Hybrid Polyester Self-Immolative Polymer Nanoparticles for Controlled Drug Release

© 2018 American Chemical Society. Delivery systems have been developed to address problematic properties of drugs, but the specific release of drugs at their targets is still a challenge. Polymers that depolymerize end-to-end in response to the cleavage of stimuli-responsive end-caps from their termini, commonly referred to as self-immolative polymers, offer high sensitivity to stimuli and have potential for the development of new high-performance delivery systems. In this work, we prepared hybrid particles composed of varying ratios of self-immolative poly(ethyl glyoxylate) (PEtG) and slowly degrading poly(d,l-lactic acid) (PLA). These systems were designed to provide a dual release mechanism consisting of a rapid burst release of drug from the PEtG domains and a slower release from the PLA domains. Using end-caps responsive to UV light and reducing thiols, it was found that triggered particles exhibited partial degradation, as indicated by a reduction in their dynamic light-scattering count rate that depended on the PEtG:PLA ratio. The particles were also shown to release the hydrophobic dye Nile red and the drug celecoxib in a manner that depended on triggering and the PEtG:PLA ratio. In vitro toxicity assays showed an effect of the stimuli on the toxicity of the celecoxib-loaded particles but also suggested it would be ideal to replace the sodium cholate surfactant that was used in the particle synthesis procedure in order to reduce the background toxicity of the delivery system. Overall, these hybrid systems show promise for tuning and controlling the release of drugs in response to stimuli

Tuning the hydrophobic cores of self-immolative polyglyoxylate assemblies

Polyglyoxylates are a recently-introduced class of self-immolative polymers, that depolymerize to small molecules upon the cleavage of a stimuli-responsive end-cap from the polymer terminus. The incorporation of different pendant ester groups or other aldehyde monomers offers the potential to tune the polymer properties, but this remains largely unexplored. With the goal of tuning the self-assembly and drug-loading properties of polyglyoxylate block copolymers, we explored the polymerization and copolymerization of n-butyl glyoxylate, L-menthyl glyoxylate, and chloral with ethyl glyoxylate to form UV light-responsive polyglyoxylates. The resulting polymers were coupled to poly(ethylene glycol) to afford amphiphilic block copolymers. Self-assembly of the different copolymers was studied and although each system formed solid particles, the cores of the assemblies differed in their stability, hydrophobicity, and their ability to load the hydrophobic drug celecoxib. All systems depolymerized and released the drug in response to UV light. The toxicity profiles for the assemblies were also evaluated using MDA-MB-231 cells. Overall, this work demonstrates that the properties of polyglyoxylates and their assemblies can be readily tuned through the incorporation of new monomers, thereby providing a promising platform for drug delivery and other applications

GSK3787-Loaded poly(Ester Amide) particles for intra-articular drug delivery

© 2020 by the authors. Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor ffi (PPARffi) in cartilage may attenuate the development or progression of OA. PPARffi antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt. % drug and had mean diameters of about 600 nm. Differential scanning calorimetry indicated the drug was in crystalline domains in the particles. Atomic force microscopy was used to measure the Young\u27s moduli of individual particles as 2.8 MPa. In vitro drug release studies showed 11% GSK3787 was released over 30 days. Studies in immature murine articular cartilage (IMAC) cells indicated low toxicity from the drug, empty particles, and drug-loaded particles and that the particles were not taken up by the cells. Ex vivo studies on murine joints showed that the particles could be injected into the joint space and resided there for at least 7 days. Overall, these results indicate that GSK3787-loaded PEA particles warrant further investigation as a delivery system for potential OA therapy

Phosphonium Polyelectrolyte Complexes for the Encapsulation and Slow Release of Ionic Cargo

© 2019 American Chemical Society. Polyelectrolyte complexation, the combination of anionically and cationically charged polymers through ionic interactions, can be used to form hydrogel networks. These networks can be used to encapsulate and release cargo, but the release of cargo is typically rapid, occurring over a period of hours to a few days and they often exhibit weak, fluid-like mechanical properties. Here we report the preparation and study of polyelectrolyte complexes (PECs) from sodium hyaluronate (HA) and poly[tris(hydroxypropyl)(4-vinylbenzyl)phosphonium chloride], poly[triphenyl(4-vinylbenzyl)phosphonium chloride], poly[tri(n-butyl)(4-vinylbenzyl)phosphonium chloride], or poly[triethyl(4-vinylbenzyl)phosphonium chloride]. The networks were compacted by ultracentrifugation, then their composition, swelling, rheological, and self-healing properties were studied. Their properties depended on the structure of the phosphonium polymer and the salt concentration, but in general, they exhibited predominantly gel-like behavior with relaxation times greater than 40 s and self-healing over 2-18 h. Anionic molecules, including fluorescein, diclofenac, and adenosine-5′-triphosphate, were encapsulated into the PECs with high loading capacities of up to 16 wt %. Fluorescein and diclofenac were slowly released over 60 days, which was attributed to a combination of hydrophobic and ionic interactions with the dense PEC network. The cytotoxicities of the polymers and their corresponding networks with HA to C2C12 mouse myoblast cells was investigated and found to depend on the structure of the polymer and the properties of the network. Overall, this work demonstrates the utility of polyphosphonium-HA networks for the loading and slow release of ionic drugs and that their physical and biological properties can be readily tuned according to the structure of the phosphonium polymer

Photodegradable poly(ester amide)s for indirect light-triggered release of paclitaxel

© The Royal Society of Chemistry 2014. Stimuli-responsive micelles formed from amphiphilic copolymers are promising materials for the delivery of drugs and can potentially lead to enhanced biological properties and efficacies. Among the available stimuli, light is particularly attractive, as it can be highly localized in time and space. Described here is the development of a new fully photodegradable poly(ester amide) (PEA) backbone. Degradation in response to UV light was demonstrated by UV-vis spectroscopy, NMR spectroscopy, and size exclusion chromatography. Upon the incorporation of an L-aspartic acid-based monomer, providing carboxylic acid functional handles along the PEA backbone, the anticancer drug paclitaxel (PTX) was conjugated by an ester linkage and poly(ethylene oxide) was conjugated via an amide linkage to impart amphiphilicity. Micelles were prepared from the resulting amphiphilic copolymer and were demonstrated to break down in response to UV irradiation. This led to accelerated release of PTX, which is believed to result from the increased exposure of the ester linkages to water upon micelle disruption. The in vitro toxicities of both UV irradiated and non-irradiated micelles were also evaluated and compared to PTX in Cremophor EL-ethanol and to micelles without drug

A comparison of covalent and noncovalent strategies for paclitaxel release using poly(ester amide) graft copolymer micelles

© 2015 Published by NRC Research Press. Micelles formed from amphiphilic copolymers are promising for the delivery of drug molecules, potentially leading to enhanced properties and efficacies. Critical aspects of these systems include the use of biocompatible, biodegradable polymer backbones as well as the ability to control the incorporation of drugs and their release rates. In this work, a poly(ester amide)-poly(ethylene oxide) graft copolymer with paclitaxel conjugated via ester linkages was prepared and assembled into micelles. For comparison, micelles with physically encapsulated paclitaxel were also prepared. The release rates of these two systems were studied, and the micelles with covalently conjugated paclitaxel exhibited a prolonged release of the drug in comparison to the noncovalent system, which rapidly released the payload. In vitro studies suggested that the poly(ester amide)-poly(ethylene oxide) copolymers were nontoxic, whereas the toxicities of the drug-loaded micelles were dependent on their release rates. Overall, these systems are promising for further development as anticancer drug carriers

A Versatile Diphosphine Ligand: cis and trans Chelation or Bridging, with Self Association through Hydrogen Bonding

The diphosphine ligand, <i>N</i>,<i>N</i>′-bis­(2-diphenylphosphinoethyl)­isophthalamide, dpipa, contains two amide groups and can form <i>cis</i> or <i>trans</i> chelate complexes or <i>cis</i>,<i>cis</i> or <i>trans</i>,<i>trans</i> bridged complexes. The amide groups are likely to be involved in intramolecular or intermolecular hydrogen bonding. This combination of properties of the ligand dpipa leads to very unusual structural properties of its complexes, which often exist as mixtures of monomers and dimers in solution. In the complex [Au₂(μ-dpipa)₂]­Cl₂, the ligands adopt the <i>trans,trans</i> bridging mode, with linear gold­(I) centers, and the amide groups hydrogen bond to the chloride anions. In [Pt₂Cl₄(μ-dpipa)₂], the ligands adopt the <i>cis,cis</i> bridging mode, with square planar platinum­(II) centers, and the amide groups form intermolecular hydrogen bonds to the chloride ligands to form a supramolecular one-dimensional polymer. Both the monomeric and dimeric complexes [PtMe₂(dpipa)] and [Pt₂Me₄(μ-dpipa)₂] have <i>cis</i>-PtMe₂ units with <i>cis</i> chelating or <i>cis,cis</i> bridging dpipa ligands respectively; each forms a supramolecular dimer through hydrogen bonding between amide groups and each contains an unusual NH···Pt interaction. An attempted oxidative addition reaction with methyl iodide gave the complex [PtIMe­(dpipa)], which contains <i>trans</i> chelating dpipa, while a reaction with bromine gave a disordered complex with approximate composition [Pt₂Me₃Br₅(μ-dpipa)₂], which contains <i>trans</i>,<i>trans</i> bridging dpipa ligands

Synthesis and properties of arborescent polyisobutylene derivatives and a paclitaxel conjugate: Towards stent coatings with prolonged drug release

© 2015 Elsevier Ltd. All rights reserved. Polyisobutylene (PIB) and its copolymers are used in a wide range of commercial products owing to their high chemical stability, impermeability, elasticity, and biocompatibility. The development of arborescent PIB (arb-PIB) opens many new possibilities for tuning PIB\u27s properties and for introducing new functionalities. In this work, arb-PIB with short isoprene-rich terminal sequences (arb-PIB-co-IP) was functionalized to provide arborescent epoxide, allylic alcohol, and carboxylic acid derivatives of PIB. The carboxylic acid derivative was used to conjugate the antiproliferative agent paclitaxel (PTX) for investigation as a potential vascular stent coating. The thermal, tensile, and rheological properties of all of the functionalized arb-PIB materials were studied and compared to their linear analogues in order to gain insight into the effects of polymer architecture on these properties as well as to determine their suitability as potential medical device coatings. A coating using the PTX conjugate was found to release PTX much more slowly than control formulations with physically encapsulated drug, yet was still able to prevent cell adhesion and proliferation on their surfaces

Thermoresponsive and Covalently Cross-Linkable Hydrogels for Intra-Articular Drug Delivery

© 2019 American Chemical Society. The local delivery of drugs to joints is a recognized strategy in the treatment of osteoarthritis. Hydrogels, particularly those that can be injected as liquids but undergo gelation in the joint, are promising platforms for intra-articular drug delivery. However, their properties must be carefully designed and tuned to achieve sustained drug release, which has been a challenge with previous hydrogels. We describe here the use of a combination of noncovalent thermal gelation and covalent cross-linking with poly(caprolactone-co-lactide)(PCLA)-poly(ethylene glycol)(PEG)-PCLA triblock copolymers to achieve hydrogels with sustained drug release in joints. The hybrid cross-linking approach afforded higher viscoelastic and compression moduli compared to noncovalent cross-linking alone and enabled celecoxib as well as other drugs to be loaded without substantially compromising the mechanical properties. Celecoxib release in vitro was much slower for the hybrid cross-linked hydrogel, with only 20% released over 22 days, compared to 90% released over 22 days for a noncovalently cross-linked hydrogel. Furthermore, the burst release of celecoxib was reduced in vivo in horse joints compared to noncovalent systems, and the drug was detected in synovial fluid for a period of two months. Overall, this new hydrogel system shows significant promise as a platform for further development in intra-articular delivery

Synthesis and Self-Association of Organoplatinum(IV) Boronic Acids

Oxidative addition of ortho,<i> </i>meta, and para isomers of BrCH₂C₆H₄B­(OH)₂ to dimethylplatinum­(II) complexes gave the corresponding organoplatinum­(IV) boronic acids [PtBrMe₂{CH₂C₆H₄B­(OH)₂}­(NN)], with the bidentate ligand NN = 4,4′-bis­(ethoxycarbonyl)-2,2′-bipyridine or 2,5-bis­(2-pyridyl)-1,3,4-oxadiazole. The complexes undergo self-assembly in the solid state through hydrogen bonding to give dimers, polymers, or sheet structures