Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer
Abstract
1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Preparation and Optimization of Stealth Blank Nanoparticles
2.2.2. Initial Screening Using the One-Factor-at-a-Time Method
Factors | Variables |
---|---|
Solvent composition (Organic phase) | Ethyl acetate (EA):Dimethylformamide (DMF) |
Ethyl acetate (EA):Dimethyl sulfoxide (DMSO) | |
Ethyl acetate (EA):Acetonitrile | |
Ethyl acetate (EA):Acetone | |
Ethyl acetate (EA):DMSO:Acetone | |
Solvent ratio (EA: other solvent) (Total volume = 2 mL) | 1.2:0.8 |
1.4:0.6 | |
1.6:0.4 | |
1.8:0.2 | |
mPEG-PLGA concentration (mg/2 mL) | 20, 50, 75, 100, 150 |
Organic: Aqueous ratio | 2:8 |
2:10 | |
2:12 | |
2:14 | |
2:16 | |
Polyvinyl alcohol concentration (%) | 0.25, 0.5, 1.0, 2.0, 3.0 |
Sonication pulse rate (on:off) | 7:3, 8:2; 9:1 |
Amplitude (%) | 25, 30, 35, 40 |
Sonication time (minutes) | 2.5, 5, 7.5, 10 |
2.2.3. Full Factorial Statistical Experimental Design
2.3. Preparation of Stealth Brusatol- and Docetaxel-Loaded Nanoparticles
2.3.1. Evaluation of Particle and Zeta Potential
2.3.2. Morphological Studies
2.3.3. Infrared Spectroscopy Analysis
2.3.4. Drug Content Determination
2.3.5. Release Profile of Docetaxel- and Brusatol-Loaded Nanoparticles
2.4. Cell Culture Experiments
2.4.1. Combination Index Determination
2.4.2. Viable Cell Count and In Vitro Cytotoxicity
2.4.3. Flow Cytometry Studies
Cell Cycle Arrest Analysis
Caspase 3/7 Activity Assay
Immunoblot Analysis
2.5. Statistical Analysis
3. Results and Discussion
3.1. Screening of Formulation and Process Variables Using the One-Factor-at-a-Time Approach
3.2. Design of Experiments—Full Factorial Statistical Experimental Design
3.3. Regression Equation
3.4. Nanoparticle Morphology, Particle Size, and Zeta Potential Characterization
3.5. Drug-Loading Studies
3.6. FT-IR Spectroscopy Evaluation
3.7. Drug Release Studies
3.8. Evaluation of Cytotoxicity of Pure Drugs and Determination of Combination Index
3.9. Cytotoxicity Evaluations of Brusatol- and Docetaxel-Loaded Nanoparticle Formulations
3.9.1. Viable Cell Count and In Vitro Cytotoxicity
3.9.2. Cell Cycle Analysis
3.9.3. Caspase-3/7 Activity
3.9.4. Immunoblotting Assay
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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Formulation | Docetaxel (mg) | Brusatol (mg) | Drug:Polymer (%) |
---|---|---|---|
1 | 7 | 3 | 20% |
2 | 6 | 4 | 20% |
3 | 5 | 5 | 20% |
4 | 4 | 6 | 20% |
5 | 2.5 | 7.5 | 20% |
6 | 3 | 7 | 20% |
7 | 2 | 8 | 20% |
8 | 1 | 9 | 20% |
9 | 4.5 | 10.5 | 30% |
10 | 3 | 12 | 30% |
Formulation Factor | Variation | Size (nm) | Process Factor | Variation | Size (nm) |
---|---|---|---|---|---|
Solvent composition | Ethyl acetate:DMF | 202.8 | Pulse (on/off, sec) | No pulse | 188.7 |
Ethyl acetate:acetone | 206.9 | 7:3 | 230.8 | ||
Ethyl acetate:DMSO | 212.8 | 8:2 | 178.1 | ||
Ethyl acetate:ACN | 207.6 | 9:1 | 175.9 | ||
Solvent ratio | 1.2:0.8 | 371.6 | Amplitude (%) | 25 | 176.9 |
1.4:0.6 | 391 | 30 | 196.1 | ||
1.6:0.4 | 179.2 | 35 | 193.3 | ||
1.8:0.2 | 200.4 | 40 | 203.8 | ||
Polymer conc. | 20 mg/2 mL | 207.1 | Sonic. time (min) | 2.5 | 199.3 |
50 mg/2 mL | 189.6 | 5 | 188.8 | ||
75 mg/2 mL | 185.7 | 7.5 | 186.8 | ||
100 mg/2 mL | 194.5 | 10 | 186.1 | ||
150 mg/2 mL | 355.1 | ||||
Organic:Aqueous | 2:8 | 203 | |||
2:10 | 193.4 | ||||
2:12 | 192.1 | ||||
2:14 | 318.5 | ||||
2:16 | 399.4 | ||||
PVA conc. (%) | 0.25 | 186.9 | |||
0.5 | 182.1 | ||||
1 | 184.5 | ||||
2 | 195 | ||||
3 | 195 |
Formulation | Polymer Conc. (mg/2 mL) | Organic:Aqu | PVA Conc. (%) | Amplitude (%) | Size (nm) | Polydispersity |
---|---|---|---|---|---|---|
1 | 25 | 2|8 | 1.5 | 30 | 225.2 | 0.149 |
2 | 50 | 2|8 | 0.5 | 30 | 212.5 | 0.048 |
3 | 25 | 2|8 | 1.5 | 26 | 230.4 | 0.134 |
4 | 50 | 2|8 | 1.5 | 26 | 201.7 | 0.104 |
5 | 50 | 2|8 | 1.5 | 30 | 206.7 | 0.049 |
6 | 37.5 | 2|10 | 1 | 28 | 195 | 0.081 |
7 | 25 | 2|8 | 0.5 | 30 | 220.5 | 0.064 |
8 | 50 | 2|8 | 1.5 | 30 | 212.9 | 0.058 |
9 | 50 | 2|12 | 0.5 | 30 | 203.3 | 0.067 |
10 | 25 | 2|12 | 1.5 | 26 | 186.7 | 0.128 |
11 | 25 | 2|8 | 1.5 | 26 | 223.8 | 0.105 |
12 | 37.5 | 2|10 | 1 | 28 | 201.8 | 0.088 |
13 | 50 | 2|12 | 1.5 | 26 | 185.6 | 0.032 |
14 | 37.5 | 2|10 | 1 | 28 | 190.6 | 0.116 |
15 | 50 | 2|8 | 0.5 | 26 | 197.8 | 0.089 |
16 | 25 | 2|12 | 1.5 | 30 | 177.3 | 0.102 |
17 | 50 | 2|12 | 0.5 | 30 | 181.6 | 0.059 |
18 | 25 | 2|8 | 1.5 | 30 | 210.5 | 0.098 |
19 | 25 | 2|12 | 1.5 | 26 | 158.4 | 0.08 |
20 | 25 | 2|12 | 0.5 | 30 | 173.3 | 0.114 |
21 | 37.5 | 2|10 | 1 | 28 | 184.9 | 0.046 |
22 | 50 | 2|12 | 1.5 | 30 | 181 | 0.085 |
23 | 25 | 2|12 | 0.5 | 26 | 173.7 | 0.042 |
24 | 25 | 2|8 | 0.5 | 26 | 203.3 | 0.079 |
25 | 50 | 2|8 | 0.5 | 30 | 192.3 | 0.089 |
26 | 25 | 2|12 | 1.5 | 30 | 170.4 | 0.093 |
27 | 37.5 | 2|10 | 1 | 28 | 175.1 | 0.147 |
28 | 25 | 2|8 | 0.5 | 30 | 186 | 0.075 |
29 | 25 | 2|12 | 0.5 | 30 | 167.7 | 0.119 |
30 | 25 | 2|8 | 0.5 | 26 | 181.9 | 0.079 |
31 | 50 | 2|12 | 0.5 | 26 | 173.1 | 0.069 |
32 | 50 | 2|12 | 1.5 | 26 | 172.7 | 0.077 |
33 | 50 | 2|8 | 1.5 | 26 | 184.1 | 0.106 |
34 | 50 | 2|12 | 1.5 | 30 | 176 | 0.061 |
35 | 25 | 2|12 | 0.5 | 26 | 171.7 | 0.105 |
36 | 50 | 2|8 | 0.5 | 26 | 183.8 | 0.138 |
37 | 50 | 2|12 | 0.5 | 26 | 159.6 | 0.071 |
Analysis of Variance | |||||
---|---|---|---|---|---|
Source | DF | Adj SS | Adj MS | F-Value | p-Value |
Model | 6 | 9113.7 | 1518.94 | 10.91 | 0.000 |
Linear | 4 | 7926.1 | 1981.54 | 14.23 | 0.000 |
Pol. Conc. (mg/2 mL) | 1 | 62.7 | 62.72 | 0.45 | 0.507 |
Org:Aqueous | 1 | 6903.1 | 6903.12 | 49.59 | 0.000 |
PVA Conc. (%) | 1 | 528.1 | 528.12 | 3.79 | 0.061 |
Amp (%) | 1 | 432.2 | 432.18 | 3.10 | 0.088 |
2-Way Interactions | 2 | 1187.5 | 593.75 | 4.27 | 0.023 |
Pol. Conc. (mg/2 mL) * Org:Aqueous | 1 | 723.9 | 723.90 | 5.20 | 0.030 |
Org:Aqueous * PVA Conc. (%) | 1 | 463.6 | 463.60 | 3.33 | 0.078 |
Error | 30 | 4176.4 | 139.21 | ||
Curvature | 1 | 4.4 | 4.36 | 0.03 | 0.863 |
Lack-of-Fit | 9 | 1301.2 | 144.58 | 1.01 | 0.466 |
Pure Error | 20 | 2870.8 | 143.54 | ||
Total | 36 | 13,290.1 |
Solution | Pol. Conc. (mg/2 mL) | Org:Aqu | PVA Conc. (%) | Amp (%) | Predicted Particle Size (nm) | Composite Desirability | Experimental Mean Particle Size (nm) |
---|---|---|---|---|---|---|---|
1 | 25 | 0.167 | 0.5 | 26 | 168.333 | 0.868436 | 169.09 |
2 | 50 | 0.1670 | 0.5 | 26 | 175.046 | 0.77953 | 175.15 |
Formulation | Doc (mg) | Bru (mg) | Size (nm) | Doc Loading (%) | Bru Loading (%) | Drug:Polymer (%) |
---|---|---|---|---|---|---|
1 | 7 | 3 | 201.87 ± 1.40 | 7.84 ± 0.17 | 0.87 ± 0.17 | 20% |
2 | 6 | 4 | 195.70 ± 1.15 | 6.37 ± 0.11 | 0.79 ± 0.07 | 20% |
3 | 5 | 5 | 198.27 ± 2.78 | 6.32 ± 0.11 | 1.14 ± 0.03 | 20% |
4 | 4 | 6 | 182.57 ± 1.90 | 3.73 ± 0.25 | 0.82 ± 0.09 | 20% |
5 | 3 | 7 | 194.97 ± 0.75 | 2.49 ± 0.13 | 0.79 ± 0.08 | 20% |
6 | 2.5 | 7.5 | 184.80 ± 1.30 | 2.04 ± 0.04 | 0.89 ± 0.02 | 20% |
7 | 2 | 8 | 188.80 ± 0.80 | 1.41 ± 0.17 | 0.99 ± 0.15 | 20% |
8 | 1 | 9 | 193.83 ± 1.59 | 0.70 ± 0.06 | 1.48 ± 0.28 | 20% |
9 | 4.5 | 10.5 | 185.07 ± 3.55 | 3.33 ± 0.96 | 0.89 ± 0.19 | 30% |
10 | 3 | 12 | 183.03 ± 5.66 | 1.88 ± 0.57 | 0.92 ± 0.30 | 30% |
Total Dose (nM) | CI in LNCaP Cells | CI in PC-3 Cells |
---|---|---|
5.0 | 0.33061 | 0.10535 |
10.0 | 0.59098 | 0.18948 |
20.0 | 0.64905 | 0.33766 |
40.0 | 0.76064 | 0.29589 |
80.0 | 0.79381 | 0.55168 |
160.0 | 0.95830 | 0.99662 |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Adekiya, T.A.; Moore, M.; Thomas, M.; Lake, G.; Hudson, T.; Adesina, S.K. Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer. Pharmaceutics 2024, 16, 114. https://doi.org/10.3390/pharmaceutics16010114
Adekiya TA, Moore M, Thomas M, Lake G, Hudson T, Adesina SK. Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer. Pharmaceutics. 2024; 16(1):114. https://doi.org/10.3390/pharmaceutics16010114
Chicago/Turabian StyleAdekiya, Tayo Alex, Madison Moore, Michael Thomas, Gabriel Lake, Tamaro Hudson, and Simeon K. Adesina. 2024. "Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer" Pharmaceutics 16, no. 1: 114. https://doi.org/10.3390/pharmaceutics16010114
APA StyleAdekiya, T. A., Moore, M., Thomas, M., Lake, G., Hudson, T., & Adesina, S. K. (2024). Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer. Pharmaceutics, 16(1), 114. https://doi.org/10.3390/pharmaceutics16010114