Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.1.1. Synthesis of Block Copolymers with Functionalized Poly(ethylene oxide) (PEO)
2.1.2. Synthesis of GE11 Peptide and GE11 Conjugation to Poly(ethylene oxide)-poly(α-carboxyl-ε-caprolactone) (PEO-PCCL) Block Copolymers
2.1.3. Preparation of Plain and GE11 Cisplatin Micelles
2.1.4. Measurement of the Size and Zeta Potential of Plain and GE11 Cisplatin Micelles
2.1.5. Measurement of the Critical Micellar Concentration (CMC) of Plain and GE11 Cisplatin Micelles
2.1.6. Measurement of Cisplatin Encapsulation
2.1.7. In Vitro Release Studies
2.1.8. Cell Culture
2.1.9. Flow Cytometric Detection of Apoptosis using Annexin V-FITC and Propidium Iodide
2.1.10. MTT Assay
2.1.11. Western Blot
2.1.12. Cisplatin Cellular Uptake
2.1.13. Statistical Analysis
3. Results
3.1. Successful Synthesis of GE11 Conjugated Poly(ethylene oxide)-poly(α-carboxyl-ε-caprolactone)(PEO-PCCL) Block Copolymer and Its Self-assembly
3.2. Hypoxia Induces Chemoresistance to Free Cisplatin in MDA-MB-231 Cells
3.3. Modification of Cisplatin Micelles with GE11 Peptide Enhances the Cellular Uptake of Cisplatin, but Does Not Affect its Cytotoxicity in MDA-MB-231 Cells
3.4. Co-Treatment with Pharmacological Inhibitors of HIF-1 and STAT3 Potentiates the Anticancer Activity of Free Cisplatin, as well as Its Micellar Formulations in Hypoxic MDA-MB-231 Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Micelle a | Average Diameter ± SD (nm) b | PDI ± SD c | Zeta potential ± SD (mV) | CMC ± SD (μg/mL) d | EE ± SD (%) e | DL ± SD (%) f | Drug/polymer ± SD (mol/mol) |
---|---|---|---|---|---|---|---|
Cisplatin plain micelle | 84.4 ± 2.6 | 0.263 ± 0.11 | −13.3 ± 1.2 | 65.1 ± 5.5 | 12.4 ± 0.99 | 12.0 ± 1.41 | 3.93 ± 0.31 |
GE11 cisplatin micelle | 84.1 ± 3.2 | 0.235 ± 0.18 | −13.6 ± 0.95 | 70.5 ± 7.2 | 13.0 ± 2.95 | 15.5 ± 3.53 | 4.01 ± 0.93 |
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Soleymani Abyaneh, H.; Soleimani, A.H.; Vakili, M.R.; Soudy, R.; Kaur, K.; Cuda, F.; Tavassoli, A.; Lavasanifar, A. Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance. Pharmaceutics 2018, 10, 196. https://doi.org/10.3390/pharmaceutics10040196
Soleymani Abyaneh H, Soleimani AH, Vakili MR, Soudy R, Kaur K, Cuda F, Tavassoli A, Lavasanifar A. Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance. Pharmaceutics. 2018; 10(4):196. https://doi.org/10.3390/pharmaceutics10040196
Chicago/Turabian StyleSoleymani Abyaneh, Hoda, Amir Hassan Soleimani, Mohammad Reza Vakili, Rania Soudy, Kamaljit Kaur, Francesco Cuda, Ali Tavassoli, and Afsaneh Lavasanifar. 2018. "Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance" Pharmaceutics 10, no. 4: 196. https://doi.org/10.3390/pharmaceutics10040196
APA StyleSoleymani Abyaneh, H., Soleimani, A. H., Vakili, M. R., Soudy, R., Kaur, K., Cuda, F., Tavassoli, A., & Lavasanifar, A. (2018). Modulation of Hypoxia-Induced Chemoresistance to Polymeric Micellar Cisplatin: The Effect of Ligand Modification of Micellar Carrier Versus Inhibition of the Mediators of Drug Resistance. Pharmaceutics, 10(4), 196. https://doi.org/10.3390/pharmaceutics10040196