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"Characterization of a clinical polymer-drug conjugate using multiscale modeling"
L.X. Peng, A. Ivetac, S. Van, G. Zhao, A.S. Chaudhari, L. Yu, S.B. Howell, J.A. McCammon, D.A. Gough
Biopolymers, ASAP, 2010. DOI : 10.1002/bip.21474
The molecular conformation of certain therapeutic agents has been shown to affect the ability to
gain access to target cells, suggesting potential value in defining conformation of candidate
molecules. This study explores how the shape and size of poly-γ-glutamyl-glutamate paclitaxel
(PGG-PTX), an amphiphilic polymer-drug with potential chemotherapeutic applications, can be
systematically controlled by varying hydrophobic and hydrophilic entities. Eighteen different
formulations of PGG-PTX varying in three PTX loading fractions of 0.18, 0.24, and 0.37 and six
spatial arrangements of PTX (‘clusters’, ‘ends,’ even’, ‘middle’, ‘random’, and ‘side) were
explored. Molecular dynamics (MD) simulations of all-atom (AA) models of PGG-PTX were
run until a statistical equilibrium was reached at 100 ns and then continued as coarse-grained
(CG) models until a statistical equilibrium was reached at an effective time of 800 ns. Circular
dichroism spectroscopy was used to suggest initial modeling configurations. Results show that a
PGG-PTX molecule has a strong tendency to form coil shapes, regardless of the PTX loading
fraction and spatial PTX arrangement, although globular shapes exist at fPTX = 0.24. Also, less
uniform PTX arrangements such as ‘ends’, ‘middle’, and ‘side’ produce coil geometries with
more curvature. The prominence of coil shapes over globules demonstrates that PGG-PTX may
confer a long circulation half-life and high propensity for accumulation to tumor endothelia.
This multiscale modeling approach may be advantageous for the design of cancer therapeutic
delivery systems.