Mohammad Mahmoudzadeh1,2, Afshin Fassihi3,4, Farid Dorkoosh5, Reyhaneh Heshmatnejad6, Karim Mahnam7, Hassan Sabzyan8, Amir Sadeghi9. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. 2. Department of Pharmaceutics, Faculty of pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. fassihi@pharm.mui.ac.ir. 4. Isfahan Pharmaceutical Sciences Research Center, Isfahan, Iran. fassihi@pharm.mui.ac.ir. 5. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. 6. Department of Chemical Engineering, Faculty of Engineering, University of Isfahan, Isfahan, Iran. 7. Biology Department, Faculty of Sciences, Shahrekord University, Shahrekord, Iran. 8. Department of Chemistry, University of Isfahan, Isfahan, Iran. 9. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. sadeghi_am5@yahoo.com.
Abstract
PURPOSE: 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. CONCLUSION: 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.
PURPOSE: 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. CONCLUSION: 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.
Authors: Romelia Salomon-Ferrer; Andreas W Götz; Duncan Poole; Scott Le Grand; Ross C Walker Journal: J Chem Theory Comput Date: 2013-08-20 Impact factor: 6.006
Authors: Garrett M Morris; Ruth Huey; William Lindstrom; Michel F Sanner; Richard K Belew; David S Goodsell; Arthur J Olson Journal: J Comput Chem Date: 2009-12 Impact factor: 3.376