Antimicrobial/Antifouling Polycarbonate Coatings: Role of Block Copolymer Architecture

The high prevalence of catheter-associated infections accounts for more than 3 billion dollars annually in hospitals, and antimicrobial polymer coatings on catheter surface may serve as an attractive weapon to mitigate infections. Triblock polycarbonate polymers consisting of three critical components including antifouling poly­(ethylene glycol) (PEG), antimicrobial cationic polycarbonate, and a tethering or adhesive functional block were synthesized. In this study, the block topology or placement of the distinctive blocks was varied and their efficacy as antimicrobial and antifouling agents investigated on coated surfaces. The individual blocks were designed to have comparable lengths that were subsequently grafted onto a prefunctionalized catheter surface through covalent bonding under mild conditions. The anchoring/adhesive functional moiety based on a maleimide functional carbonate was positioned at either the center or end of the polymer block and subsequently tethered to the surface via Michael addition chemistry. The placement of the adhesive block was investigated in terms of its effect on antimicrobial and antifouling properties. The surface coated with the polymer containing the center-positioned tethering block (2.4k-V) was unable to prevent bacteria fouling, even though demonstrated higher bacteria killing efficacy in solution as compared to the surface coated with the polymer containing the end-positioned tethering block (2.4k-S). In contrast, the 2.4k-S coating resisted fouling of both Gram-positive <i>S. aureus</i> and Gram-negative <i>E. coli</i> effectively under conditions that simulate the device lifetime (1 week). Moreover, the coating prevented protein fouling and platelet adhesion without inducing significant hemolysis. Consequently, this antibacterial and antifouling polymer coating is an interesting candidate to prevent catheter-associated bloodstream infections

Expanding the Cationic Polycarbonate Platform: Attachment of Sulfonium Moieties by Postpolymerization Ring Opening of Epoxides

Postpolymerization modification is a critical strategy for the development of functional polycarbonate scaffolds for medicinal applications. To expand the scope of available postpolymerization functionalization methods, polycarbonates containing pendant thioether groups were synthesized by organocatalyzed ring-opening polymerization. The thioether group allowed for the postpolymerization ring-opening of functional epoxides, affording a wide variety of sulfonium-functionalized A-B diblock and A-B-A triblock polycarbonate copolymers. The pendant thioether groups were found to be compatible with previously developed postsynthesis functionalization methods allowing for selective and orthogonal modifications of the polycarbonates

Antimicrobial Polycarbonates: Investigating the Impact of Nitrogen-Containing Heterocycles as Quaternizing Agents

Synthetic polymeric antimicrobials have received enormous attention recently on the back of increasing multidrug-resistance microbes. While conventional small molecular antibiotics act on specific targets to inhibit microbe activities, macromolecular antimicrobials physically destroy cell membranes of the organism rendering them ineffective; the mechanism of the latter aids in the prevention of developing drug-resistance microbes. In this investigation, we report on the synthesis of biodegradable cationic polycarbonates containing propyl and hexyl side chains quaternized with various nitrogen-containing heterocycles, such as imidazoles and pyridines, and their <i>in vitro</i> antimicrobial application. These polymers demonstrate a wide spectrum of activity (using minimum inhibitory concentrations analysis) against <i>Staphylococcus aureus</i> (Gram-positive), <i>Escherichia coli</i> (Gram-negative), <i>Pseudomonas aeruginosa</i> (Gram-negative), and <i>Candida albicans</i> (fungus). Hemolysis experiments also show high selectivity toward the tested microbes over mammalian (rat) red blood cells (<i>r</i>RBCs). In particular, some of the polymers can achieve >250 times selectivity of <i>S. aureus</i> over <i>r</i>RBCs. In addition, the polymers function via a membrane-lytic mechanism; hence, they are less likely to develop drug resistance. All these properties make them ideal candidates as antimicrobial agents

Biodegradable Strain-Promoted Click Hydrogels for Encapsulation of Drug-Loaded Nanoparticles and Sustained Release of Therapeutics

Biodegradable polycarbonate-based ABA triblock copolymers were synthesized via organocatalyzed ring-opening polymerization and successfully formulated into chemically cross-linked hydrogels by strain-promoted alkyne–azide cycloaddition (SPAAC). The synthesis and cross-linking of these polymers are copper-free, thereby eliminating the concern over metallic contaminants for biomedical applications. Gelation occurs rapidly within a span of 60 s by simple mixing of the azide- and cyclooctyne-functionalized polymer solutions. The resultant hydrogels exhibited pronounced shear-thinning behavior and could be easily dispensed through a 22G hypodermic needle. To demonstrate the usefulness of these gels as a drug delivery matrix, doxorubicin (DOX)-loaded micelles prepared using catechol-functionalized polycarbonate copolymers were incorporated into the polymer solutions to eventually form micelle/hydrogel composites. Notably, the drug release rate from the hydrogels was significantly more gradual compared to the solution formulation. DOX release from the micelle/hydrogel composites could be sustained for 1 week, while the release from the micelle solution was completed rapidly within 6 h of incubation. Cellular uptake of the released DOX from the micelle/hydrogel composites was observed at 3 h of incubation of human breast cancer MDA-MB-231 cells. A blank hydrogel containing PEG-(Cat)₁₂ micelles showed almost negligible toxicity on MDA-MB-231cells where cell viability remained high at >80% after treatment. When the cells were treated with the DOX-loaded micelle/hydrogel composites, there was a drastic reduction in cell viability with only 25% of cells surviving the treatment. In all, this study introduces a simple method of formulating hydrogel materials with incorporated micelles for drug delivery applications

Injectable Coacervate Hydrogel for Delivery of Anticancer Drug-Loaded Nanoparticles in vivo

In this study, bortezomib (BTZ, a cytotoxic water-insoluble anticancer drug) was encapsulated in micellar nanoparticles having a catechol-functionalized polycarbonate core through a pH-sensitive covalent bond between phenylboronic acid (PBA) in BTZ and catechol, and these drug-loaded micelles were incorporated into hydrogels to form micelle/hydrogel composites. A series of injectable, biodegradable hydrogels with readily tunable mechanical properties were formed and optimized for sustained delivery of the BTZ-loaded micelles through ionic coacervation between PBA-functionalized polycarbonate/poly­(ethylene glycol) (PEG) “ABA” triblock copolymer and a cationic one having guanidinium- or thiouronium-functionalized polycarbonate as “A” block. An in vitro release study showed the pH dependence in BTZ release. At pH 7.4, the BTZ release from the micelle/hydrogel composite remained low at 7%, whereas in an acidic environment, ∼85% of BTZ was released gradually over 9 days. In vivo studies performed in a multiple myeloma MM.1S xenograft mouse model showed that the tumor progression of mice treated with BTZ-loaded micelle solution was similar to that of the control group, whereas those treated with the BTZ-loaded micelle/hydrogel composite resulted in significant delay in the tumor progression. The results demonstrate that this hydrogel has great potential for use in subcutaneous and sustained delivery of drug-loaded micelles with superior therapeutic efficacy