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Pharmaceutical Research

, 35:90 | Cite as

Rational Design of Cholesterol Derivative for Improved Stability of Paclitaxel Cationic Liposomes

  • Jasmin Monpara
  • Chryso Kanthou
  • Gillian M. Tozer
  • Pradeep R. Vavia
Research Paper

Abstract

Purpose

This work explores synthesis of novel cholesterol derivative for the preparation of cationic liposomes and its interaction with Paclitaxel (PTX) within liposome membrane using molecular dynamic (MD) simulation and in-vitro studies.

Methods

Cholesteryl Arginine Ethylester (CAE) was synthesized and characterized. Cationic liposomes were prepared using Soy PC (SPC) at a molar ratio of 77.5:15:7.5 of SPC/CAE/PTX. Conventional liposomes were composed of SPC/cholesterol/PTX (92:5:3 M ratio). The interaction between paclitaxel, ligand and the membrane was studied using 10 ns MD simulation. The interactions were studied using Differential Scanning Calorimetry (DSC) and Small Angle Neutron Scattering analysis. The efficacy of liposomes was evaluated by MTT assay and endothelial cell migration assay on different cell lines. The safety of the ligand was determined using the Comet Assay.

Results

The cationic liposomes improved loading efficiency and stability compared to conventional liposomes. The increased PTX loading could be attributed to the hydrogen bond between CAE and PTX and deeper penetration of PTX in the bilayer. The DSC study suggested that inclusion of CAE in the DPPC bilayer eliminates Tg. SANS data showed that CAE has more pronounced membrane thickening effect as compared to cholesterol. The cationic liposomes showed slightly improved cytotoxicity in three different cell lines and improved endothelial cell migration inhibition compared to conventional liposomes. Furthermore, the COMET assay showed that CAE alone does not show any genotoxicity.

Conclusions

The novel cationic ligand (CAE) retains paclitaxel within the phospholipid bilayer and helps in improved drug loading and physical stability.

Graphical Abstract

KEY WORDS

COMET assay molecular dynamic simulation paclitaxel-loaded cationic liposomes trans-well migration assay 

ABBREVIATIONS

1HNMR

Proton nuclear magnetic resonance

CAE

Cholesteryl arginine ethylester

DMEM

Dulbecco’s modified eagle’s medium

DPX

Disterene plasticizer xylene

H5V

Mouse endothelial cell line

HDMEC

Human dermal microvascular endothelial cells

IC50

Concentration at which 50% inhibition seen

IntraHB

Intramolecular hydrogen bonds

LMP

Low melting point

MD Simulation

Molecular dynamic simulation

MDA-MB 231

Human breast cancer adenocarcinoma cell line

MolSA

Molecular surface area

MTT

3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide

OD

Optical density

OPLS3

Optimized potentials for liquid simulations

POPC

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

PSA

Polar surface area

PTX

Paclitaxel

RMSD

Relative mean square deviation

SASA

Solvent accessible surface area

SPC

Soy phosphatidylcholine

TIP3P

Transferable intermolecular potential with 3 points

TLC

Thin layer chromatography

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jasmin Monpara
    • 1
  • Chryso Kanthou
    • 2
  • Gillian M. Tozer
    • 2
  • Pradeep R. Vavia
    • 1
  1. 1.Department of Pharmaceutical Sciences and Technology, University under Section 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, TEQIP Phase II FundedInstitute of Chemical TechnologyMumbaiIndia
  2. 2.Tumor Microcirculation Group, Department of Oncology & Metabolism School of MedicineThe University of SheffieldSheffieldUK

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