of 95% for Neq0551 at 10 μM. Similarly in pancreatic cancer cells, changes in the cell cycle profile were the most evident results, as well as the suppression of migration and colony formation ability, with 50 % retention of the colony development of MiaPaCa-2 cells by Neq0554 at 10 μM. In contrast, to protozoa from Trypanosoma cruzi Y strain, the inhibitors tested showed an interesting selectivity against the parasites concerning the host cell LLC-MK2, also promoting the in vitro cell invasion suppression in about 80% when the host cell was pre-treated with Neq0662 10 μM for 2 h. Finally, the encapsulation of Neq0554 promoted an increase in its anticancer activity against pancreatic cancer cells, with IC 50 of 79 μM alongside > 200 μM to fibroblast cells, besides increasing its selectivity. In general, the results corroborate the hypothesis that the inhibition of cysteine proteases in the cellular systems is efficient to promote cytostatic effects, being an interesting tool to be used as control and development suppression of some pathologies. Also, CP activity in protozoa cells and pancreatic cancer showed a similar profile of action, in which cysteine protease inhibitors did not promote death at a significant level for the cells, but emphasized cytostatic effects about cell growth.

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An Apoferritin‐based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib

Cited by 60 publications

References 38 publications

Development of novel apoferritin formulations for antitumour benzothiazoles

Development of novel apoferritin formulations for antitumour benzothiazoles

Ferritin: Versatile Host, Nanoreactor, and Delivery Agent

Planejamento molecular, atividade tripanossomicida e anticancerígena de inibidores covalentes reversíveis de cisteíno proteases

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