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Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

ABSTRACT: One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L₂(Metal)₃]⁶⁺ where Metal = Cu²⁺, Zn²⁺ or Mn²⁺) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L₂Cu₃]⁶⁺ and [L₂Zn₃]⁶⁺ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO₄³-, SO₄²- or PhOPO₃²-) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L₂Cu₃]⁶⁺ and [L₂Zn₃]⁶⁺ complexes but via different mechanisms.

SUBMITTER: Allison SJ

PROVIDER: S-EPMC8222254 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

Allison Simon J SJ Bryk Jaroslaw J Clemett Christopher J CJ Faulkner Robert A RA Ginger Michael M Griffiths Hollie B S HBS Harmer Jane J Jane Owen-Lynch P P Pinder Emma E Wurdak Heiko H Phillips Roger M RM Rice Craig R CR

Nature communications 20210623 1

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which sho ...[more]

PMID: 34162854

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Project description:Gold(iii) porphyrin-PEG conjugates [Au(TPP-COO-PEG5000-OCH3)]Cl (1) and [Au(TPP-CONH-PEG5000-OCH3)]Cl (2) have been synthesized and characterized. Based on the amphiphilic character of the conjugates, they were found to undergo self-assembly into nanostructures with size 120-200 nm and this did not require the presence of other surfactants or components for nano-assembly, unlike most conventional drug nano-formulations. With a readily hydrolyzable ester linkage, chemotherapeutic [Au(TPP-COOH)]+ exhibited triggered release from the conjugate 1 in acidic buffer solution as well as in vitro and in vivo without the formation of toxic side products. The nanostructures of 1 showed higher cellular uptake into cancer cells compared to non-tumorigenic cells, owing to their energy-dependent uptake mechanism. This, together with a generally higher metabolic rate and more acidic nature of cancer cells which can lead to faster hydrolysis of the ester bond, afforded 1 with excellent selectivity in killing cancer cells compared with non-tumorigenic cells in vitro. This was corroborated by fluorescence microscopy imaging and flow cytometric analysis of co-culture model of colon cancer (HCT116) and normal colon (NCM460) cells. In vivo experiments showed that treatment of nude mice bearing HCT116 xenografts with 1 resulted in significant inhibition of tumor growth and, more importantly, minimal systemic toxicity as revealed by histopathological analysis of tissue sections and blood biochemisty. The latter is explained by a lower accumulation of 1 in organs of treated mice at its effective dosage, as compared to that of other gold(iii) porphyrin complexes. Co-assembly of 1 and doxorubicin resulted in encapsulation of doxorubicin by the nanostructures of 1. The nanocomposites demonstrated a strong synergism on killing cancer cells and could overcome efflux pump-mediated drug-resistance in a doxorubicin-resistant ovarian cancer cell line (A2780adr) which was found in cells incubated with doxorubicin alone. Also, the nanocomposites accumulated more slowly in non-tumorigenic cells, resulting in a lower toxicity toward non-tumorigenic cells. These results indicate the potential application of 1 not only as an anti-cancer agent but also as a nanoscale drug carrier for chemotherapy.

Project description:Supramolecular hydrogels have emerged as a class of promising biomaterials for applications such as drug delivery and tissue engineering. Self-assembling peptides have been well studied for such applications, but low molecular weight (LMW) amino acid-derived gelators have attracted interest as low-cost alternatives with similar emergent properties. Fluorenylmethyloxycarbonyl-phenylalanine (Fmoc-Phe) is one such privileged motif often chosen due to its inherent self-assembly potential. Previously, we developed cationic Fmoc-Phe-DAP gelators that assemble into hydrogel networks in aqueous NaCl solutions of sufficient ionic strength. The chloride anions in these solutions screen the cationic charge of the gelators to enable self-assembly to occur. Herein, we report the effects of varying the anions of sodium salts on the gelation potential, nanoscale morphology, and hydrogel viscoelastic properties of Fmoc-Phe-DAP and two of its fluorinated derivatives, Fmoc-3F-Phe-DAP and Fmoc-F5-Phe-DAP. It was observed that both the anion identity and gelator structure had a significant impact on the self-assembly and gelation properties of these derivatives. Changing the anion identity resulted in significant polymorphism of the nanoscale morphology of the assembled states that was dependent on the chemical structure of the gelator. The emergent viscoelastic character of the hydrogel networks was also found to be reliant on the anion identity and gelator structure. These results demonstrate the complex interplay between the gelator and environment that have a profound and often unpredictable impact on both self-assembly properties and emergent viscoelasticity in supramolecular hydrogels formed by LMW compounds. This work also illustrates the current lack of understanding that limits the rational design of potential biomaterials that will be in contact with complex biological fluids and provides motivation for additional research to correlate the chemical structure of LMW gelators with the structure and emergent properties of the resulting supramolecular assemblies as a function of environment.

Dataset Information

Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

Publications

Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

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