1 The Deposition and Aggregation of Aspirin Molecules on a Phospholipid Bilayer Pattern Guangzhao Mao, * Dongzhong Chen, § Hitesh Handa Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202, USA Wenfei Dong, Dirk G. Kurth, † Helmuth Möhwald Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany [email protected]RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) TITLE RUNNING HEAD: ASPIRIN DEPOSITION ON BILAYER PATTERN * Corresponding author. § Current address: Key Laboratory of Mesoscopic Chemistry of MOE and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China. † National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
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The Deposition and Aggregation of Aspirin Molecules on a
Phospholipid Bilayer Pattern
Guangzhao Mao,* Dongzhong Chen,§ Hitesh Handa
Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202, USA
Wenfei Dong, Dirk G. Kurth,† Helmuth Möhwald
Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
TITLE RUNNING HEAD: ASPIRIN DEPOSITION ON BILAYER PATTERN
* Corresponding author.
§ Current address: Key Laboratory of Mesoscopic Chemistry of MOE and Department of Polymer Science & Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
† National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
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ABSTRACT
Aspirin and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) are deposited from their alcoholic
mixed solution onto highly oriented pyrolytic graphite (HOPG) by spin coating. The film structure and
morphology are characterized by atomic force microscopy (AFM). The barely soluble DMPE forms a highly
oriented stripe phase due to its 1-D epitaxy with the HOPG lattice. The bilayer stripe pattern exposes the cross
section of the lipid bilayer lamellae, and enables the direct visualization of the molecular interactions of drug or
biological molecules with either the hydrophobic or hydrophilic part of the phospholipid bilayer. The bilayer
pattern affects the aspirin molecular deposition and aggregation. AFM shows that the aspirin molecules prefer
to deposit and aggregate along the aliphatic interior part of the bilayer pattern, giving rise to parallel dimer rods
in registry with the underlying pattern. The nonpolar interactions between aspirin and the phospholipid bilayer
are consistent with the lipophilic nature of aspirin. The bilayer pattern not only stabilizes the rod-like aggregate
structure of aspirin at low aspirin concentration, but also inhibits crystallization of aspirin at high aspirin
concentration. Molecular models show that the width of the DMPE aliphatic chain interior can accommodate no
more than 2 aspirin dimers. The bilayer confinement may prevent aspirin from reaching its critical nucleus size.
This study illustrates a general method to induce a metastable or amorphous form of an active pharmaceutical
ingredient (API) by chemical confinement under high undercooling conditions. Metastable and amorphous solids
often display better solubility and bioavailability than the stable crystalline form of the API.
KEYWORDS: Phospholipid bilayer, aggregation, crystallization, patterning, and AFM.
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INTRODUCTION
The ability to manipulate and characterize materials at the nanoscale has led to explosive research activities in
the molecular thin films, crystals, and devices. In supramolecular pharmaceutics, the same active pharmaceutical
ingredient (API) molecules are manipulated by various non-covalent interactions (hydrogen bonding, van der
Waals, π-π stacking, and electrostatic interactions) into different solid-state forms ranging from amorphous to
crystalline states.1 The solid-state form of the API affects its compressibility, solubility, dissolution rate, chemical
stability, and bioavailability. Some new drug discovery methods involve screening different crystallization
conditions in small volume2 and on engineered surfaces.3 Micro-patterns of self-assembled monolayers (SAMs)
have been used to control crystallization by relying on guest molecules to recognize different surface functional
groups and by micro-confinement.4 The integration of bottom-up to top-down approaches in the developing
technologies, such as the high-throughput screening of drugs, requires the knowledge of placing molecules on
ever diminishing patterns.
Alkanes and alkane derivatives are known to self-assemble into a long-range ordered stripe phase on highly
oriented pyrolytic graphite (HOPG) due to the one-dimensional (1-D) epitaxial match between the 1,3-
methylene group distance (= 0.251 nm) and the distance of the next nearest neighbor of the HOPG lattice (=
0.246 nm).5,6 Recently, this molecular pattern has been used to align small organic molecules7,8 as well as
macromolecules.9,10,11,12 The amphiphilic pattern at the solid and liquid interface has been reproduced in thin
solid films by spin coating, and has been used to synthesize sulfide molecular rod arrays on the copper
arachidate template.13 Both the arachidate pattern and the subsequent inorganic rod arrays have been
characterized by atomic force microscopy (AFM). AFM is capable of resolving the location and shape of guest
molecular aggregates in relation to a specific type of functional groups on the host pattern. The amphiphilic
pattern of phospholipids serves as a model for the study of the molecular interactions of drug or biological
compounds with biomembranes and cells. The phospholipid stripe phase is structurally similar to the plane
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perpendicular to the bilayer lamellae. The bilayer pattern exposes the hydrophobic and hydrophilic parts
simultaneously for guest molecular recognition and also for AFM imaging. This enables detailed structural
analysis of drug or biological molecular interactions with specific functional groups of the phospholipid bilayer.
This paper reports the effect of the phospholipid bilayer pattern on the deposition and aggregation behavior of
aspirin. Aspirin, also called acetylsalicylic acid or 2-(acetyloxy)-benzoic acid, was first synthesized by Bayer in
1897. Aspirin is a nonsteroidal anti-inflammatory drug (NSAID), widely used to treat human inflammatory
disorders, such as blood coagulation, thrombosis, and atherosclerosis, by inhibiting platelet aggregation.14
Recently, aspirin has also been found to reduce the risk of heart attack and to be effective against colorectal
cancer. The primary mechanism of aspirin drug action is its interference with the biosynthesis of inflammatory
prostaglandins (PGs).15 Another known effect of NSAIDs is their capability to perturb the phospholipid
ordering in the biomembranes, and thus affecting the normal functions of the membrane proteins.16 Aspirin is a
weak acid and lipophilic.17 Aspirin is found to increase the fluidity of liposomes by inserting itself in between the
hydrocarbon chains of the phospholipid molecules. Aspirin has only one crystal form,18 which makes its
structural analysis less complicated. The aspirin crystal consists of hydrogen-bonded dimers. The hydrogen-
bonded dimers are the most common supramolecular synthon for monocarboxylic acid crystals.19 The
supramolecular synthon is the smallest molecular building block, whose symmetry and connectivity predispose
the symmetry and packing in the final crystal structure. This paper presents a first study on the adsorption of
supramolecular aggregates in a predefined way on the graphite-based templates. The study of the aggregation
behavior of the aspirin dimers may shed light on nanoscale confinement means to engineer crystals with self-