Mercury-containing supramolecular micelles with highly sensitive pH-responsiveness for selective cancer therapy

Alemayehu, Yihalem Abebe; Ilhami, Fasih Bintang; Manayia, Abere Habtamu; Cheng, Chih‐Chia

doi:10.1016/j.actbio.2021.05.044

Cited by 15 publications

(26 citation statements)

References 63 publications

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“…The findings above inspired us to explore the structural stability of Cy-PEG and UrCy-PEG nanogels in DMEM containing 10 V% FBS at different pH values (pH 7.4 and 6.0) by DLS at 25 °C. DMEM containing FBS can act as a hydrogen-bond destabilizing agent and cause disintegration of self-assembled structures. − As shown in Figure c, the average particle diameter of UrCy-PEG nanogels was almost unchanged at pH 7.4 after 24 h incubation in DMEM containing FBS, whereas the particle diameter of Cy-PEG gradually decreased from 65 to 31 nm over time, indicating the UrCy quadruple hydrogen-bonding units within the nanogel play a predominant role in maintaining the stability of the self-assembled structures under serum-containing biological conditions. In other words, the weak double hydrogen bonds between the Cy units cannot maintain the structural integrity of the nanogels in FBS-containing biological media.…”

Section: Resultsmentioning

confidence: 96%

“…After 3 h incubation, around 73% HeLa cells incubated with DOXloaded nanogels still remained viable (Figure 5j,n), suggesting that both nanogels were gradually endocytosed by HeLa cells and that the DOX entrapped in the nanogels was released extremely slowly during the early stages of internalization. After an incubation period of 24 h with DOX-loaded UrCy-PEG nanogels, the percentages of early apoptosis and late apoptosis in HeLa cells substantially increased to 40.6 and 50.7%, respectively, while only 7.6% cells remained viable (Figure 5p), In contrast, only 49 DOX-loaded Cy-PEG nanogels for 24 h were apoptotic (39.3% early apoptotic cells and 9.8% late-apoptotic cells; Figure 5l). These results clearly demonstrate that DOX-loaded UrCy-PEG nanogels induced a more rapid chemotherapeutic effect than the Cy-PEG system, possibly due to more rapid disruption of the self-assembled nanogels in the acidic intracellular environment of the cancer cells promoting faster triggered intracellular drug release (Figure 3e,f) that induces a high level of apoptotic cell death.…”

Section: Resultsmentioning

confidence: 99%

“…Drug-loaded nanocarriers must possess long-term structural stability in the normal physiological environment to achieve safe, effective delivery of medicines . Thus, we further evaluated the drug-entrapment stability of Cy-PEG and UrCy-PEG nanogels in FBS-rich DMEM at pH 7.4 and 6.0 by DLS at 25 °C. − As shown in Figure d, neither of the DOX-loaded nanogels exhibited significant changes in their particle size after incubation at pH 7.4 for 24 h, revealing that the nanogels have extremely high levels of drug-entrapped structural stability, even at DOX loading contents as high as 23% for Cy-PEG and 55% for UrCy-PEG. Surprisingly, DOX-loaded Cy-PEG nanogels showed apparently higher stability compared to the empty nanogels (Figure c), implying that the presence of stable intermolecular interactions between the DOX and aromatic Cy moieties within the nanogels significantly improved the structural stability of the nanogels.…”

Section: Resultsmentioning

confidence: 99%

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Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment

et al. 2021

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This study provides a significant contribution to the development of multiple hydrogen-bonded supramolecular nanocarrier systems by demonstrating that controlling the hydrogen bond strength within supramolecular polymers represents a crucial factor to tailor the drug delivery performance and enhance the effectiveness of cancer therapy. Herein, we successfully developed two kinds of poly(ethylene glycol)-based telechelic polymers Cy-PEG and UrCy-PEG having selfconstituted double and quadruple hydrogen-bonding cytosine (Cy) and ureido-cytosine (UrCy) end-capped groups, respectively, which directly assemble into spherical nanogels with a number of interesting physical characteristics in aqueous solutions. The UrCy-PEG nanogels containing quadruple hydrogen-bonded UrCy dimers exhibited excellent long-term structural stability in a serum-containing biological medium, whereas the double hydrogen-bonded Cy moieties could not maintain the structural integrity of the Cy-PEG nanogels. More importantly, after the drug encapsulation process, a series of in vitro experiments clearly confirmed that drug-loaded UrCy-PEG nanogels induced selective apoptotic cell death in cancer cells without causing significant cytotoxicity to healthy cells, while drug-loaded Cy-PEG nanogels exerted nonselective cytotoxicity toward both cancer and normal cells, indicating that increasing the strength of hydrogen bonds in nanogels plays a key role in enhancing the selective cellular uptake and cytotoxicity of drugs and the subsequent induction of apoptosis in cancer cells.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment

et al. 2021

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“…All solvents were high-performance liquid chromatography-grade and were obtained from TEDIA (Fairfield, OH, USA). BU-PPG and Hg-BU-PPG polymers were synthesized and characterized as previously described. , …”

Section: Methodsmentioning

confidence: 99%

Photoreactive Mercury-Containing Metallosupramolecular Nanoparticles with Tailorable Properties That Promote Enhanced Cellular Uptake for Effective Cancer Chemotherapy

et al. 2023

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A new potential route to enhance the efficiency of supramolecular polymers for cancer chemotherapy was successfully demonstrated by employing a photosensitive metallosupramolecular polymer (Hg-BU-PPG) containing an oligomeric poly(propylene glycol) backbone and highly sensitive pH-responsive uracil-mercury-uracil (U-Hg-U) bridges. This route holds great promise as a multifunctional bioactive nano-object for development of more efficient and safer cancer chemotherapy. Owing to the formation of uracil photodimers induced by ultraviolet irradiation, Hg-BU-PPG can form a photo-cross-linked structure and spontaneously forms spherical nanoparticles in aqueous solution. The irradiated nanoparticles possess many unique characteristics, such as unique fluorescence behavior, highly sensitive pH-responsiveness, and intriguing phase transition behavior in aqueous solution as well as high structural stability and antihemolytic activity in biological media. More importantly, a series of cellular studies clearly confirmed that the U-Hg-U photo-cross-links in the irradiated nanoparticles substantially enhance their selective cellular uptake by cancer cells via macropinocytosis and the mercury-loaded nanoparticles subsequently induce higher levels of cytotoxicity in cancer cells (compared to non-irradiated nanoparticles), without harming normal cells. These results are mainly attributed to cancer cell microenvironment-triggered release of mercury ions from disassembled nanoparticles, which rapidly induce massive levels of apoptosis in cancer cells. Overall, the pH-sensitive U-Hg-U photo-cross-links within this newly discovered supramolecular system are an indispensable factor that offers a potential path to remarkably enhance the selective therapeutic effects of functional nanoparticles toward cancer cells.

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“…To circumvent these challenges, nanomedicines have been the subject of extensive research to assess their applicability as platforms for cancer therapy [ 7 ]. Examples include polymers [ 8 ], liposomes [ 9 ], quantum dots [ 10 ], and metals [ 11 ], all of which are used to shield hydrophobic drugs from the RES; these moieties also release drugs at the target site in a controlled manner, thereby minimizing side effects and toxicity. Despite these advantages, few nanomedicines have been clinically approved [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Smart Vitamin Micelles as Cancer Nanomedicines for Enhanced Intracellular Delivery of Doxorubicin

Lee

Chandrasekaran

et al. 2021

IJMS

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Chemotherapy is one of the most effective treatments for cancer. However, intracellular delivery of many anticancer drugs is hindered by their hydrophobicity and low molecular weight. Here, we describe highly biocompatible and biodegradable amphiphilic vitamin conjugates comprising hydrophobic vitamin E and hydrophilic vitamin B labeled with dual pH and glutathione-responsive degradable linkages. Vitamin-based micelles (vitamicelles), formed by self-assembly in aqueous solutions, were optimized based on their stability after encapsulation of doxorubicin (DOX). The resulting vitamicelles have great potential as vehicles for anticancer drugs because they show excellent biocompatibility (>94% after 48 h of incubation) and rapid biodegradability (>90% after 2.5 h). Compared with free DOX, DOX-loaded vitamicelles showed a markedly enhanced anticancer effect as they released the drug rapidly and inhibited drug efflux out of cells efficiently. By exploiting these advantages, this study not only provides a promising strategy for circumventing existing challenges regarding the delivery of anticancer drugs but also extends the utility of current DOX-induced chemotherapy.

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Mercury-containing supramolecular micelles with highly sensitive pH-responsiveness for selective cancer therapy

Cited by 15 publications

References 63 publications

Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment

Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment

Photoreactive Mercury-Containing Metallosupramolecular Nanoparticles with Tailorable Properties That Promote Enhanced Cellular Uptake for Effective Cancer Chemotherapy

Smart Vitamin Micelles as Cancer Nanomedicines for Enhanced Intracellular Delivery of Doxorubicin

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