Hydrogen-Bonding Layer-by-Layer-Assembled Biodegradable Polymeric Micelles as Drug Delivery Vehicles from Surfaces

Abstract

We present the integration of amphiphilic block copolymer micelles as nanometer-sized vehicles for hydrophobic drugs within layer-by-layer (LbL) films using alternating hydrogen bond interactions as the driving force for assembly for the first time, thus enabling the incorporation of drugs and pH-sensitive release. The film was constructed based on the hydrogen bonding between poly(acrylic acid) (PAA) as an H-bond donor and biodegradable poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles as the H-bond acceptor when assembled under acidic conditions. By taking advantage of the weak interactions of the hydrogen-bonded film on hydrophobic surfaces, it is possible to generate flexible free-standing films of these materials. A free-standing micelle LbL film of (PEO-b-PCL/PAA)60 with a thickness of 3.1 microm was isolated, allowing further characterization of the bulk film properties, including morphology and phase transitions, using transmission electron microscopy and differential scanning calorimetry. Because of the sensitive nature of the hydrogen bonding employed to build the multilayers, the film can be rapidly deconstructed to release micelles upon exposure to physiological conditions. However, we could also successfully control the rate of film deconstruction by cross-linking carboxylic acid groups in PAA through thermally induced anhydride linkages, which retard the drug release to the surrounding medium to enable sustained release over multiple days. To demonstrate efficacy in delivering active therapeutics, in vitro Kirby-Bauer assays against Staphylococcus aureus were used to illustrate that the drug-loaded micelle LbL film can release significant amounts of an active antibacterial drug, triclosan, to inhibit the growth of bacteria. Because the micellar encapsulation of hydrophobic therapeutics does not require specific chemical interactions, we believe this noncovalent approach provides a new route to integrating active small, uncharged, and hydrophobic therapeutics into LbL thin films for biological and biomedical coatings.

Small-molecule-hosting nanocomposite films with multiple bacteria-triggered responses

“…23,24 Moreover, antibacterial surfaces have been designed that can respond to light or pH. 25,26 The present study goes beyond this prior work by describing a new type of coating that was engineered to combine permanent, contactkilling protection with bacteria-triggered, on-demand release of antimicrobials. By exploring clay-containing nanocomposites rather than all-polymer films as matrices to host an antibiotic, we were able to prevent low-level tail release of antibiotics that consequently minimizes the development of antibiotic resistance.…”

Layer-by-Layer-Assembled Multilayer Films for Transcutaneous Drug and Vaccine Delivery

“…[18][19][20][21] Drug-loaded degradable multilayers have been explored for the sustained release of small-molecule antibiotics, protein therapeutics, or plasmid DNA. 3,7,18,19,[21][22][23][24] The mild aqueous conditions for encapsulating molecules into multilayer films preserves the bioactivity of fragile biomolecules such as proteins and nucleic acids. 21,22,25 By employing degradable polyelectrolytes as building blocks, the ability to tune the degradation kinetics of multilayer assemblies has been demonstrated and used to control the release kinetics of compounds embedded in these films.…”

“…20,26 Applications envisioned for such drug-loaded films include antimicrobial-or anti-inflammatory coatings on implants and drug-releasing coatings for stents. 24,27,28 Given the ability of multilayers to be conformally coated on a broad range of substrates, to load both small-molecule and macromolecular drugs, and to regulate the release of drugs over a period of hours to days, we became interested in the potential of these polyelectrolyte films in a new application area: transcutaneous drug delivery. Skin is an attractive site for non-invasive delivery of therapeutics, due to the ease of access to this organ and the ability of transcutaneous delivery to limit first-pass drug metabolism and alter the pharmacokinetics and pharmacodynamics of drugs.…”

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

“…Covalent approach involves diffusion based loading strategy to form chemically bonded conjugates where the binding sites must be accessible and protected against possible hinderances such as electrostatic repulsion, steric repulsion, entropic repulsion etc. On the other hand non-covalent systems involving dynamic association (including hydrophobic, electrostatic, hydrogen bonding and steric immobilization) between drug and polymeric carriers within their local aqueous environment allow the loaded drug to diffuse to the surface of the corona and the target environment during drug delivery (220,221). The overall balance between these cooperative forces within the polymer-drug system is vital to the architecture, conformational flexibility, thermodynamic stability and the drug release mechanism from the conjugate.…”