Position Matters: Pyridine Regioisomers Influence Secondary Structure and Micelle Morphology in Polymer-Homopolypeptide Micelles.

Polymer-homopolypeptide block copolymers are a class of bioinspired materials that combine the processability and stability of synthetic polymers with the biocompatibility and unique secondary structures of peptides, such as α-helices and ß-sheets. These properties make them ideal candidates for a wide variety of applications, for example, in the pharmaceutical field, where they are frequently explored as building blocks for polymeric micelle drug delivery systems. While homopolypeptide side chains can be furnished with an array of different moieties to impart the copolymers with desirable properties, such as stimulus responsivity, pyridine derivatives represent an underutilized functional group for this purpose. Additionally, the interplay between polypeptide side chain structure, secondary conformation, and micelle morphology is not yet well understood, particularly in the case of structural regioisomers. Therefore, in this work, a series of polymer-homopolypeptide copolymers were prepared from a poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-PGA) backbone, where the pendant carboxylic acid groups were covalently conjugated to a series of pyridine regioisomers by carbodiimide coupling. These pyridine regioisomers differed only in the position of the nitrogen heteroatom, ortho, meta or para, relative to the linking group, generating a series of PEG-b-poly(pyridinylmethyl glutamate) (PEG-b-PMG) copolymers. Following self-assembly of the copolymers in aqueous solutions, dynamic light scattering (DLS) revealed differences in micelle hydrodynamic diameter (Dh) (ranging from ∼60 to 120 nm), while transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) revealed distinctive morphologies ranging from ellipsoidal, to cylindrical, and disc-like, suggesting that subtle changes in positional isomers in the polypeptide block may influence the micelle structure. Analysis of the PEG-b-PMG copolymer micelles by circular dichroism (CD) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy revealed that differences in the morphology were associated with changes in polypeptide secondary structure, which in turn was influenced by the position of the pyridine heteroatom. Overall, these findings contribute to the broader understanding of the relationship between polypeptide structure and micelle morphology and serve as useful insight for the rational design of polymer-polypeptide nanoparticles.

Exploring the versatility of pentafulvene-maleimide cycloaddition as a ligation strategy: buffer and pH effects.

Ligation chemistries are often required to perform under stringent conditions that preserve the integrity and function of (bio)conjugates, including specific biological buffers. To explore the versatility of the pentafulvene-maleimide ligation for (bio)conjugations, we studied the stability of the coupling partners and their Diels-Alder cycloaddition (DAC) in buffers used commonly in biological assays, protein chemistry and bioconjugates. The stability of 6,6-dialkylpentafulvene and maleimide derivatives to a panel of buffers with pH values between 3.7 and 10.1 was monitored via1H NMR spectroscopy. While the pentafulvene displayed excellent stability, hydrolysis of the maleimide was observed in several cases, although the extent of hydrolysis did not correlate with pH. For almost all buffers the pentafulvene-maleimide DAC proceeded efficiently and at a significantly faster rate than maleimide hydrolysis under the conditions studied. The buffer composition nor pH appeared to have a significant effect on the kinetics of the DAC with second-order rate constants (k2) ranging from 0.14 to 0.33 M-1 s-1 (23 ± 1 °C). This study highlights the versatility of the pentafulvene-maleimide ligation to proceed under a wide range of conditions relevant for (bio)conjugations and that maleimide hydrolysis in aqueous system may be promoted or inhibited by certain buffers.

Retro Diels-Alder Fragmentation of Fulvene-Maleimide Bioconjugates for Mass Spectrometric Detection of Biomolecules.

Diels-Alder chemistry is a well-explored avenue for the synthesis of bioactive materials; however, its potential applications have recently expanded following the development of reactions that can be performed in buffered aqueous environments at low temperatures, including fulvene-maleimide [4 + 2] cycloadditions. In this study, we synthesized two novel amine-reactive fulvene linkers to demonstrate the application of this chemistry for generating mass spectrometry-cleavable labels ("mass tags"), which can be used for the labeling and detection of proteins. Successful conjugation of these linkers to maleimide-labeled peptides was observed at low temperatures in phosphate-buffered saline, allowing the non-destructive modification of proteins with such mass tags. The labile nature of fulvene-maleimide adducts in the gas phase also makes them suitable for both matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) mass spectrometric analysis. Unlike previous examples of MALDI mass tags, we show that fulvene-maleimide cycloaddition adducts fragment predictably upon gas-phase activation without the need for bulky photocleavable groups. Further exploration of this chemistry could therefore lead to new approaches for mass spectrometry-based bioassays.

Pentafulvene-Maleimide Cycloaddition for Bioorthogonal Ligation.

The applications of bioconjugation chemistry are rapidly expanding, and the addition of new strategies to the bioconjugation and ligation toolbox will further advance progress in this field. Herein, we present a detailed study of the Diels-Alder cycloaddition (DAC) reaction between pentafulvenes and maleimides in aqueous solutions and investigate the reaction as an emerging bioconjugation strategy. The DAC reactions were found to proceed efficiently, quantitatively yielding cycloadducts with reaction rates ranging up to ∼0.7 M-1 s-1 for a series of maleimides, including maleimide-derivatized peptides and proteins. The absence of cross-reactivity of the pentafulvene with a large panel of functional (bio)molecules and biological media further demonstrated the bioorthogonality of this approach. The utility of the DAC reaction for bioorthogonal bioconjugation applications was further demonstrated in the presence of biological media and proteins, as well as through protein derivatization and labeling, which was comparable to the widely employed sulfhydryl-maleimide coupling chemistry.

An overview of the cycloaddition chemistry of fulvenes and emerging applications.

The unusual electronic properties and unique reactivity of fulvenes have interested researchers for over a century. The propensity to form dipolar structures at relatively low temperatures and to participate as various components in cycloaddition reactions, often highly selectively, makes them ideal for the synthesis of complex polycyclic carbon scaffolds. As a result, fulvene cycloaddition chemistry has been employed extensively for the synthesis of natural products. More recently, fulvene cycloaddition chemistry has also found application to other areas including materials chemistry and dynamic combinatorial chemistry. This highlight article discusses the unusual properties of fulvenes and their varied cycloaddition chemistry, focussing on applications in organic and natural synthesis, dynamic combinatorial chemistry and materials chemistry, including dynamers, hydrogels and charge transfer complexes. Tables providing comprehensive directories of fulvene cycloaddition chemistry are provided, including fulvene intramolecular and intermolecular cycloadditions complete with reactant partners and their resulting cyclic adducts, which provide a useful reference source for synthetic chemists working with fulvenes and complex polycyclic scaffolds.

Titanium Dioxide Nanoparticles as Radiosensitisers: An In vitro and Phantom-Based Study.

Objective: Radiosensitisation caused by titanium dioxide nanoparticles (TiO2-NPs) is investigated using phantoms (PRESAGE® dosimeters) and in vitro using two types of cell lines, cultured human keratinocyte (HaCaT) and prostate cancer (DU145) cells. Methods: Anatase TiO2-NPs were synthesised, characterised and functionalised to allow dispersion in culture-medium for in vitro studies and halocarbons (PRESAGE® chemical compositions). PRESAGE® dosimeters were scanned with spectrophotometer to determine the radiation dose enhancement. Clonogenic and cell viability assays were employed to determine cells survival curves from which the dose enhancement levels "radiosensitisation" are deduced. Results: Comparable levels of radiosensitisation were observed in both phantoms and cells at kilovoltage ranges of x-ray energies (slightly higher in vitro). Significant radiosensitisation (~67 %) of control was also noted in cells at megavoltage energies (commonly used in radiotherapy), compared to negligible levels detected by phantoms. This difference is attributed to biochemical effects, specifically the generation of reactive oxygen species (ROS) such as hydroxyl radicals (•OH), which are only manifested in aqueous environments of cells and are non-existent in case of phantoms. Conclusions: This research shows that TiO2-NPs improve the efficiency of dose delivery, which has implications for future radiotherapy treatments. Literature shows that Ti2O3-NPs can be used as imaging agents hence with these findings renders these NPs as theranostic agents.

Nonwoven Carboxylated Agarose-Based Fiber Meshes with Antimicrobial Properties.

Hydrogel forming polysaccharides, such as the seaweed derived agarose, are well suited for wound dressing applications as they have excellent cell and soft tissue compatibility. For wound dressings, fibrous structure is desirable as the high surface area can favor adsorption of wound exudate and promote drug delivery. Although electrospinning offers a straightforward means to produce nonwoven fibrous polymeric structures, processing agarose and its derivatives into fibers through electrospinning is challenging as it has limited solubility in solvents other than water. In this study we describe the processing of carboxylated agarose (CA) fibers with antibacterial properties by electrospinning from a solution of the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([Bmim]+Cl-) possessing antimicrobial properties. The extent of carboxylation was found to impact fiber diameter, mesh elastic modulus, fiber swelling, and the loading and release of IL. IL-bearing CA fibers inhibited the growth of Staphylococcus aureus and Pseudomonas aeruginosa, bacteria commonly found in wound exudate. In sum, nonwoven CA fibers processed from IL are promising as biomaterials for wound dressing applications.

Cyclodextrin-based supramolecular assemblies and hydrogels: recent advances and future perspectives.

The application of cyclodextrin (CD)-based host-guest interactions towards the fabrication of functional supramolecular assemblies and hydrogels is of particular interest in the field of biomedicine. However, as of late they have found new applications as advanced functional materials (e.g., actuators and self-healing materials), which have renewed interest across a wide range of fields. Advanced supramolecular materials synthesized using this noncovalent interaction, exhibit specificity and reversibility, which can be used to impart reversible cross-linking, specific binding sites, and functionality. In this review, various functional CD-based supramolecular assemblies and hydrogels will be outlined with the focus on recent advances. In addition, an outlook will be provided on the direction of this rapidly developing field.

Stereospecific cyclic poly(methyl methacrylate) and its topology- guided hierarchically controlled supramolecular assemblies.

In this study, the stereocomplexation between a novel stereospecific cyclic vinyl polymer, that is, cyclic syndiotactic poly(methyl methacrylate) (st-PMMA), with the complementary linear isotactic (it-) PMMA was investigated. Surprising new insight into the effects of the topology (i.e., end groups), size, and tacticity of the assembling components on stereocomplex formation was obtained. Characterization of the stereocomplexes revealed that the self-assembly of cyclic st-PMMAs and linear it-PMMAs resulted in the formation of an unprecedented "polypseudorotaxane-type" supramolecular assembly. This stereocomplex exhibited remarkably different physical properties as compared to the conventional PMMA triple-helix stereocomplex as a result of the restricted topology imposed by the cyclic st-PMMA assembling component.

Oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive micelles: Influence of oligo(2-vinyl pyridine)-loading on drug-loading, release and cytotoxicity.

pH-responsive polymeric micelles have been extensively studied for nanomedicine and take advantage of pH differentials in tissues for the delivery of large doses of cytotoxic drugs at specific target sites. Despite significant advances in this area, there is a lack of versatile and adaptable strategies to render micelles pH-responsive that could be widely applied to different payloads and applications. To address this deficiency, we introduce the concept of oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive polymeric micelles as a highly effective approach with broad scope. Herein, we investigate the influence of the oligoelectrolyte, oligo(2-vinyl pyridine) (OVP), loading and polymer molecular weight on the pH-sensitivity, drug loading/release and cytotoxicity of poly(ethylene glycol-b-ε-caprolactone) (PEG-b-PCL) micelles using copolymers with either short or long hydrophobic blocks (PEG4PCL4 and PEG10PCL10, respectively). The micelles were characterized as a function of pH (7.4 to 3.5). Dynamic light scattering (DLS) revealed narrow particle size distributions (PSDs) for both the blank and OVP-loaded micelles at pH 7.4. While OVP encapsulation resulted in an increase in the hydrodynamic diameter (Dh) (cf. blank micelles), a decrease in the pH below 6.5 led to a decrease in the Dh consistent with the ionization and release of OVP and core collapse, which were further supported by proton nuclear magnetic resonance (1H NMR) spectroscopy and UV-visible (UV-vis) spectrophotometry. The change in zeta potential (ζ) with pH for the OVP-loaded PEG4PCL4 and PEG10PCL10 micelles was different, suggesting that the location/distribution of OVP in the micelles is influenced by the polymer molecular weight. In general, co-encapsulation of drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX) or 7-ethyl-10-hydroxycamptothecin (SN38)) and OVP in the micelles proceeded efficiently with high encapsulation efficiency percentages (EE%). In vitro release studies revealed the rapid, pH-triggered release of drugs from OVP-loaded PEG10PCL10 micelles within hours, with higher OVP loadings providing faster and more complete release. In comparison, no triggered release was observed for the OVP-loaded PEG4PCL4 micelles, implying a strong molecular weight dependency. In metabolic assays the drug- and OVP-loaded PEG10PCL10 micelles were found to result in significant enhancement of the cytotoxicity compared to drug-loaded micelles (no OVP) or other controls. Importantly, micelles with low OVP loadings were found to be nearly as effective as those with high OVP loadings. These results provide key insights into the tunability of the oligoelectrolyte-mediated approach for the effective formulation of pH-responsive micelles and pH-triggered drug release.

Increasing surface hydrophilicity with biopolymers: a combined single bubble collision, QCM-D and AFM study.

HYPOTHESIS: Naturally extracted polysaccharides, such as guar gum, are promising candidates for environmentally friendly flotation reagents. It is hypothesized that the kinetics of collision of sub- to millimeter gas bubbles with a hydrophobic graphite surface, and the stability of thin liquid film formed between the bubble and surface is affected by an adsorbed layer of guar gum. EXPERIMENTS: A combination of gravimetric (quartz crystal microbalance with dissipation) and imaging (atomic force microscopy) techniques was used to investigate the adsorption of guar gum on graphite surface, while high-speed camera imaging allowed for direct observation of the bubble collision process with guar gum-modified graphite surfaces with millisecond resolution. FINDINGS: Atomic force microscope topography images revealed a guar gum concentration-dependent interconnected network of guar gum molecules adsorbed at graphite surface. These adsorbed molecules at low surface coverage, changed the wettability of the graphite surface, resulting in a film drainage time longer by an order of magnitude, while at higher surface coverage successfully prevented bubble attachment to the graphite surface. Most importantly, the adsorbed layer changed the strength of the bubble's bouncing off the graphite surface. This enhanced bubble bouncing can be correlated with the film drainage time and used to predict a successful bubble-particle attachment.

Teaching an Old Dog New Tricks: A Global Approach to Enhancing the Cytotoxicity of Drug-Loaded, Non-responsive Micelles Using Oligoelectrolytes.

Polymeric micelles have been extensively studied as vectors for the delivery of hydrophobic drugs for the treatment of cancers and other diseases. Despite intensive research, few formulations provide significant benefits, and even fewer have been clinically approved. While many traditional non-responsive micelles have excellent safety profiles, they lack the ability to respond to the intracellular environment and release their cargo in a spatiotemporally defined manner to effectively deliver large doses of cytotoxic drugs into the cytosol of cells that overwhelm efflux pumps. As a novel and adaptable strategy, we hypothesized that well-established non-responsive polymeric micelles could be augmented with a pH-trigger via the co-encapsulation of cytocompatible oligoelectrolytes, which would allow rapid cargo release in the endosome, leading to increased cytotoxicity. Herein, we demonstrate how this strategy can be applied to render non-responsive micelles pH-responsive, resulting in abrupt cargo release at specific and tunable pH values compatible with endosomal delivery, which significantly increased their cytotoxicity up to 3-fold in an ovarian adenocarcinoma (SKOV-3) cell line compared to non-responsive micelles. In comparison, the oligoelectrolyte-loaded micelles were significantly less toxic to healthy 3T3 fibroblasts, indicating a selective cargo release in cancer cell lines. Oligoelectrolytes can be co-encapsulated in the micelles along with drugs at high encapsulation efficiency percentages, which are both ejected from the micelle core upon oligoelectrolyte ionization. Mechanistically, the increase in cytotoxicity appears to also result from the accelerated endosomal escape of the cargo caused by disruption of the endosomal membrane by the simultaneous release of the oligoelectrolytes from the micelles. Furthermore, we show how this approach is broadly applicable to non-responsive micelles regardless of their composition and various classes of hydrophobic chemotherapeutics. The preliminary studies presented here reveal the versatility and wide scope of oligoelectrolyte-mediated, pH-triggered drug release as a compelling and powerful strategy to enhance the cytotoxicity of non-responsive polymeric micelles.

Ring-opening metathesis polymerization with the second generation Hoveyda-Grubbs catalyst: an efficient approach toward high-purity functionalized macrocyclic oligo(cyclooctene)s.

Herein, we present a facile and general strategy to prepare functionalized macrocyclic oligo(cyclooctene)s (cOCOEs) in high purity and high yield by exploiting the ring-opening metathesis polymerization (ROMP) intramolecular backbiting process with the commercially available second generation Hoveyda-Grubbs (HG2) catalyst. In the first instance, ROMP of 5-acetyloxycyclooct-1-ene (ACOE) followed by efficient quenching and removal of the catalyst using an isocyanide derivative afforded macrocyclic oligo(5-acetyloxycyclooct-1-ene) (cOACOE) in high yield (95%), with a weight-average molecular weight (Mw) of 1.6 kDa and polydispersity index (PDI) of 1.6, as determined by gel permeation chromatography (GPC). The structure and purity of the macrocycles were confirmed by NMR spectroscopy and elemental analysis, which indicated the complete absence of end-groups. This was further supported by GPC-matrix assisted laser desorption ionization time-of-flight mass spectroscopy (GPC-MALDI ToF MS), which revealed the exclusive formation of macrocyclic derivatives composed of up to 45 repeat units. Complete removal of residual ruthenium from the macrocycles was confirmed by inductively coupled plasma atomic emission spectroscopy (ICP-AES). The same methodology was subsequently extended to the ROMP of 5-bromocyclooct-1-ene and 1,5-cyclooctadiene to prepare their macrocyclic derivatives, which were further derivatized to produce a library of functionalized macrocyclic oligo(cyclooctene)s. A comparative study using the second and third generation Grubbs catalysts in place of the HG2 catalyst for the polymerization of ACOE provided macrocycles contaminated with linear species, thus indicating that the bidendate benzylidene ligand of the Hoveyda-Grubbs catalyst plays an important role in the observed product distributions.

Low-fouling, biospecific films prepared by the continuous assembly of polymers.

We report that the continuous assembly of polymers (CAP) approach, mediated by ring-opening metathesis polymerization (ROMP), is a facile and versatile technology to prepare engineered nanocoatings for various biomedical applications. Low-fouling coatings on particles were obtained by the formation of multicompositional, layered films via simple and efficient tandem CAP(ROMP) processes that are analogous to chain extension reactions. In addition, the CAP(ROMP) approach allows for the efficient postfunctionalization of the CAP films with bioactive moieties via cross-metathesis reactions between the surface-immobilized catalysts and symmetrical alkene derivatives. The combined features of the CAP(ROMP) approach (i.e., versatile polymer selection and facile functionalization) allow for the fabrication and surface modification of various types of polymer films, including those with intrinsic protein-repellent properties and selective protein recognition capabilities. This study highlights the various types of advanced coatings and materials that the CAP approach can be used to generate, which may be useful for biomedical applications.

Composition-Property Relationships of pH-Responsive Poly[(2-vinylpyridine)-co-(butyl methacrylate)] Copolymers for Reverse Enteric Coatings.

The taste-masking of bitter-tasting active pharmaceutical ingredients is key to ensuring patient compliance when producing oral pharmaceutical formulations. This is generally achieved via the incorporation of pH-responsive, reverse enteric polymers, that prevent the dissolution of the formulation in the oral environment, but rapidly mediate it within the gastric environment. Reverse enteric polymers are commonly applied as coatings on oral dosage forms via spray atomisation (e.g., fluidised-bed spray coating), and generally exhibit the most efficient taste-masking. However, currently used reverse enteric coatings require high mass gains (% w/w) during coating to mediate taste-masking, and thereby exhibit delayed release within the gastric environment. Therefore, there remains a need for the development of new reverse enteric coatings, that can efficiently taste-mask at low mass gains and maintain rapid release characteristics within the gastric environment. Herein we report the synthesis and evaluation of a series of addition copolymers of 2-vinylpyridine and butyl methacrylate, methyl methacrylate and isobornyl methacrylate. The thermal, solubility, and water absorption properties of the copolymers were effectively tuned by altering the mol% fraction of the constitutive monomers. Based on their physical properties, selected copolymers were preliminarily evaluated for their compatibility with fluidised-bed spray coating, and effectiveness as taste-masking reverse enteric coatings. The copolymers poly[(2-vinylpyridine)-co-(butyl methacrylate)] (mol% ratio 40:60) and poly[(2-vinylpyridine)-co-(butyl methacrylate)-co-(methyl methacrylate)] (mol% ratio 40:50:10) were found to exhibit excellent taste-masking properties following fluidised-bed spray coating onto Suglets® sugar spheres. Suglets® bearing a film coating of either copolymer (5.2-6.5% w/w mass gain) were found to effectively impede the release of a model drug formulation for up to 72 h in a simulated salivary environment, and rapidly release it (<10 min) within a simulated gastric environment. The results demonstrated the potential of poly[(2-vinylpyridine)-co-(butyl methacrylate)] copolymers to form effectively taste-masked, reverse enteric dosage forms, and suggested that these copolymers may provide improved performance compared to currently available polymers.

pH-Responsive Poly(ethylene glycol)-b-poly(2-vinylpyridine) Micelles for the Triggered Release of Therapeutics.

The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system-e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers-there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46-235 RUs). All copolymers exhibited narrow dispersity values (D ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4-4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery-albeit for select, compatible hydrophobic drugs-which warrants their further investigation to develop and evaluate clinically relevant micelle systems.

pH-Responsive Polymer Implants for the Protection of Native Mammals: Assessment of Material Properties and Poison Incorporation on Performance.

Efforts to mitigate the effects of feral cats through the management of remnant or reintroduced populations of threatened species, are often unsuccessful due to predation by control-averse feral cats, or 'problem individuals'. In order to target these animals, we have developed the Population Protecting Implant (PPI). PPIs are designed to be implanted subcutaneously in a native animal. If the animal is preyed upon, and the implant ingested by a feral cat, release of a toxic payload is triggered in the acidic stomach environment and the problem individual is eliminated. We introduce the first toxic implant incorporating the poison sodium fluoroacetate. Manufactured via fluidised-bed spray coating, toxic implants exhibited uniform reverse enteric coatings and low intra-batch variation. Toxic implants were found to exhibit favourable stability at subcutaneous pH in vitro, and rapidly release their toxic payload in vitro at gastric pH. However, limited stability was demonstrated in rats in vivo (~39-230 d), due to the use of a filament scaffold to enable coating and was likely exacerbated by metachromatic interactions caused by 1080. This work highlights that future development of the PPIs should primarily focus on removal of the filament scaffold, to afford implants with increased in vivo stability.

Influence of Lyophilization and Cryoprotection on the Stability and Morphology of Drug-Loaded Poly(ethylene glycol-b-ε-caprolactone) Micelles.

Polymeric micelles are promising carriers for the delivery of poorly water-soluble drugs, providing enhanced drug solubility, blood circulation times, and bioavailability. Nevertheless, the storage and long-term stability of micelles in solution present challenges requiring the lyophilization and storage of formulations in the solid state, with reconstitution immediately prior to application. Therefore, it is important to understand the effects of lyophilization/reconstitution on micelles, particularly their drug-loaded counterparts. Herein, we investigated the use of ß-cyclodextrin (ß-CD) as a cryoprotectant for the lyophilization/reconstitution of a library of poly(ethylene glycol-b-ε-caprolactone) (PEG-b-PCL) copolymer micelles and their drug-loaded counterparts, as well as the effect of the physiochemical properties of different drugs (phloretin and gossypol). The critical aggregation concentration (CAC) of the copolymers decreased with increasing weight fraction of the PCL block (fPCL), plateauing at ~1 mg/L when the fPCL was >0.45. The blank (empty) and drug-loaded micelles were lyophilized/reconstituted in the absence and presence of ß-CD (9% w/w) and analyzed via dynamic light scattering (DLS) and synchrotron small-angle X-ray scattering (SAXS) to assess for changes in aggregate size (hydrodynamic diameter, Dh) and morphology, respectively. Regardless of the PEG-b-PCL copolymer or the use of ß-CD, the blank micelles displayed poor redispersibility (<10% relative to the initial concentration), while the fraction that redispersed displayed similar Dh to the as-prepared micelles, increasing in Dh as the fPCL of the PEG-b-PCL copolymer increased. While most blank micelles displayed discrete morphologies, the addition of ß-CD or lyophilization/reconstitution generally resulted in the formation of poorly defined aggregates. Similar results were also obtained for drug-loaded micelles, with the exception of several that retained their primary morphology following lyophilization/reconstitution, although no obvious trends were noted between the microstructure of the copolymers or the physicochemical properties of the drugs and their successful redispersion.

Using GPCRs as Molecular Beacons to Target Ovarian Cancer with Nanomedicines.

The five-year survival rate for women with ovarian cancer is very poor despite radical cytoreductive surgery and chemotherapy. Although most patients initially respond to platinum-based chemotherapy, the majority experience recurrence and ultimately develop chemoresistance, resulting in fatal outcomes. The current administration of cytotoxic compounds is hampered by dose-limiting severe adverse effects. There is an unmet clinical need for targeted drug delivery systems that transport chemotherapeutics selectively to tumor cells while minimizing off-target toxicity. G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, and many are overexpressed in solid tumors, including ovarian cancer. This review summarizes the progress in engineered nanoparticle research for drug delivery for ovarian cancer and discusses the potential use of GPCRs as molecular entry points to deliver anti-cancer compounds into ovarian cancer cells. A newly emerging treatment paradigm could be the personalized design of nanomedicines on a case-by-case basis.

A europium metal-organic framework for dual Fe3+ ion and pH sensing.

Metal-organic frameworks (MOFs) with ratiometric sensing properties are desirable for many applications due to their intrinsic self-calibration. We report the re-assessment of the sensing properties of a MOF, originally reported as containing europium(III) and 2-hydroxyterephtalic acid, and having fluorescent ratiometric iron(III) sensing properties. Synchrotron single-crystal X-ray diffraction and proton nuclear magnetic resonance (1H NMR) spectroscopy revealed that the MOF is composed of 2-methoxyterephthalate, not 2-hydroxyterephthalate as originally reported. We found that the MOF exhibits a sensor turn-off response towards Fe3+ ion concentrations in the range 0.5-3.7 ppm (band 425 nm), and a turn-on response towards a decrease of pH from 5.4 to 3.0 (band 375 nm), both resulting from the addition of acidic Fe3+ salt solution to a MOF suspension. Thus, the ratiometric sensing properties and the originally proposed mechanism no longer apply; our work reveals a dynamic quenching mechanism for the fluorescence turn-off response due to the presence of Fe3+ ions, and a ligand protonation mechanism for the turn-on response to a decrease in pH. Our work highlights the importance of a thorough investigation of the structure of any newly synthesized MOF, and, in the case of potential sensors, their selectivity and any environmental effects on their sensing behavior.