Elucidation of Molecular Mechanisms Behind the Self-Assembly Behavior of Chitosan Amphiphilic Derivatives Through Experiment and Molecular Modeling.
OBJECTIVE
Chitosan-based polymeric micelles (CBPMs) are considered as promising carriers for delivery of anticancer drugs, imaging agents and genes. To optimize the physicochemical, pharmaceutical and biological properties of CBPMs, the molecular mechanisms behind the self-assembly behavior of chitosan (CHI) amphiphilic derivatives are elucidated.


METHODS
This study has two stages. In the experimental stage, dexamethasone (DEX) as a hydrophobic group is grafted to CHI in three degrees of substitution in order to obtain CHI derivatives with different degrees of hydrophobicity. These new CHI amphiphilic derivatives (CHI_DEXs) form micelles in water where their critical aggregation concentration (CAC), size and zeta potential are measured. Through comparing the results of these measurements, the change of self-assembly behavior of CHI_DEXs in response to increasing their hydrophobicity is evaluated. Correlating this evaluation with the results of the 13 MD simulations conducted on CHI_DEXs in atomistic molecular dynamics (MD) simulation stage, reveals the molecular mechanisms behind the self-assembly behavior of CHI_DEXs.


RESULTS
Our evaluation of the experimental results reveals that increasing hydrophobicity of a CHI amphiphilic derivative would not necessarily cause it to form micelles with lower CAC value, smaller size and lower zeta potential. The MD simulations reveal that there exists a balance between intra- and inter-chain interactions which is responsible for the self-assembly behavior of CHI amphiphilic derivatives.


CONCLUSIONS
An increase in DS of the hydrophobic group triggers a cascade of molecular events that shifts the balance between intra- and inter-chain interactions leading to changes in the CAC, size and zeta potential of the CBPMs.
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.|Department of Pharmaceutics, Faculty of pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
Mohammad
M
Mahmoudzadeh
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. fassihi@pharm.mui.ac.ir.|Isfahan Pharmaceutical Sciences Research Center, Isfahan, Iran. fassihi@pharm.mui.ac.ir.
Afshin
A
Fassihi
Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Farid
F
Dorkoosh
Department of Chemical Engineering, Faculty of Engineering, University of Isfahan, Isfahan, Iran.
Reyhaneh
R
Heshmatnejad
Biology Department, Faculty of Sciences, Shahrekord University, Shahrekord, Iran.
Karim
K
Mahnam
Department of Chemistry, University of Isfahan, Isfahan, Iran.
Hassan
H
Sabzyan
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. sadeghi_am5@yahoo.com.
Amir
A
Sadeghi
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D048271:Chitosan / Q000737:chemistry*; D003907:Dexamethasone / Q000008:administration & dosage; D004337:Drug Carriers / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D018931:Antineoplastic Agents, Hormonal; D004337:Drug Carriers; D008823:Micelles; D014867:Water; D003907:Dexamethasone; D048271:Chitosan
chitosan; molecular dynamics simulation; molecular mechanisms; polymeric micelles; self-assembly