Nontoxic Cationic Coumarin Polyester Coatings Prevent Pseudomonas aeruginosa Biofilm Formation.

The rapid increase in bacterial infections and antimicrobial resistance is a growing public health concern. Infections arising from bacterial contamination of surgical tools, medical implants, catheters, and hospital surfaces can potentially be addressed by antimicrobial polymeric coatings. The challenge in developing such polymers for in vivo use is the ability to achieve high antimicrobial efficacy while at the same time being nontoxic to human cells. Although several classes of antimicrobial polymers have been developed, many of them cannot be used in the clinical setting due to their nonselective toxicity toward bacteria and mammalian cells. Here, we demonstrate that coumarin polyesters with cationic pendant groups are very effective against Gram negative Pseudomonas aeruginosa. Coumarin polyesters with pendant cationic amine groups were coated onto glass coverslips and tested for their antimicrobial activity against P. aeruginosa colonization of the surface. The results demonstrate that the cationic coumarin polyester kills the surface attached bacterial cells preventing biofilm formation but does not show any hemolytic activity or discernible toxicity toward mammalian cells. The antimicrobial polyesters described in this work have several advantages desired in antimicrobial coatings such as high antimicrobial activity, low toxicity toward mammalian cells, visualization and ease of synthesis and fabrication, all of which are necessary for translation to the clinic.

Assessment of alkoxylphenacyl-based polycarbonates as a potential platform for controlled delivery of a model anti-glaucoma drug.

Treatment strategies for glaucoma will benefit from injectable and/or implantable delivery systems that can achieve sustained delivery of neuroprotective agents (to the posterior segment) and/or intraocular pressure lowering drugs (to the anterior segment). In this regard, we have evaluated the suitability of a new polymer (alkoxylphenacyl-based polycarbonates copolymer with polycaprolactone; AP-PCL 20% w/w) as a platform for ocular drug delivery. Brimonidine tartrate (BRT) was applied as a model anti-glaucoma drug. The polymer was applied to develop injectable (nanoparticles) and implantable (microfilms) delivery systems. Nanoparticles fabricated from AP-PCL were stable and have an average size less than 200nm. The AP-PCL microfilms prepared by compression molding showed a gradual hydrolytic in-vitro degradation monitored by water uptake, weight loss, microscopy, DSC and FT-IR measurements. AP-PCL microfilms achieve sustained delivery of BRT for up to 90days. Biocompatibility of AP-PCL-based delivery systems was demonstrated from studies in human trabecular meshwork cell line as well as after intravitreal injections in rats. The overall trend demonstrated that AP-PCL delivery systems may be considered as suitable candidates for prolonged drug delivery in chronic ocular disorders such as glaucoma.

Micropatterned coumarin polyester thin films direct neurite orientation.

Guidance and migration of cells in the nervous system is imperative for proper development, maturation, and regeneration. In the peripheral nervous system (PNS), it is challenging for axons to bridge critical-sized injury defects to achieve repair and the central nervous system (CNS) has a very limited ability to regenerate after injury because of its innate injury response. The photoreactivity of the coumarin polyester used in this study enables efficient micropatterning using a custom digital micromirror device (DMD) and has been previously shown to be biodegradable, making these thin films ideal for cell guidance substrates with potential for future in vivo applications. With DMD, we fabricated coumarin polyester thin films into 10×20 µm and 15×50 µm micropatterns with depths ranging from 15 to 20 nm to enhance nervous system cell alignment. Adult primary neurons, oligodendrocytes, and astrocytes were isolated from rat brain tissue and seeded onto the polymer surfaces. After 24 h, cell type and neurite alignment were analyzed using phase contrast and fluorescence imaging. There was a significant difference (p<0.0001) in cell process distribution for both emergence angle (from the body of the cell) and orientation angle (at the tip of the growth cone) confirming alignment on patterned surfaces compared to control substrates (unpatterned polymer and glass surfaces). The expected frequency distribution for parallel alignment (≤15°) is 14% and the two micropatterned groups ranged from 42 to 49% alignment for emergence and orientation angle measurements, where the control groups range from 12 to 22% for parallel alignment. Despite depths being 15 to 20 nm, cell processes could sense these topographical changes and preferred to align to certain features of the micropatterns like the plateau/channel interface. As a result this initial study in utilizing these new DMD micropatterned coumarin polyester thin films has proven beneficial as an axon guidance platform for future nervous system regenerative strategies.

Formulation and photoirradiation parameters that influenced photoresponsive drug delivery using alkoxylphenacyl-based polycarbonates.

Recently, we reported the synthesis and biocompatibility of alkoxylphenacyl-based polycarbonates (APP); a promising new class of polymers that undergo photo-induced chain scission. In the current study, nanoparticles (NPs) were prepared from the APP polymer (APP-NPs) and loaded with doxorubicin (DOX) (DOX-APP-NPs) in order to identify and evaluate formulation and photoirradiation parameters that influence photoresponsive efficacy. Stable and spherical APP-NPs were prepared with diameters between 70-80nm depending on APP concentration (10-40mg/mL). There was a direct relationship between APP concentration and resultant particle size. Drug release studies indicated that exposure to the photo-trigger was capable of altering the rate and extent of DOX released. Photoresponsive DOX release was markedly influenced by the frequency of photoirradiation while the effect of APP concentration was most likely propagated through NP size. DOX released by photoactivation retained its efficacy as assessed by cytotoxicity studies in human lung adenocarcinoma (A549) cells. Studies in BALB/c mice indicated that DOX-APP-NPs induce less cardiotoxicity than DOX alone and that DOX-APP-NPs are not susceptible to dose dumping after photoirradiation.

Photoresponsive polyesters by incorporation of alkoxyphenacyl or coumarin chromophores along the backbone.

The synthesis and photochemical characterization of two classes of photoresponsive polyesters are described. These polyesters contain either alkoxyphenacyl or coumarin chromophores embedded along the polymer chain. The alkoxyphenacyl polyesters undergo efficient photoinduced chain scission upon irradiation at 300 nm in solution or as a nanoparticle suspension. At 254 nm the coumarin polyesters undergo polymer chain scission. Irradiation of the coumarin polyesters in solution at 350 nm results in both chain crosslinking and chain scission behavior, while irradiation of the coumarin polyesters as nanoparticles results in chain crosslinking. The properties of the alkoxyphenacyl and coumarin polyesters are influenced by the choice of diacid as seen from their thermal behavior. The use of glutamic acid enabled surface or bulk functionalization of the photoresponsive polymers. In addition, controlled release of Nile Red from coumarin polyester nanoparticles is demonstrated by modulation of the wavelength and intensity of irradiation.

Biocompatibility and in vivo tolerability of a new class of photoresponsive alkoxylphenacyl-based polycarbonates.

Potential toxicities of chromophoric or polymeric units of most photoresponsive delivery systems have impacted clinical relevance. Herein, we evaluated the biocompatibility and tolerability of alkoxylphenacyl-based polycarbonates (APPs) as a new class of photoresponsive polymers. The polymers were applied as homopolymer or copolymers of polyethylene glycol (10%, w/w) or polycaprolactone (10%, w/w). APP polymers were comparable to poly(lactic-co-glycolic acid) (PLGA) based on cytotoxicity, macrophage activation, and blood compatibility. Data from biodistribution studies in BALB/c mice showed preferential accumulation in kidney and liver. Meanwhile, potential application of APP polymers as immediate or sustained (implants) drug delivery systems indicated that liver and kidney functions were not distorted. Also, plasma levels of tumor necrosis factor-alpha and interleukin-6 were comparable to PLGA-treated mice (p > 0.05). A histological analysis of liver and kidney sections showed no detectable damage for APP polymers. The overall data strongly supported potential consideration of APP polymers as photoresponsive delivery systems especially as implantable or tissue-mimicking photopatterned biomaterials.

Photoinduced Polymer Chain Scission of Alkoxyphenacyl Based Polycarbonates.

We report the design and development of a new class of alkoxyphenacyl based photodegradable polycarbonates. These polymers incorporate the photoactive moiety in the backbone and, when irradiated at 300 nm, undergo controlled chain scission. Micropatterned thin films of these polymers were fabricated by photolithographic techniques. The use of these photodegradable polymers for controlled release applications was demonstrated by the release of Nile Red from polymeric nanoparticles. In addition, these polymers are mechanically robust, thermally stable, and hydrolytically degradable.