Interaction of Docetaxel with Phosphatidylcholine Membranes: A Combined Experimental and Computational Study
Elisa Aranda1,2, José A Teruel1, Antonio Ortiz1
1Departamento de Bioquímica y Biología Molecular-A, Facultad de Veterinaria, Universidad de Murcia, 30100, Murcia, Spain.
Abstract:
The antineoplastic drug Docetaxel is a second generation taxane which is used against a great variety of cancers. The drug is highly lipophilic and produces a great array of severe toxic effects that limit its therapeutic effectiveness. The study of the interaction between Docetaxel and membranes is very scarce, however, it is required in order to get clues in relation with its function, mechanism of toxicity and possibilities of new formulations. Using phosphatidylcholine biomimetic membranes, we examine the interaction of Docetaxel with the phospholipid bilayer combining an experimental study, employing a series of biophysical techniques like Differential Scanning Calorimetry, X-Ray Diffraction and Infrared Spectroscopy, and a Molecular Dynamics simulation. Our experimental results indicated that Docetaxel incorporated into DPPC bilayer perturbing the gel to liquid crystalline phase transition and giving rise to immiscibility when the amount of the drug is increased. The drug promotes the gel ripple phase, increasing the bilayer thickness in the fluid phase, and is also able to alter the hydrogen-bonding interactions in the interfacial region of the bilayer producing a dehydration effect. The results from computational simulation agree with the experimental ones and located the Docetaxel molecule forming small clusters in the region of the carbon 8 of the acyl chain palisade overlapping with the carbonyl region of the phospholipid. Our results support the idea that the anticancer drug is embedded into the phospholipid bilayer to a limited amount and produces structural perturbations which might affect the function of the membrane.
Insights
The anticancer drug Docetaxel interacts with phospholipid bilayers, causing structural changes that may influence its function and toxicity. This study reveals how Docetaxel perturbs cell membranes at a molecular level.
Area of Science:
- Biophysics
- Pharmacology
- Materials Science
Background:
- Docetaxel is a vital anticancer drug with significant toxic side effects.
- Understanding Docetaxel's interaction with cell membranes is crucial for improving its efficacy and reducing toxicity.
- Limited research exists on the molecular interactions between Docetaxel and lipid bilayers.
Purpose of the Study:
- To investigate the interaction of Docetaxel with phosphatidylcholine biomimetic membranes.
- To elucidate the effects of Docetaxel on phospholipid bilayer structure and dynamics.
- To provide insights into Docetaxel's mechanism of action, toxicity, and potential for new formulations.
Main Methods:
- Combined experimental biophysical techniques (Differential Scanning Calorimetry, X-Ray Diffraction, Infrared Spectroscopy) with Molecular Dynamics simulations.
- Utilized dipalmitoylphosphatidylcholine (DPPC) biomimetic membranes to model cell membranes.
- Analyzed structural and dynamic changes induced by Docetaxel incorporation.
Main Results:
- Docetaxel incorporation perturbs the gel to liquid crystalline phase transition of DPPC bilayers.
- Increased Docetaxel concentration leads to immiscibility and promotes the gel ripple phase.
- Docetaxel increases bilayer thickness and alters interfacial hydrogen bonding, causing dehydration.
- Molecular dynamics simulations confirm Docetaxel clustering within the acyl chain region of the bilayer.
Conclusions:
- Docetaxel embeds into phospholipid bilayers to a limited extent.
- The drug induces structural perturbations in the membrane that may impact membrane function.
- Findings offer a molecular basis for Docetaxel's effects and suggest avenues for formulation development.
