Cross-linkable star-hyperbranched unimolecular micelles for the enhancement of the anticancer activity of clotrimazole

Gosecki, Mateusz; Ziemczonek, Piotr; Gosecka, Monika; Wielgus, Ewelina; Urbaniak, Malgorzata; Marcinkowska, Monika; Janaszewska, Anna; Klajnert‐Maculewicz, Barbara

doi:10.1039/d2tb02629e

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…Analyzing the IC 50 values contained in Table , it can be concluded that all systems (except for PBGE-PGGE_2_CLOT_a) retained the tumor cell selectivity characteristic for the free drug. , The cytotoxicity of drug-loaded copolymers was not correlated with the amount of the drug entrapped in the analyzed structures. Comparing the clotrimazole loading within the copolymer (Table ) with the IC 50 values (Table ), it can be concluded that systems with a low drug loading were the most effective, as previously observed for star-hyperbranched amphiphilic constructs, and this can be explained that the high clotrimazole content in the polymer structure hindered its release and immediate action.…”

Section: Resultsmentioning

confidence: 99%

“…A P(AM- ran -2-AAPBA) copolymer was obtained according to the procedure described previously 36 using AIBN (0.082 g; 0.5 mmol), acrylamide (4.68 g; 65.84 mmoL), and 2-acrylamidephenylboronic acid pinacol ester (2 g; 7.31 mmoL). The polymerization was carried out in 15 mL of a dimethylformamide (DMF)/dioxane mixture (5:1 v/v) at 70 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Dermal microvascular endothelium cells (HMEC-1) and human cervical cancer endothelial (HeLa) cells were grown according to the procedure described previously. 36 2.15. Determination of Cytotoxicity.…”

Section: Lap Shear Adhesion Test (Bioadhesion Test)mentioning

confidence: 99%

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Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy

Gosecka,

Gosecki,

Ziemczonek

et al. 2024

ACS Appl. Mater. Interfaces

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In the face of severe side effects of systemic chemotherapy used in cervical cancer, topical selective drug carriers with long-lasting effects are being sought. Hydrogels are suitable platforms, but their use is problematic in the case of delivery of hydrophobic drugs with anticancer activity. Herein, hydrogels constructed of unimolecular micelles displaying enhanced solubilization of aromatic lipophilic bioactive compounds are presented. Star-shaped poly(benzyl glycidyl ether)-block-poly(glycidyl glycerol ether) with an aryl-enriched core show high encapsulation capacity of poor watersoluble nifuratel and clotrimazole. Nifuratel attained selectivity against cervical cancer cells, whereas clotrimazole preserved its original selectivity. The combination of unimolecular micelles loaded with both drugs provided synergism; however, they were still selective against cervical cancer cells. The cross-linking of drug-loaded unimolecular micelles via dynamic boronic esters provided injectable and self-healable hydrogel drug carriers also displaying synergistic anticancer activity, suitable for intravaginal administration and assuring the effective coverage of the afflicted tissue area and efficient tissue permeability with hydrophobic bioactive compounds. Here, we show that the combination of star-shaped polyether amphiphiles and boronic ester cross-linking chemistry provides a new strategy for obtaining hydrogel platforms suitable for efficient hydrophobic drug delivery.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy

Gosecka,

Gosecki,

Ziemczonek

et al. 2024

ACS Appl. Mater. Interfaces

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“…CLT was encapsulated within aryl-enriched HbPGL using a solvent evaporation method 23 using methanol as a good solvent for both drug and polymer. Among all investigated formulations, a molar ratio of drug/macromolecule equal to 32 was optimal to obtain uniform gel-like structured fluids for all HbPGL derivatives of significantly reduced flow properties.…”

Section: Resultsmentioning

confidence: 99%

“…The complete release of CLT from these hydrogel carriers was limited to several hours. Recently, a novel synthetic strategy of CLT-enriched hydrogels constructed of dynamic cross-links has been elaborated based on the usage of drug-loaded unimolecular micelles displaying prolonged CLT release reaching 40 h. − This approach required, however, the use of a cross-linking agent for hydrogel formation.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Solubility and Bioavailability of Clotrimazole in Aqueous Solutions with Hydrophobized Hyperbranched Polyglycidol for Improved Antifungal Activity

Jaworska-Krych,

Gosecka,

Gosecki

et al. 2024

ACS Appl. Mater. Interfaces

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The poor solubility of clotrimazole in the aqueous medium and the uncontrolled removal of the drug-loaded suppository content limit its effectiveness in the treatment of vulvovaginal candidiasis. We present here the aqueous formulations of clotrimazole in the form of non-Newtonian structured fluids, i.e., Bingham plastic or pseudoplastic fluids constructed of hyperbranched polyglycidol, HbPGL, with a hydrophobized core with aryl groups such as phenyl or biphenyl. The amphiphilic constructs were obtained by the modification of linear units containing monohydroxyl groups with benzoyl chloride, phenyl isocyanate, and biphenyl isocyanate, while the terminal 1,2-diol groups in the shell were protected during the modification step, followed by their deprotection. The encapsulation of clotrimazole within internally hydrophobized HbPGLs using a solvent evaporation method followed by water addition resulted in structured fluids formation. Detailed Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses performed for aryl-HbPGLs with clotrimazole revealed the difference in drug compatibility among polymers. Clotrimazole in biphenyl-enriched HbPGL, unlike phenyl derivatives, was molecularly distributed in both the dry and the hydrated states, resulting in transparent formulations. The shear-thinning properties of the obtained fluid formulations make them injectable and thus suitable for the intravaginal application. Permeability tests performed with the usage of the Franz diffusion cell showed a 5-fold increase in the permeability constant of clotrimazole compared to drugs loaded in a commercially available disposable tablet and a 50-fold increase of permeability in comparison to the aqueous suspension of clotrimazole. Furthermore, the biphenyl-modified HbPGL-based drug liquid showed enhanced antifungal activity against both Candida albicans and Candida glabrata that was retained for up to 7 days, in contrast to the phenyl-HbPGL derivatives and the tablet. With their simple formulation, convenient clotrimazole/biphenyl-HbPGL formulation strategy, rheological properties, and enhanced antifungal properties, these systems are potential antifungal therapeutics for gynecological applications. This study points in the synthetic direction of improving the solubility of poorly water-soluble aryl-enriched pharmaceuticals.

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Intermediate conductance calcium-activated potassium channel (KCa3.1) in cancer: Emerging roles and therapeutic potentials

Thi Hong Van,

Hyun Nam

2024

Biochemical Pharmacology

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Cross-linkable star-hyperbranched unimolecular micelles for the enhancement of the anticancer activity of clotrimazole

Abstract: Clotrimazole, a hydrophobic drug routinely used in the treatment of vaginal candidiasis, also shows antitumor activity. However, its use in chemotherapy has been unsuccessful due to its low solubility in...

Cited by 7 publications

References 51 publications

Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy

Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy

Enhanced Solubility and Bioavailability of Clotrimazole in Aqueous Solutions with Hydrophobized Hyperbranched Polyglycidol for Improved Antifungal Activity

Intermediate conductance calcium-activated potassium channel (KCa3.1) in cancer: Emerging roles and therapeutic potentials

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