Dynamical Interactions of 5-Fluorouracil Drug with Dendritic Peptide Vectors: The Impact of Dendrimer Generation, Charge, Counterions, and Structured Water.
Molecular dynamics simulations are utilized to investigate the interactions between the skin cancer drug 5-fluorouracil (5FU) and peptide-based dendritic carrier systems. We find that these drug-carrier interactions do not conform to the traditional picture of long-time retention of the drug within a hydrophobic core of the dendrimer carrier. Rather, 5FU, which is moderately soluble in its own right, experiences weak, transient chattering interactions all over the dendrimer, mediated through multiple short-lived hydrogen bonding and close contact events. We find that charge on the periphery of the dendrimer actually has a negative effect on the frequency of drug-carrier interactions due to a counterion screening effect that has not previously been observed. However, charge is nevertheless an important feature since neutral dendrimers are shown to have a significant mutual attraction that can lead to clustering or agglomeration. This clustering is prevented due to charge repulsion for the titrated dendrimers, such that they remain independent in solution.
Integrated Materials Design Centre (IMDC), School of Chemical Engineering, UNSW Australia , Sydney, New South Wales 2052, Australia.
Sergio
S
De Luca
Integrated Materials Design Centre (IMDC), School of Chemical Engineering, UNSW Australia , Sydney, New South Wales 2052, Australia.
Prasenjit
P
Seal
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau , Macau, China.
Defang
D
Ouyang
School of Pharmacy, The University of Queensland , Brisbane, Queensland 4072, Australia.
Harendra S
HS
Parekh
IBM Research-Australia , 204 Lygon Street, Carlton, Victoria 3053, Australia.
Sridhar Kumar
SK
Kannam
Integrated Materials Design Centre (IMDC), School of Chemical Engineering, UNSW Australia , Sydney, New South Wales 2052, Australia.
Sean C
SC
Smith
D000595:Amino Acid Sequence; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D005472:Fluorouracil / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
D050091:Dendrimers; D004337:Drug Carriers; D010455:Peptides; D014867:Water; D005472:Fluorouracil