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A Facile and Efficient Approach for the Production of Reversible Disulfide Cross-linked Micelles
Published on: December 23, 2016
Mithramycin encapsulated in polymeric micelles by microfluidic technology as novel therapeutic protocol for
Lorenzo Capretto1, Stefania Mazzitelli, Eleonora Brognara
1Engineering Sciences, University of Southampton, Southampton, UK.
Abstract:
This report shows that the DNA-binding drug, mithramycin, can be efficiently encapsulated in polymeric micelles (PM-MTH), based on Pluronic(®) block copolymers, by a new microfluidic approach. The effect of different production parameters has been investigated for their effect on PM-MTH characteristics. The compared analysis of PM-MTH produced by microfluidic and conventional bulk mixing procedures revealed that microfluidics provides a useful platform for the production of PM-MTH with improved controllability, reproducibility, smaller size, and polydispersity. Finally, an investigation of the effects of PM-MTH, produced by microfluidic and conventional bulk mixing procedures, on the erythroid differentiation of both human erythroleukemia and human erythroid precursor cells is reported. It is demonstrated that PM-MTH exhibited a slightly lower toxicity and more pronounced differentiative activity when compared to the free drug. In addition, PM-MTH were able to upregulate preferentially γ-globin messenger ribonucleic acid production and to increase fetal hemoglobin (HbF) accumulation, the percentage of HbF-containing cells, and their HbF content without stimulating α-globin gene expression, which is responsible for the clinical symptoms of β-thalassemia. These results represent an important first step toward a potential clinical application, since an increase in HbF could alleviate the symptoms underlying β-thalassemia and sickle cell anemia. In conclusion, this report suggests that PM-MTH produced by microfluidic approach warrants further evaluation as a potential therapeutic protocol for β-thalassemia.
Insights
A new microfluidic method efficiently creates mithramycin-loaded polymeric micelles (PM-MTH). These PM-MTH show reduced toxicity and enhanced therapeutic effects for beta-thalassemia by boosting fetal hemoglobin production.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Pharmacology
Background:
- Mithramycin is a DNA-binding drug with therapeutic potential.
- Polymeric micelles (PMs) offer a promising drug delivery system.
- Efficient and controlled production of PMs is crucial for clinical applications.
Purpose of the Study:
- To develop a microfluidic approach for efficient encapsulation of mithramycin into polymeric micelles (PM-MTH).
- To characterize PM-MTH produced via microfluidics and compare them to conventionally produced micelles.
- To evaluate the therapeutic potential of PM-MTH in erythroid differentiation and its relevance to beta-thalassemia.
Main Methods:
- Utilized a novel microfluidic technique for synthesizing mithramycin-loaded polymeric micelles (PM-MTH) using Pluronic(®) block copolymers.
- Investigated the impact of various production parameters on PM-MTH characteristics.
- Compared microfluidic-produced PM-MTH with those from conventional bulk mixing procedures.
- Assessed the effects of PM-MTH on erythroid differentiation in human erythroleukemia and precursor cells.
Main Results:
- Microfluidics enabled efficient PM-MTH production with improved control, reproducibility, smaller size, and lower polydispersity compared to bulk methods.
- PM-MTH demonstrated slightly lower toxicity and more pronounced differentiative activity than free mithramycin.
- PM-MTH preferentially upregulated gamma-globin mRNA, increased fetal hemoglobin (HbF) accumulation, and HbF-containing cells without affecting alpha-globin expression.
Conclusions:
- Microfluidic production of PM-MTH is a viable and advantageous platform for drug delivery.
- PM-MTH show significant potential for alleviating symptoms of beta-thalassemia and sickle cell anemia by increasing HbF.
- Further evaluation of microfluidically produced PM-MTH is warranted for potential therapeutic applications in hemoglobinopathies.
