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1.  Biodegradable Salicylate-Based Poly(anhydride-ester) Microspheres For Controlled Insulin Delivery 
Salicylate-based poly(anhydride-esters) (PAEs) chemically incorporate salicylic acid (SA) into the polymer backbone, which is then delivered in a controlled manner upon polymer hydrolysis. In this work, a salicylate-based PAE is a carrier to encapsulate and deliver insulin. Polymer microspheres were formulated using a water/oil/water double-emulsion solvent evaporation technique. The microspheres obtained had a smooth surface, high protein encapsulation efficiency, and relatively low emulsifier content. Insulin was released in vitro for 15 days, with no signs of aggregation or unfolding of the secondary structure. The released insulin also retained bioactivity in vitro. Concurrently, SA was released from the microspheres with polymer degradation and anti-inflammatory activity was observed. Based upon these results, the formulated microspheres enable simultaneous delivery of insulin and SA, both retaining bioactivity following processing.
PMCID: PMC3952025  PMID: 24027012
poly(anhydride-esters); microspheres; controlled release; insulin; salicylic acid
2.  Cationic Amphiphilic Macromolecule (CAM)-lipid Complexes for Efficient siRNA Gene Silencing 
The accumulated evidence has shown that lipids and polymers each have distinct advantages as carriers for siRNA delivery. Composite materials comprising both lipids and polymers may present improved properties that combine the advantage of each. Cationic amphiphilic macromolecules (CAMs) containing a hydrophobic alkylated mucic acid segment and a hydrophilic poly(ethylene glycol) (PEG) tail were non-covalently complexed with two lipids.1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), to serve as a siRNA delivery vehicle. By varying the weight ratio of CAM to lipid, cationic complexes with varying compositions were obtained in aqueous media and their properties evaluated. CAM-lipid complex sizes were relatively independent of composition, ranging from 100 to 200 nm, and zeta potentials varied from 10 to 30 mV. Transmission electron microscopy confirmed the spherical morphology of the complexes. The optimal N/P ratio was 50 as determined by electrophoretic mobility shift assay. The ability to achieve gene silencing was evaluated by anti-luciferase siRNA delivery to a U87-luciferase cell line. Several weight ratios of CAM-lipid complexes were found to have similar delivery efficiency compared to the gold standard, Lipofectamine. Isothermal titration calorimetry revealed that siRNA binds more tightly at pH = 7.4 than pH = 5 to CAM-lipid (1:10 w/w). Further intracellular trafficking studies monitored the siRNA escape from the endosomes at 24 h following transfection of cells. The findings in the paper indicate that CAM-lipid complexes can serve as a novel and efficient siRNA delivery vehicle.
PMCID: PMC4090228  PMID: 24727076
Cationic Amphiphilic Macromolecule; Lipid; siRNA Delivery
3.  Role of Branching of Hydrophilic Domain on Physicochemical Properties of Amphiphilic Macromolecules 
Polymer chemistry  2014;5(4):1457-1462.
A novel series of amphiphilic macromolecules (AMs) composed of a sugar backbone, aliphatic chains, and branched, hydrophilic poly(oligoethylene glycol) methyl ether methacrylate (POEGMA)were developed for drug delivery applications. The branched, hydrophilic domains (POEGMA homopolymers with one hydroxyl group) were prepared via atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) monomers using 2-hydroxyethyl-2-bromoisobutyrate (HEBiB) as an initiator and copper bromide/bipyridine (CuBr/Bpy) as the catalyst system. To form the amphiphilic structures, the branched POEGMAs were coupled to hydrophobic domains that were formed via acylation of a sugar backbone. The impact of branching in the hydrophilic domain was investigated by comparing the AMs’ solution and thermal properties with those of the linear counterparts. Although these highly branched AMs showed similar critical micelle concentration (CMC) values as compared to linear analogues, they possessed quite low glass transition (Tg) temperatures. Consequently, these novel AMs with branched hydrophilic domain combine the desirable thermal properties of POEGMA with favorable solution properties of amphiphilic architectures, which make them suitable for injectable drug delivery systems.
PMCID: PMC3920977  PMID: 24533034
4.  Biodegradable polyesters containing ibuprofen and naproxen as pendant groups 
Biomacromolecules  2013;14(10):10.1021/bm400889a.
Controlled release of non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen could be beneficial for the treatment of inflammatory diseases while reducing the side effects resulting from their continuous use. Novel biodegradable polyesters solely comprised of biocompatible components (e.g., tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups) have been synthesized using tin (II) 2-ethylhexanoate as catalyst at 130 °C and subsequently characterized to determine their structures and physicochemical properties. The polymers release the free drug (ibuprofen or naproxen) in vitro in a controlled manner without burst release, unlike the release rates achieved when the drugs are encapsulated in other polymers. These new biomaterials are not cytotoxic towards mouse fibroblasts up to 0.10 mg/mL. The drugs retain their chemical structure following hydrolytic degradation of the polymer, suggesting that bioactivity is preserved.
PMCID: PMC3812688  PMID: 23957612
ibuprofen; naproxen; tartaric acid; biodegradable; polyester; prodrug
5.  Locally Delivered Salicylic Acid from a Poly(anhydride-ester): Impact on Diabetic Bone Regeneration 
Diabetes mellitus (DM) involves metabolic changes that can impair bone repair, including a prolonged inflammatory response. A salicylic acid-based poly(anhydride-ester) (SA-PAE) provides controlled and sustained release of salicylic acid (SA) that locally resolves inflammation. This study investigates the effect of polymer-controlled SA release on bone regeneration in diabetic rats where enhanced inflammation is expected. Fifty-six Sprague-Dawley rats were randomly assigned to two groups: diabetic group induced by streptozotocin (STZ) injection or normoglycemic controls injected with citrate buffer alone. Three weeks after hyperglycemia development or vehicle injection, 5 mm critical sized defects were created at the rat mandibular angle and treated with SA-PAE/bone graft mixture or bone graft alone. Rats were euthanized 4 and 12 weeks after surgery, then bone fill percentage in the defect region was assessed by micro-computed tomography (CT) and histomorphometry. It was observed that bone fill increased significantly at 4 and 12 weeks in SA-PAE/bone graft-treated diabetic rats compared to diabetic rats receiving bone graft alone. Accelerated bone formation in normoglycemic rats caused by SA-PAE/bone graft treatment was observed at 4 weeks but not at 12 weeks. This study shows that treatment with SA-PAE enhances bone regeneration in diabetic rats and accelerates bone regeneration in normoglycemic animals.
PMCID: PMC3757941  PMID: 23827476
poly(anhydride-ester); salicylic acid; diabetes; bone regeneration
6.  Biodegradable Coumaric Acid-based Poly(anhydride-ester) Synthesis and Subsequent Controlled Release 
Macromolecular rapid communications  2013;34(15):1231-1236.
p-Coumaric acid (pCA), a naturally occurring bioactive, has been chemically incorporated into a poly(anhydride-ester) backbone through solution polymerization following a Knoevenagel synthetic approach to overcome drug delivery issues associated with its short half-life in vivo. Nuclear magnetic resonance and Fourier transform infrared spectroscopies indicated that pCA was successfully incorporated without noticeable alterations in structural integrity. The weight-average molecular weight and thermal properties were determined for the polymer, which exhibited a molecular weight of over 26,000 Da and a glass transition temperature of 57 °C. In addition, in vitro pCA release via hydrolytic anhydride and ester bond cleavage demonstrated pCA release over 30 days and maintained its antioxidant activity, demonstrating its potential as a controlled release system.
PMCID: PMC3789234  PMID: 23836606
biodegradable; polymer; poly(anhydride-ester); coumaric acid; drug delivery systems
7.  Formulation of salicylate-based poly(anhydride-ester) microspheres for short- and long-term salicylic acid delivery 
The formulation of salicylate-based poly(anhydride-ester) (PAE) microspheres was optimized by altering polymer concentration and homogenization speed to improve the overall morphology. The microspheres were prepared using three salicylate-based PAEs with different chemical compositions comprised of either a heteroatomic, linear aliphatic, or branched aliphatic moiety. These PAEs broadened the range of complete salicylic acid release to now include days, weeks and months. The molecular weight (Mw), polydispersity index (PDI) and glass transition temperature (Tg) of the formulated polymers were compared to the unformulated polymers. In general, the Mw and PDI exhibited decreased and increased values, respectively, after formulation, whereas the Tg changes did not follow a specific trend. Microsphere size and morphology were determined using scanning electron microscopy. These microspheres exhibited smooth surfaces, no aggregation, and size distributions ranging from 2-34 m in diameter. In vitro release studies of the chemically incorporated salicylic acid displayed widely tunable release profiles.
PMCID: PMC3571728  PMID: 23420391
drug delivery; microspheres; salicylic acid; biodegradable
8.  PolyMorphine: an innovative biodegradable polymer drug for extended pain relief 
Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed “PolyMorphine”, was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopies, and infrared spectroscopy. The weight-average molecular weight and the thermal properties were determined. The hydrolytic degradation pathway of the polymer was determined by in vitro studies, showing that free morphine is released. In vitro cytocompatibility studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. The animals retained full responsiveness to morphine after being subjected to an acute morphine challenge.
PMCID: PMC3455147  PMID: 22877734
morphine; biodegradable; polymer; extended release; pain treatment; prodrug
9.  Tunable drug release profiles from salicylate-based poly(anhydride-ester) matrices using small molecule admixtures 
Poly(anhydride-esters) with salicylic acid, a nonsteroidal anti-inflammatory drug, chemically incorporated into the polymer backbone provide high inherent drug loading. These poly(anhydride-esters) hydrolytically degrade to release salicylic acid over extended time periods (>30 days); however, an initial lag period of no salicylic acid release is observed. This lag period could be unfavorable in applications where immediate salicylic acid release is desired. Poly(anhydride-esters) with short (2 days) and long (11 days) lag periods were admixed with various small molecules as a means to shorten or eliminate the lag period. Salicylic acid, larger salicylic acid prodrugs, and 1:1 combinations of the two were physically admixed, each at 1%, 5%, and 10% (w/w). All admixtures resulted in immediate salicylic acid release and a decrease in glass transition temperatures compared to polymer alone. By varying the amounts of salicylic acid and salicylic acid prodrugs incorporated into the polymer matrix, immediate and constant salicylic acid release profiles over varied time periods were achieved.
PMCID: PMC3782750  PMID: 24078768
Biodegradable; polymer; salicylic acid; salicylic acid prodrugs; drug delivery; sustained release; poly(anhydride-ester); timed release
10.  Impact of ionizing radiation on physicochemical and biological properties of an amphiphilic macromolecule 
Polymer degradation and stability  2012;97(9):1686-1689.
An amphiphilic macromolecule (AM) was exposed to ionizing radiation (both electron beam and gamma) at doses of 25 kGy and 50 kGy to study the impact of these sterilization methods on the physicochemical properties and bioactivity of the AM. Proton nuclear magnetic resonance and gel permeation chromatography were used to determine the chemical structure and molecular weight, respectively. Size and zeta potential of the micelles formed from AMs in aqueous media were evaluated by dynamic light scattering. Bioactivity of irradiated AMs was evaluated by measuring inhibition of oxidized low-density lipoprotein uptake in macrophages. From these studies, no significant changes in the physicochemical properties or bioactivity were observed after the irradiation, demonstrating that the AMs can withstand typical radiation doses used to sterilize materials.
PMCID: PMC3496278  PMID: 23162175
amphiphilic macromolecule; electron beam radiation; gamma radiation; oxLDL inhibition; stability
11.  Stability of a salicylate-based poly(anhydride-ester) to electron beam and gamma radiation 
Polymer degradation and stability  2011;96(9):1625-1630.
The effect of electron beam and gamma radiation on the physicochemical properties of a salicylate-based poly(anhydride-ester) was studied by exposing polymers to 0 (control), 25 and 50 kGy. After radiation exposure, salicylic acid release in vitro was monitored to assess any changes in drug release profiles. Molecular weight, glass transition temperature and decomposition temperature were evaluated for polymer chain scission and/or crosslinking as well as changes in thermal properties. Proton nuclear magnetic resonance and infrared spectroscopies were also used to determine polymer degradation and/or chain scission. In vitro cell studies were performed to identify cytocompatibility following radiation exposure. These studies demonstrate that the physicochemical properties of the polymer are not substantially affected by exposure to electron beam and gamma radiation.
PMCID: PMC3167163  PMID: 21909173
polyanhydride; sterilization; drug release; gamma irradiation; electron beam; stability
12.  Microscale Plasma-Initiated Patterning of Electrospun Polymer Scaffolds 
Microscale plasma-initiated patterning (μPIP) is a novel micropatterning technique used to create biomolecular micropatterns on polymer surfaces. The patterning method uses a polydimethylsiloxane (PDMS) stamp to selectively protect regions of an underlying substrate from oxygen plasma treatment resulting in hydrophobic and hydrophilic regions. Preferential adsorption of the biomolecules onto either the plasma-exposed (hydrophilic) or plasma-protected (hydrophobic) regions leads to the biomolecular micropatterns. In the current work, laminin-1 was applied to an electrospun polyamide nanofibrillar matrix following plasma treatment. Radial glial clones (neural precursors) selectively adhered to these patterned matrices following the contours of proteins on the surface. This work demonstrates that textured surfaces, such as nanofibrillar scaffolds, can be micropatterned to provide external chemical cues for cellular organization.
PMCID: PMC3062666  PMID: 21345656
Extracellular matrix; micropatterning; nanofibers; laminin-1; glial cells; nerve regeneration
13.  Salicylic acid-derived poly(anhydride-ester) electrospun fibers designed for regenerating the peripheral nervous system 
Continuous biomaterial advances and the regenerating potential of the adult human peripheral nervous system offer great promise for restoring full function to innervated tissue following traumatic injury via synthetic nerve guidance conduits. To most effectively facilitate nerve regeneration, a tissue engineering scaffold within a conduit must be similar to the linear microenvironment of the healthy nerve. To mimic the native nerve structure, aligned poly(lactic-co-glycolic acid)/bioactive polyanhydride fibrous substrates were fabricated through optimized electrospinning parameters with diameters of 600 ± 200 nm. Scanning electron microscopy images show fibers with a high degree of alignment. Schwann cells and dissociated rat dorsal root ganglia demonstrated elongated and healthy proliferation in a direction parallel to orientated electrospun fibers with significantly longer Schwann cell process length and neurite outgrowth when compared to randomly orientated fibers. Results suggest that an aligned polyanhydride fiber mat holds tremendous promise as a supplement scaffold for the interior of a degradable polymer nerve guidance conduit. Bioactive salicylic acid based polyanhydride fibers are not limited to nerve regeneration and offer exciting promise for a wide variety of biomedical applications.
PMCID: PMC3096072  PMID: 21442724
Nerve regeneration; electrospinning; fibers; polyanhydride; salicylic acid
14.  Storage Stability Study of Salicylate-based Poly(anhydride-esters) 
Polymer degradation and stability  2010;95(9):1778-1782.
Storage stability was evaluated on a biodegradable salicylate-based poly(anhydride-ester) to elucidate the effects of storage conditions over time. The hydrolytically labile polymer samples were stored in powdered form at five relevant storage temperatures (−12 °C, 4 °C, 27 °C, 37 °C, 50 °C) and monitored over four weeks for changes in color, glass transition temperature, molecular weight, and extent of hydrolysis. Samples stored at lower temperatures remained relatively constant with respect to bond hydrolysis and molecular weight. Whereas, samples stored at higher temperatures displayed significant hydrolysis. For hydrolytically degradable polymers, such as these poly(anhydride-esters), samples are best stored at low temperatures under an inert atmosphere.
PMCID: PMC2997568  PMID: 21152105
Polyanhydride; Stability; Degradation; Biodegradable; Hydrolysis
15.  Impact of Hydrophobic Chain Composition on Amphiphilic Macromolecule Antiatherogenic Bioactivity 
Biomacromolecules  2014;15(9):3328-3337.
Amphiphilic macromolecules (AMs) composed of sugar backbones modified with branched aliphatic chains and a poly(ethylene glycol) (PEG) tail can inhibit macrophage uptake of oxidized low-density lipoproteins (oxLDL), a major event underlying atherosclerosis development. Previous studies indicate that AM hydrophobic domains influence this bioactivity through interacting with macrophage scavenger receptors, which can contain basic and/or hydrophobic residues within their binding pockets. In this study, we compare two classes of AMs to investigate their ability to promote athero-protective potency via hydrogen-bonding or hydrophobic interactions with scavenger receptors. A series of ether-AMs, containing methoxy-terminated aliphatic arms capable of hydrogen-bonding, was synthesized. Compared to analogous AMs containing no ether moieties (alkyl-AMs), ether-AMs showed improved cytotoxicity profiles. Increasing AM hydrophobicity via incorporation of longer and/or alkyl-terminated hydrophobic chains yielded macromolecules with enhanced oxLDL uptake inhibition. These findings indicate that hydrophobic interactions and the length of AM aliphatic arms more significantly influence AM bioactivity than hydrogen-bonding.
PMCID: PMC4157764  PMID: 25070717
16.  Amphiphilic Nanoparticles Repress Macrophage Atherogenesis: Novel Core/Shell Designs for Scavenger Receptor Targeting and Down-Regulation 
Molecular Pharmaceutics  2014;11(8):2815-2824.
Atherosclerosis, an inflammatory lipid-rich plaque disease is perpetuated by the unregulated scavenger-receptor-mediated uptake of oxidized lipoproteins (oxLDL) in macrophages. Current treatments lack the ability to directly inhibit oxLDL accumulation and foam cell conversion within diseased arteries. In this work, we harness nanotechnology to design and fabricate a new class of nanoparticles (NPs) based on hydrophobic mucic acid cores and amphiphilic shells with the ability to inhibit the uncontrolled uptake of modified lipids in human macrophages. Our results indicate that tailored NP core and shell formulations repress oxLDL internalization via dual complementary mechanisms. Specifically, the most atheroprotective molecules in the NP cores competitively reduced NP-mediated uptake to scavenger receptor A (SRA) and also down-regulated the surface expression of SRA and CD36. Thus, nanoparticles can be designed to switch activated, lipid-scavenging macrophages to antiatherogenic phenotypes, which could be the basis for future antiatherosclerotic therapeutics.
PMCID: PMC4144725  PMID: 24972372
atherosclerosis; amphiphilic macromolecules; scavenger receptor; nanoparticle; macrophages; atherogenesis; oxidized lipoproteins
17.  Carbohydrate-Derived Amphiphilic Macromolecules: A Biophysical Structural Characterization and Analysis of Binding Behaviors to Model Membranes 
The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) “stealth lipids” built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials.
PMCID: PMC4493506  PMID: 25855953
amphiphilic macromolecule; membrane lipid bilayers; quartz crystal microbalance with dissipation (QCM-D); molecular dynamics simulations; quantitative structure-activity relationship (QSAR) model
18.  Poly(anhydride-esters) Comprised Exclusively of Naturally Occurring Antimicrobials and EDTA: Antioxidant and Antibacterial Activities 
Biomacromolecules  2014;15(5):1889-1895.
Carvacrol, thymol, and eugenol are naturally occurring phenolic compounds known to possess antimicrobial activity against a range of bacteria, as well as antioxidant activity. Biodegradable poly(anhydride-esters) composed of an ethylenediaminetetraacetic acid (EDTA) backbone and antimicrobial pendant groups (i.e., carvacrol, thymol, or eugenol) were synthesized via solution polymerization. The resulting polymers were characterized to confirm their chemical composition and understand their thermal properties and molecular weight. In vitro release studies demonstrated that polymer hydrolytic degradation was complete after 16 days, resulting in the release of free antimicrobials and EDTA. Antioxidant and antibacterial assays determined that polymer release media exhibited bioactivity similar to that of free compound, demonstrating that polymer incorporation and subsequent release had no effect on activity. These polymers completely degrade into components that are biologically relevant and have the capability to promote preservation of consumer products in the food and personal care industries via antimicrobial and antioxidant pathways.
PMCID: PMC4020595  PMID: 24702678
19.  Nanoscale amphiphilic macromolecules as lipoprotein inhibitors: the role of charge and architecture 
A series of novel amphiphilic macromolecules composed of alkyl chains as the hydrophobic block and poly(ethylene glycol) as the hydrophilic block were designed to inhibit highly oxidized low density lipoprotein (hoxLDL) uptake by synthesizing macromolecules with negatively charged moieties (ie, carboxylic acids) located in the two different blocks. The macromolecules have molecular weights around 5,500 g/mol, form micelles in aqueous solution with an average size of 20–35 nm, and display critical micelle concentration values as low as 10−7 M. Their charge densities and hydrodynamic size in physiological buffer solutions correlated with the hydrophobic/hydrophilic block location and quantity of the carboxylate groups. Generally, carboxylate groups located in the hydrophobic block destabilize micelle formation more than carboxylate groups in the hydrophilic block. Although all amphiphilic macromolecules inhibited unregulated uptake of hoxLDL by macrophages, inhibition efficiency was influenced by the quantity and location of the negatively charged-carboxylate on the macromolecules. Notably, negative charge is not the sole factor in reducing hoxLDL uptake. The combination of smaller size, micellar stability and charge density is critical for inhibiting hoxLDL uptake by macrophages.
PMCID: PMC2676825  PMID: 18203436
polymeric micelles; amphiphilic macromolecules; highly oxidized low-density lipoproteins; scavenger receptor inhibition
20.  In silico design of anti-atherogenic biomaterials 
Biomaterials  2013;34(32):10.1016/j.biomaterials.2013.07.011.
Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(-ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties.
PMCID: PMC3880781  PMID: 23891521
Amphiphilic macromolecules; Macrophages; Atherosclerosis; Molecular modeling; Structure-activity relations
21.  Nanoscale Amphiphilic Macromolecules with Variable Lipophilicity and Stereochemistry Modulate Inhibition of Oxidized Low-Density Lipoprotein Uptake 
Biomacromolecules  2013;14(8):2463-2469.
Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies.
PMCID: PMC3773991  PMID: 23795777
Amphiphilic polymer; atherosclerosis; self-assembled micelle; oxLDL inhibition
22.  Biodegradable Ferulic Acid-containing Poly(anhydride-ester): Degradation Products with Controlled Release and Sustained Antioxidant Activity 
Biomacromolecules  2013;14(3):854-861.
Ferulic acid (FA) is an antioxidant and photoprotective agent used in biomedical and cosmetic formulations to prevent skin cancer and senescence. Although FA exhibits numerous health benefits, physicochemical instability leading to decomposition hinders its efficacy. To minimize inherent decomposition, a FA-containing biodegradable polymer was prepared via solution polymerization to chemically incorporate FA into a poly(anhydride-ester). The polymer was characterized using nuclear magnetic resonance and infrared spectroscopies. The molecular weight and thermal properties were also determined. In vitro studies demonstrated that the polymer was hydrolytically degradable, thus providing controlled release of the chemically incorporated bioactive with no detectable decomposition. The polymer degradation products were found to exhibit antioxidant and antibacterial activity comparable to free FA and in vitro cell viability studies demonstrated that the polymer is non-cytotoxic towards fibroblasts. This renders the polymer a potential candidate for use as a controlled release system for skin care formulations.
PMCID: PMC3595371  PMID: 23327626
biodegradable; polymer; poly(anhydride-ester); ferulic acid; antioxidant; controlled release
23.  Synthesis and Characterization of 5-Aminosalicylic Acid Based Poly(anhydride-esters) by Solution Polymerization 
PMCID: PMC3889020  PMID: 24431483
5-aminosalicylic acid; polyanhydride; polymer drug; solution polymerization; triphosgene
24.  Carbohydrate Composition of Amphiphilic Macromolecules Influences Physicochemical Properties and Binding to Atherogenic Scavenger Receptor A 
Acta biomaterialia  2012;8(11):3956-3962.
Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) mediated by scavenger receptor A (SR-A) and counteract foam cell formation, the characteristic “atherosclerotic” phenotype. A series of AMs were prepared by altering the carbohydrate chemistry to evaluate the influence of backbone architecture on the physicochemical and biological properties. Upon evaluating the degree of polymer-based inhibition of oxLDL uptake in human embryonic kidney cells expressing SR-A, two AMs (2a and 2c) were found to have the most efficacy. Molecular modeling and docking studies show that these same AMs have the most favorable binding energies and most close interactions with the molecular model of SR-A collagen-like domain. Thus, minor changes in the AMs architecture can significantly affect the physicochemical properties and inhibition of oxLDL uptake. These insights can be critical for designing optimal AM-based therapeutics for management of cardiovascular disease.
PMCID: PMC3462273  PMID: 22835678
Amphiphilic polymer; atherosclerosis; self-assembled micelle; oxLDL inhibition
25.  Synthesis and characterization of antiseptic-based poly(anhydride-esters) 
Poly(anhydride-esters) were prepared from catechol, fenticlor and hexachlorophene. The molecular weights (Mw) of the polymers were typically > 10,000 Da with glass transition temperatures (Tg) ranging from 23 to 84 °C. The thermal characteristics of the polymers paralleled the melting temperatures of the chemically incorporated antiseptic molecules. The in vitro release of the chemically incorporated antiseptic molecules were monitored over a 12 week period. For comparison, the in vitro release of physically admixed antiseptic molecules were also observed. After 12 weeks, the polymers were not completely degraded with drug release ranging from less than 1 to 55 %. Sessile-drop contact angles indicated that the polymers were relatively hydrophobic, contributing to the slow polymer degradation rates.
PMCID: PMC3769797  PMID: 24039323

Results 1-25 (38)