Antiproliferative Imidazo-Pyrazole-Based Hydrogel: A Promising Approach for the Development of New Treatments for PLX-Resistant Melanoma
"> Figure 1
<p>IMP derivatives selected for screening on MM cells.</p> "> Figure 2
<p>Representative optical microphotographs of R4HG after sonication and drying at 100 °C until a constant weight equal to that before swelling was achieved (R4HG-D). Objective 10× (<b>a</b>,<b>b</b>), 20× (<b>c</b>) and 40× objective (<b>d</b>).</p> "> Figure 3
<p>Fully dried hydrogel R4HG-4I-D obtained after drying R4HG-4I at 100 °C until a constant weight equal to that before swelling was achieved. Objective 10× (<b>a</b>), 20× (<b>b</b>,<b>c</b>) and 40× (<b>d</b>).</p> "> Figure 4
<p>SEM micrographs of lyophilized R4HG (<b>a</b>) and R4HG-4I (<b>b</b>).</p> "> Figure 5
<p>Cumulative mass loss percentage curves of R4HG (purple line) and R4HG-4I (light purple line) over time in PBS at 37 °C (<b>a</b>); Korsmeyer–Peppas kinetic models fitting data of the cumulative mass loss curves of R4HG and R4HG-4I (<b>b</b>).</p> "> Figure 6
<p>Water loss profile of R4HG (purple line) and R4HG-4I (light purple line) over time and heating at 45–50 °C (<b>a</b>); Korsmeyer–Peppas kinetic models (<b>b</b>).</p> "> Figure 7
<p>Cumulative swelling ratio percentage curves of R4HG and of R4HG-4I.</p> "> Figure 8
<p>Potentiometric titration of R4HG and R4HG-4I (solid lines with round indicators); first derivatives (dpH/dV) of the titration curves (dotted lines with square indicators). FD = first derivative.</p> "> Figure 9
<p>Cumulative release curves of <b>4I</b> from R4HG-4I and from an aqueous suspension of <b>4I</b>.</p> "> Figure 10
<p>Cell viability was evaluated in MEOV NT (<b>a</b>) and MEOV PLX-R (<b>b</b>) cells exposed to increasing concentrations of <b>4G</b> (0–100 µM) for 24, 48, and 72 h. Bar graphs summarize quantitative data of the means ± SEM of three independent experiments. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001 vs. Control (Ctr) cells.</p> "> Figure 11
<p>Cell viability was evaluated in MEOV NT (<b>a</b>) and MEOV PLX-R (<b>b</b>) cells exposed to increasing concentrations of <b>4I</b> (0–100 µM) for 24, 48 and 72 h. Bar graphs summarize quantitative data of the means ± SEM of three independent experiments. * <span class="html-italic">p</span> < 0.05, *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001 vs. Control (Ctr) cells.</p> "> Figure 12
<p>Cell viability evaluated in MEOV PLX-R cells exposed to increasing concentrations of PLX and <b>4I</b> (0–20 µM) for 72 h. Bar graphs summarize quantitative data of the means ± SEM of three independent experiments. *** <span class="html-italic">p</span> < 0.001 vs. Control (Ctr) cells; ° <span class="html-italic">p</span> < 0.05 vs. PLX; °° <span class="html-italic">p</span> < 0.01 vs. PLX.</p> "> Figure 13
<p>H<sub>2</sub>O<sub>2</sub> production was analyzed in MEOV NT (<b>a</b>) and MEOV PLX-R (<b>b</b>) cells exposed to increasing concentrations (0–100 µM) of <b>4I</b> for 24, 48, and 72 h. Bar graphs summarize quantitative data of the means ± SEM of three independent experiments. ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001, **** <span class="html-italic">p</span> < 0.0001 vs. Control cells.</p> "> Figure 14
<p>Values of ROS DCFH positive cells (%) vs. cell viability of MEOV NT population (<b>a</b>) and of MEOV PLX-R population (<b>b</b>), measured in the experiments carried out with <b>4I</b> on MEOV NT and MOV PLX-R melanoma cells.</p> "> Scheme 1
<p>Reverse suspension co-polymerization of M4 to achieve R4. The number 4 refers to the number of methylene groups in the chain linking the phenyl ring and the ammonium group both in M4 and in R4. In the structure of R4, n = 4. EBA = ethylene bis-acrylamide; SPAN 85 = (Z,Z,Z)-Sorbitan tri-9-octadecenoate; APS = ammonium persulfate; TMEDA = Tetramethylethylenediamine.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Instruments
2.2. Chemistry
2.2.1. Preparation of R4HG and R4-HG-4I
2.2.2. Scanning Electron Microscopy (SEM)
2.2.3. Chemometric-Assisted ATR-FTIR Spectroscopy
2.2.4. Content of 4I in R4HG-4I, Drug Loading (DL%) and Entrapment Efficiency (EE%)
Statistical Analysis
2.2.5. Biodegradability of R4HG and R4HG-4I over Time by In Vitro Mass Loss Experiments
2.2.6. Water Loss Tests
2.2.7. Equilibrium Swelling Rate
2.2.8. Potentiometric Titration of R4HG and R4HG-4I
2.2.9. Rheological Experiments
2.2.10. Evaluation of 4I in Vitro Releases
2.3. Biological Screening
2.3.1. Cell Culture Conditions
2.3.2. Treatments
2.3.3. Cell Viability Assay
2.3.4. Detection of Hydrogen Peroxide (H2O2) Production
2.3.5. Statistical Analyses
3. Results and Discussion
3.1. Chemistry
3.1.1. Synthesis and Characterization of R4
3.1.2. Preparation of R4HG and R4HG-4I
3.1.3. SEM Analysis
3.1.4. Chemometric-Assisted ATR-FTIR Analyses
Principal Components Analysis (PCA)
3.1.5. Determination of the Exact Amount of 4I Loaded in R4HG-4I
3.1.6. Evaluation of Biodegradability of R4HG and R4-HG-4I over Time by Mass Loss Experiments
3.1.7. Water Loss Experiments
3.1.8. Equilibrium Swelling Rate Experiments
Kinetic Studies
3.1.9. Potentiometric Titrations of R4HG and R4HG-4I
3.1.10. Rheological Studies
3.1.11. Evaluation of 4I in Vitro Release Profile
Kinetic Studies
3.2. Biological Evaluations
3.2.1. Cytotoxic Effects of 4I and 4G on MM Cells
3.2.2. Dose-Dependent Reactive Oxygen Species (ROS) Production in MEOV NT and MEOV PLXR Cells
3.2.3. Correlation between H2O2 Production and Cytotoxicity of 4I
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Times | 4G (μM) | 4I (μM) | ||
---|---|---|---|---|
MEOV NT | MEOV PLX-R | MEOV NT | MEOV PLX-R | |
24 h | 120.7 ± 0.0 | 224.9 ± 45.5 | 112 ± 9.9 | 162.8 ± 4.9 |
48 h | 28.6 ± 0.9 | 128.6 ± 36.6 | 26.3 ± 5.3 | 72.9 ± 10.2 |
72 h | 18.5 ± 2.3 | 16.3 ± 0.1 | 10.9 ± 1.7 | 15.8 ± 4.4 |
Entry | Vi (mL) | Wi (mg) | R4 Vi/Wi (mL/mg) | R4+4I Vi/Wi (mL/mg) | Vf Hydrogel (mL) | H2O (mL) | Dosage (mg/mL) (% wt/v) | EDS (%) | EWC (%) |
---|---|---|---|---|---|---|---|---|---|
R4 | 0.69 | 203.1 | 4.50 | 3.81 | 53.3 * (5.3) | 552.2 1 | 84.7 1 | ||
4I | 0.1 | 21.4 | 0.69/203.1 | 0.79/224.5 | 6.00 | 5.21 | 43.1 ** (4.3) | 659.5 2 | 86.8 2 |
Abs | 4I (mg/mL) | 4I (mg) in 82.6 mg * | 4I (mg) in 224.5 mg ** | DL (%) | EE/DLC (%) |
---|---|---|---|---|---|
0.9496 | 0.697 | 6.97 ± 0.19 | 18.9 ± 0. 5 | 8.4 | 88.3 |
0.9400 | 0.678 | ||||
0.9586 | 0.715 |
Kinetic Model | R2 of R4HG | R2 of R4HG-4I |
---|---|---|
Zero-order | 0.7500 | 0.6239 |
First-order | 0.8284 | 0.7754 |
Hixson–Crowel | 0.7500 | 0.6239 |
Higuchi | 0.8971 | 0.8392 |
Korsmeyer–Peppas | 0.9266 | 0.8690 |
R4 | R4HG-4I-D | |
---|---|---|
WePSO * | 3.9139 | 0.4286 |
K2 ** | 0.6574 | 0.7424 |
Entry | Weight (mg) | HCl 0.1 N (mL) | NH2 (mmol) | mmoles NH2/g | µmoles NH2/g |
---|---|---|---|---|---|
R4HG | 50.3 | 0.4 ± 0.01 | 0.04 ± 0.001 | 0.7952 ± 0.0199 | 795.2 ± 10.9 |
R4HG-4I | 52.8 | 0.4 ± 0.02 | 0.04 ± 0.002 | 0.7576 ± 0.0379 | 757.6 ± 37.9 |
Entry | n | Yield Stress | |||
---|---|---|---|---|---|
R4HG | −1.0005 | 0.1013 | 101.3 | 0.46 | 2.87 |
R4HG-4I | −1.0594 | 4.2424 | 4242.4 | 42.7 | 25.71 |
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Alfei, S.; Milanese, M.; Brullo, C.; Valenti, G.E.; Domenicotti, C.; Russo, E.; Marengo, B. Antiproliferative Imidazo-Pyrazole-Based Hydrogel: A Promising Approach for the Development of New Treatments for PLX-Resistant Melanoma. Pharmaceutics 2023, 15, 2425. https://doi.org/10.3390/pharmaceutics15102425
Alfei S, Milanese M, Brullo C, Valenti GE, Domenicotti C, Russo E, Marengo B. Antiproliferative Imidazo-Pyrazole-Based Hydrogel: A Promising Approach for the Development of New Treatments for PLX-Resistant Melanoma. Pharmaceutics. 2023; 15(10):2425. https://doi.org/10.3390/pharmaceutics15102425
Chicago/Turabian StyleAlfei, Silvana, Marco Milanese, Chiara Brullo, Giulia Elda Valenti, Cinzia Domenicotti, Eleonora Russo, and Barbara Marengo. 2023. "Antiproliferative Imidazo-Pyrazole-Based Hydrogel: A Promising Approach for the Development of New Treatments for PLX-Resistant Melanoma" Pharmaceutics 15, no. 10: 2425. https://doi.org/10.3390/pharmaceutics15102425
APA StyleAlfei, S., Milanese, M., Brullo, C., Valenti, G. E., Domenicotti, C., Russo, E., & Marengo, B. (2023). Antiproliferative Imidazo-Pyrazole-Based Hydrogel: A Promising Approach for the Development of New Treatments for PLX-Resistant Melanoma. Pharmaceutics, 15(10), 2425. https://doi.org/10.3390/pharmaceutics15102425