Enhanced drug delivery to cancer cells through a pH-sensitive polycarbonate platform.

Polymer-drug conjugates are widely investigated to enhance the selectivity of therapeutic drugs to cancer cells, as well as increase circulation lifetime and solubility of poorly soluble drugs. In order to direct these structures selectively to cancer cells, targeting agents are often conjugated to the nanoparticle surface as a strategy to limit drug accumulation in non-cancerous cells and therefore reduce systemic toxicity. Here, we report a simple procedure to generate biodegradable polycarbonate graft copolymer nanoparticles that allows for highly efficient conjugation and intracellular release of S-(+)-camptothecin, a topoisomerase I inhibitor widely used in cancer therapy. The drug-polymer conjugate showed strong efficacy in inhibiting cell proliferation across a range of cancer cell lines over non-cancerous phenotypes, as a consequence of the increased intracellular accumulation and subsequent drug release specifically in cancer cells. The enhanced drug delivery towards cancer cells in vitro demonstrates the potential of this platform for selective treatments without the addition of targeting ligands.

Biocompatible polypeptide-based interpenetrating network (IPN) hydrogels with enhanced mechanical properties.

Hydrogels are widely used for biomedical applications such as drug delivery, tissue engineering, or wound healing owing to their mimetic properties in relation to biological tissues. The generation of peptide-based hydrogels is a topic of interest due to their potential to increase biocompatibility. However, their usages can be limited when compared to other synthetic hydrogels because of their inferior mechanical properties. Herein, we present the synthesis of novel synthetic polypeptide-based interpenetrating network (IPN) hydrogels with enhanced mechanical properties. The polypeptide single network is obtained from alkyne functional polypeptides crosslinked with di, tri and tetra azide functional PEG by copper-catalysed alkyne-azide cycloaddition (CuAAC). Interpenetrating networks were subsequently obtained by loading of the polypeptide single network with PEG-dithiol and orthogonally UV-crosslinking with varying molar ratios of pentaerythritol tetraacrylate. The characteristics, including the mechanical strength (i.e. compressive strength (UCS), fracture strain (εbreak), and Young's modulus (E)) and cell compatibility (i.e. metabolic activity and Live/Dead of human Mesenchymal Stem Cells), of each synthetic polypeptide-based IPN hydrogel were studied and evaluated in order to demonstrate their potential as mechanically robust hydrogels for use as artificial tissues. Moreover, 1H NMR diffusometry was carried out to examine the water mobility (DH2O) within the polypeptide-based hydrogels and IPNs. It was found that both the mechanical and morphological properties could be tailored concurrently with the hydrophilicity, rate of water diffusion and 'swellability'. Finally it was shown that the polypeptide-based IPN hydrogels exhibited good biocompatibility, highlighting their potential as soft tissue scaffolds.

Progress and Current Trends in the Synthesis of Novel Polymers with Enhanced Mucoadhesive Properties.

Mucoadhesion is defined as the adherence of a synthetic or natural polymer to a mucosal membrane via physical or chemical interactions. Mucoadhesive materials are widely used to develop dosage forms for transmucosal drug delivery via ocular, nasal, esophageal, oral, vaginal, rectal, and intravesical routes of administration. This review will discuss some of the most prominent and recent synthetic methodologies employed to modify polymeric materials in order to enhance their mucoadhesive properties. This includes chemical conjugation of polymers with molecules bearing thiol-, catechol-, boronate-, acrylate-, methacrylate-, maleimide-, and N-hydroxy(sulfo)succinimide ester- groups.

pH-Responsive, Functionalizable Spyrocyclic Polycarbonate: A Versatile Platform for Biocompatible Nanoparticles.

Polymeric nanoparticles are widely investigated to enhance the selectivity of therapeutics to targeted sites, as well as to increase circulation lifetime and water solubility of poorly soluble drugs. In contrast to the encapsulation of the cargo into the nanostructures, the conjugation directly to the polymer backbone allows better control on the loading and selective triggered release. In this work we report a simple procedure to create biodegradable polycarbonate graft copolymer nanoparticles via a ring opening polymerization and subsequent postpolymerization modification strategies. The polymer, designed with both pH-responsive acetal linkages and a norbornene group, allows for highly efficient postpolymerization modifications through a range of chemistries to conjugate imaging agents and solubilizing arms to direct self-assembly. To demonstrate the potential of this approach, polycarbonate-based nanoparticles were tested for biocompatibility and their ability to be internalized in A549 and IMR-90 cell lines.

Synthesis and evaluation of mucoadhesive acryloyl-quaternized PDMAEMA nanogels for ocular drug delivery.

Poly((2-dimethylamino)ethyl methacrylate) (PDMAEMA) nanogels were synthesized via surfactant-free free-radical polymerization technique in aqueous conditions utilizing N,N'-methylene-bis-acrylamide (MBA) as a crosslinking agent. The PDMAEMA nanogels were subsequently quaternized with acryloyl chloride in order to yield mucoadhesive materials which incorporate two mucoadhesive concepts; electrostatic interactions and covalent bond forming acrylate groups. The native PDMAEMA nanogels were found to exhibit good mucoadhesive properties on ex vivo bovine conjunctival tissues, which was found to increase proportionally with the degree of quaternization. With a view to determine the ocular drug delivery capabilities of the materials, both quaternized and native nanogels were loaded with pilocarpine hydrochloride via an absorption method, and their in vitro release profiles were analysed. The nanogels were found to exhibit a high loading capacity (>20% of total weight) and a sustained release over 6h.

Synthesis, properties and biomedical applications of hydrolytically degradable materials based on aliphatic polyesters and polycarbonates.

Polyester-based polymers represent excellent candidates in synthetic biodegradable and bioabsorbable materials for medical applications owing to their tailorable properties. The use of synthetic polyesters as biomaterials offers a unique control of morphology, mechanical properties and degradation profile through monomer selection, polymer composition (i.e. copolymer vs. homopolymer, stereocomplexation etc.) and molecular weight. Within this review, the synthetic routes, degradation modes and application of aliphatic polyester- and polycarbonate-based biomaterials are discussed.

Maleimide-bearing nanogels as novel mucoadhesive materials for drug delivery.

Novel maleimide-functionalised nanogels have been synthesised via the polymerisation of 2,5-dimethylfuran-protected 3-maleimidoethyl butylacrylate in the presence of presynthesised poly(N-vinylpyrrolidone) (PVP) nanogel scaffolds using surfactant-free emulsion polymerisation techniques. The protected maleimide nanogels were subsequently deprotected to generate the reactive maleimide group via a retro-Diels-Alder reaction. These activated nanogels were found to exhibit excellent mucoadhesive properties on ex vivo conjunctival tissue when compared to the known mucoadhesive chitosan. In order to determine the viability of the materials as drug carriers, nanogels were loaded with a model drug compound and the in vitro release kinetics were analysed. The nanogels could sustain the release of a model drug compound over several hours owing to the swellable hydrophilic nanogel structure, exhibiting first order release kinetics. As a consequence, these findings support the potential of these maleimide-bearing nanogels as a novel platform for sustained drug delivery.