Imidazole-modified deferasirox encapsulated polymeric micelles as pH-responsive iron-chelating nanocarrier for cancer chemotherapy

Theerasilp, Man; Chalermpanapun, Punlop; Ponlamuangdee, Kanyawan; Sukvanitvichai, Dusita

doi:10.1039/c6ra26669j

Cited by 25 publications

(21 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…54 Methoxy- and imidazole-substituted derivatives of deferasirox have shown antiproliferative activity related to iron depletion in lysosomes of treated cancerous liver and prostate cell lines in the range of submicromolar to micromolar concentrations. 55 Some of this promise is hindered by the nephrotoxicity frequently present in young and elderly patients after many years of therapy. 56 The finding of a proliferative effect in both cancer and normal cells, for undetermined reasons, further limits the application of deferasirox (or even BHPT) alone as an anticancer agent.…”

Section: Resultsmentioning

confidence: 99%

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

et al. 2017

View full text Add to dashboard Cite

The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV). This metal affinity preference drives deferasirox to facilitate the release of cytotoxic Ti(IV) intracellularly in exchange for Fe(III). An aqueous speciation study performed by potentiometric titration from pH 4 to 8 with micromolar levels of Ti(IV) deferasirox at a 1:2 ratio reveals exclusively Ti(deferasirox)2 in solution. The predominant complex at pH 7.4, [Ti(deferasirox)2]2−, exhibits the one of the highest aqueous stabilities observed for a potent cytotoxic Ti(IV) species, demonstrating little dissociation even after 1 month in cell culture media. UV–vis and 1H NMR studies show that the stability is unaffected by the presence of biomolecular Ti(IV) binders such as citrate, STf, and albumin, which have been shown to induce dissociation or regulate cellular uptake and can alter the activity of other antiproliferative Ti(IV) complexes. Kinetic studies on [Ti(deferasirox)2]2− transmetalation with Fe(III) show that a labile Fe(III) source is required to induce this process. The initial step of this process occurs on the time scale of minutes, and equilibrium for the complete transmetalation is reached on a time scale of hours to a day. This work reveals a mechanism to deliver Ti(IV) compounds into cells and trigger Ti(IV) release by a labile Fe(III) species. Cellular studies including other cTfm ligands confirm the Fe(III) depletion mechanism of these compounds and show their ability to induce early and late apoptosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…It is commercially used as an oral drug for the treatment of Feoverload. Def is currently being tested against several cancer cell lines [164][165][166][167] because it has the capacity to induce DNA fragmentation, inhibit DNA synthesis, deplete Fe, trigger caspase-related apoptosis, amongst other activities.…”

Section: Ono Ligandsmentioning

confidence: 99%

Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

et al. 2018

View full text Add to dashboard Cite

A very promising direction in the development of anticancer drugs is inhibiting the molecular pathways that keep cancer cells alive and able to metastasize. Copper and iron are two essential metals that play significant roles in the rapid proliferation of cancer cells and several chelators have been studied to suppress the bioavailability of these metals in the cells. This review discusses the major contributions that Cu and Fe play in the progression and spreading of cancer and evaluates select Cu and Fe chelators that demonstrate great promise as anticancer drugs. Efforts to improve the cellular delivery, efficacy, and tumor responsiveness of these chelators are also presented including a transmetallation strategy for dual targeting of Cu and Fe. To elucidate the effectiveness and specificity of Cu and Fe chelators for treating cancer, analytical tools are described for measuring Cu and Fe levels and for tracking the metals in cells, tissue, and the body.

show abstract

“…Therefore, to enhance its oral bioavailability, increasing its aqueous solubility is crucial. So far, few studies were performed to improve the solubility of DFX, such as encapsulated imidazole-modified DFX into polymeric micelles as a nano carrier [7], or to increase the solubility of DFX by decreasing its particle size and using sodium lauryl sulfate or Pluronic F127 as surfactants [8].…”

Section: Introductionmentioning

confidence: 99%

A Solid Ultra Fine Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) of Deferasirox for Improved Solubility: Optimization, Characterization, and In Vitro Cytotoxicity Studies

et al. 2020

View full text Add to dashboard Cite

The research work was designed to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of deferasirox (DFX). According to the solubility studies of DFX in different components, Peceol, Kolliphor EL, and Transcutol were selected as excipients. Pseudo-ternary phase diagrams were constructed, and then SNEDDS formation assessment studies and solubility of DFX in selected SNEDDSs formulations were performed. DFX loaded SNEDDS were prepared and characterized. The optimum DFX-SNEDDS formulations were developed. The relative safety of the optimized SNEDDS formulation was examined in a human immortalized myelogenous leukemia cell line, K562 cells, using the MTT cell viability test. Cytotoxicity studies revealed more cell viability (71.44%) of DFX loaded SNEDDS compared to pure DFX (3.99%) at 40 μM. The selected DFX-SNEDDS formulation was converted into S-SNEDDS by adsorbing into porous carriers, in order to study its dissolution behavior. The in vitro drug release studies indicated that DFX release (Q5%) from S-SNEDDS solidified with Neusilin UFL2 was significantly higher (93.6 ± 0.7% within 5 min) compared with the marketed product (81.65 ± 2.10%). The overall results indicated that the S-SNEDDS formulation of DFX could have the potential to enhance the solubility of DFX, which would in turn have the potential to improve its oral bioavailability as a safe novel delivery system.

show abstract

Imidazole-modified deferasirox encapsulated polymeric micelles as pH-responsive iron-chelating nanocarrier for cancer chemotherapy

Abstract: Modified deferasirox encapsulated polymeric micelles demonstrate pH-responsive and ON–OFF release behavior to deplete the iron level in cancer cells. The cellular iron deficiency is a novel strategy for cancer treatment.

Cited by 25 publications

References 48 publications

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes

Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

A Solid Ultra Fine Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) of Deferasirox for Improved Solubility: Optimization, Characterization, and In Vitro Cytotoxicity Studies

Contact Info

Product

Resources

About