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Sustained and localized delivery of chemotherapeutics in postoperative cancer treatment leads to a radical improvement in prognosis and a much decreased risk of tumor recurrence. In this work, polydopamine (PDA)-coated superparamagnetic iron oxide nanoparticle (SPION)-loaded polycaprolactone and poly(lactic-co-glycolic acid) fibers were developed as a potential implant to ensure safe and sustained release of the chemotherapeutic drug methotrexate (MTX), as well as provide local contrast for magnetic resonance imaging (MRI). Fibres were prepared by co-axial electrospinning and loaded with MTX-layered double hydroxide (LDH) nanocomposites in the core, yielding organic-inorganic hybrids ranging from 1.23 to 1.48 µm in diameter. After surface coating with PDA, SPIONs were subsequently loaded on the fibre surface and found to be evenly distributed, providing high MRI contrast. In vitro drug release studies showed the PDA coated fibres gave sustained release of MTX over 18 days, and the release profile is responsive to conditions representative of the tumor microenvironment such as slightly acidic pH values or elevated concentrations of the reducing agent glutathione (GSH). In vitro studies with Caco-2 and A549 cells showed highly effective killing with the PDA coated formulations, which was further enhanced at higher levels of GSH. The fibres hence have the potential to act as an implantable drug-eluting platform for the sustained release of cytotoxic agents within a tumor site, providing a novel treatment option for post-operative cancer patients.

The management of pain and inflammation arising from wounds is essential in obtaining effective healing rates. The application of a wound dressing loaded with an anti-inflammatory drug would enable both issues to be ameliorated, and the aim of this work was to fabricate such a dressing by electrospinning. Fibers comprising ethyl cellulose (EC) and poly(vinyl pyrrolidone) (PVP) loaded with naproxen (Nap) were developed to be used in the early stages of wound care. A family of PVP/EC/Nap systems was prepared by varying the PVP: EC ratio. In all cases, the products of electrospinning comprise non-woven mats of fibers which generally have smooth and cylindrical morphologies. The formulations exist as amorphous solid dispersions, and there appear to be intermolecular interactions between the three components. Adjusting the polymer ratios results in tunable drug release, and formulations have been produced which give zero-order drug release over 20 and 80 h. The fiber mats generated in this work thus have great potential to be used as dressings for the treatment of wound pain and inflammation.

In this study, we developed novel thermal and redox-responsive micelles based on the Pluronic F127 tri-block copolymer and employed these for redox-responsive intratumor release of bufalin, an anti-cancer drug. Pluronic F127 was first functionalized with carboxylate groups, and then assembled into micelles. The HOOC-F127-COOH micelles are 20 ± 4 nm in size at 37 °C, but expand to 281 ± 5 nm when cooled to 4 °C. This allows for the free diffusion of bufalin into the micellar cores at low temperatures, while at 37 °C the micelles are much more compact and the drug molecules can be effectively held in their interiors. A high encapsulation efficiency and loading content were obtained via drug incorporation at 4 °C. The drug-loaded micelles were cross-linked with cystamine, which contains a disulfide bond responsive to the local cancer microenvironment. In vitro studies showed that drug release from the cross-linked micelles was low under normal physiological conditions, but markedly accelerated upon exposure to conditions representative of the intracellular tumor environment. Confocal microscopy revealed that the cross-linked micelles gave high levels of drug release inside the cells. In vivo studies in mice showed the drug-loaded cross-linked micelles have potent anti-tumor activity, leading to high levels of apoptosis of tumor cells and significant reductions in tumor volume. The drug-loaded cross-linked micelles did not significantly influence body weight, and there was no evidence for detrimental off-target effects. These results indicate that the Pluronic-based micelles developed in this work are promising drug delivery systems for the targeted treatment of cancer.

Graphical abstract, Viral infections represent 44% of newly emerging infections, and as is shown by the COVID-19 outbreak constitute a major risk to human health and wellbeing. Although there are many efficient antiviral agents, they still have drawbacks such as development of virus resistance and accumulation within off-target organs. Encapsulation of antiviral agents into nanoparticles (NPs) has been shown to improve bioavailability, control release, and reduce side effects. However, there is little quantitative understanding of how the uptake of NPs into virally infected cells compares to uninfected cells. In this work, the uptake of fluorescently labeled polymer NPs was investigated in several models of rhinovirus (RV) infected cells. Different multiplicities of RV infections (MOI) and timings of NPs uptake were also investigated. In some cases, RV infection resulted in a significant increase of NPs uptake, but this was not universally noted. For HeLa cells, RV-A16 and RV-A01 infection elevated NPs uptake upon increasing the incubation time, whereas at later timepoints (6 h) a reduced uptake was noted with RV-A01 infection (owing to decreased cell viability). Beas-2B cells exhibited more complex trends: decreases in NPs uptake (cf. uninfected cells) were observed at short incubation times following RV-A01 and RV-A16 infection. At later incubation times (4 h), we found a marked decrease of NPs uptake for RV-A01 infected cells but an increase in uptake with RV-A16 infected cells. Where increases in NPs uptake were found, they were very modest compared to results previously reported for a hepatitis C/ Huh7.5 cell line model. An increase in RV dose (MOI) was not associated with any notable change of NPs uptake. We argue that the diverse endocytic pathways among the different cell lines, together with changes in virus nature, size, and entry mechanism are responsible for these differences. These findings suggest that NPs entry into virally infected cells is a complex process, and further work is required to unravel the different factors which govern this. Undertaking this additional research will be crucial to develop potent nanomedicines for the delivery of antiviral agents.

In nature, the combination of composition, structure, and shape determines the matter's functional performance to a large extent. Inspired by which, two electrospun Janus nanofiber formulations were created using side-by-side electrospinning in this work. Tamoxifen citrate (TAM) was used as a model drug and ethyl cellulose (EC) and polyvinylpyrrolidone K60 (PVP) as the polymer carrier matrices. The fibers have linear cylindrical morphologies and distinct Janus structures by scanning electron microscopy. One side of the fibers took a round shape, while the other was crescent-shaped. The drug was present in both polymer matrices in the form of amorphous solid dispersions, owing to strong intermolecular interactions between drug and polymer. In vitro dissolution tests demonstrated that both sets of fibers could provide biphasic drug release due to the difference in solubility of PVP and EC. The different shape of TAM-EC and TAM-PVP side of the Janus structure resulted in a considerable variation in the drug release profiles. The Janus structure with crescent TAM-PVP side and round TAM-EC side gave a more rapid burst release in the first phase of release, and slower sustained release in the second phase. This work thus reports a new strategy for systematically developing advanced functional nanomaterials based on both shape- and structure-performance relationships.

A human panel study was performed to investigate the acceptability of orodispersible electrospun and solvent cast films. 50 healthy volunteers took two drug-free samples of polyvinyl alcohol films prepared by the two methods. On a 5-point hedonic scale, the volunteers assessed the films’ perceived size, stickiness, thickness, disintegration time, thickening effect on saliva, and handling. The films manufactured by both methods were similar in their end-user acceptability. The modal values of perceived size, thickness, disintegration time, saliva thickening effect, and handling were high (4 or 5). However, for both, the stickiness mode was 2 (strongly sticky) and the only negative attribute. Both films were reported to take approximately 30 s to disintegrate completely in the mouth. Electrospun films scored similarly high to solvent cast orodispersible films in most attributes of end-user acceptability. Electrospun films were marginally preferred, with 27 out of 50 participants picking electrospinning when presented with a forced choice test of both fabrication methods. This is the first study to show that electrospinning enables the fabrication of orodispersible films that are acceptable to adult human participants in terms of handling and mouthfeel and suggests that the potential for clinical translation of such formulations is high.

Increasing numbers of elderly people require multi-drug therapies. One route to improve adherence rates is to prepare fixed dose combinations (FDCs), in which multiple active ingredients are loaded into a single formulation. Here, we report the use of electrospinning to prepare fast-dissolving oral FDCs containing amlodipine besylate and valsartan, two drugs prescribed as FDCs for the treatment of hypertension. Electrospun fibers were prepared loaded with one or both drugs, using polyvinylpyrrolidone as the polymer matrix. The fibers were largely cylindrical in morphology and comprise amorphous solid dispersions except with the highest loadings of amlodipine besylate. HPLC demonstrated drug entrapment efficiencies of >85% of the theoretical dose. The mats have folding endurances and thicknesses suitable for use as oral films. The amlodipine besylate-loaded systems are fast-dissolving, with >90% release obtained within 120 s. In contrast, valsartan release from its single-drug formulations took longer, ranging from 360 s to 24 min. With the FDC formulations, rapid release within 360 s was achieved when the loading was 5% w/w of each drug, but again the release time increased with drug loading. Electrospun fibers therefore have significant promise as FDCs, but the target drug and its loading need to be carefully considered.

To prepare temperature and pH dual-responsive drug delivery systems, the thermosensitive polymer poly(N-isopropylacrylamide) (PNIPAAm) was first synthesized by free-radical polymerization. It was then co-dissolved with the pH-sensitive polymer Eudragit® L100-55 (EL100-55) and processed into fibers using electrospinning. Ketoprofen (KET), a model drug, was also incorporated into the composite fibers, and fibers based on a single polymer additionally prepared. The fibers had smooth cylindrical morphologies, and no obvious phase separation could be seen. Using X-ray diffraction, KET was determined to be present in the amorphous state in the fiber matrix. FTIR spectroscopy also indicated the successful incorporation of amorphous KET in the fibers. In vitro drug release studies in media at different pH (4.5 or 7.4) or temperature (25 and 37 °C) showed that the release of KET from the blend PNIPAAm/EL100-55 fibers was dependent both on environmental temperature and pH, reflecting the dual-responsive properties of the fibers. The MTT assay was used to explore the biocompatibility of the PNIPAAm/EL100-55 composite fibers towards L929 fibroblasts. Viability was always found to be >80%, even at polymer concentrations of 100 mg/L. Therefore, the fibers prepared here could lead to the development of multi-responsive materials for drug delivery and tissue engineering.

Most conventional chemotherapeutics have narrow therapeutic windows, and thus their delivery remains challenging and often raises safety and efficacy concerns. Theranostic platforms, with simultaneous encapsulation of therapeutic and diagnostic agents, have been proposed as next-generation formulations which can overcome this issue. In this work, we used electrohydrodynamic approaches to fabricate core@shell formulations comprising a pH responsive Eudragit L100 shell embedded with superparamagnetic iron oxide nanoparticles (SPIONs), and a thermo-responsive poly(N-isopropylacrylamide) (PNIPAM)/ethyl cellulose core loaded with the model drug carmofur. By varying the weight ratio of core polymer to shell polymer, the morphology of PNIPAM/ethyl cellulose@Eudragit L100 microparticles could be changed from concave to spherical. Smooth cylindrical fibres could also be generated. All the formulations exist as amorphous solid dispersions of drug-in-polymer, with distinct core@shell architectures. The fibres have clear thermo-responsive drug release profiles, while no thermo-responsive properties can be seen with the particles. All the formulations can protect SPIONs from degradation in gastric fluids (pH ∼ 1.5), and around the physiological pH range the materials offer effective and pH-responsive relaxivity. The r2 values also display clear linear relationships with drug release data, suggesting the potential of using MRI signals to track drug release in vivo. Mathematical equations were established to track drug release in vitro, with very similar experimental and predicted release profiles obtained.

Fixed dose combinations (FDCs) offer an accessible way to simplify complex therapeutic regimens by the simultaneous presentation of multiple drugs in a single entity to the patient. However, encapsulation of hydrophobic drugs into FDCs possess a number of technical challenges. Electrospinning comprises a convenient way to incorporate multiple hydrophobic drugs into a single formulation in a single step, via the use of an appropriate organic solvent system during fabrication. In this study, we report a series of novel fiber formulations comprising ethyl cellulose loaded with two hydrophobic drugs, spironolactone and nifedipine, either individually or in combination. The drugs are found to be present in the fibers in the form of amorphous solid dispersions, and these are stable at room temperature for 4 months. The products showed extended release profiles over more than 30 h. This formulation strategy offers potential to manage chronic cardiovascular conditions and overcome patient related non-adherence by providing a simplified treatment model.

Surface functionalisation of polymeric electrospun scaffolds with therapeutic biomolecules is often explored in regenerative medicine and tissue engineering. However, the bioconjugation method must be carefully selected to prevent partial or full loss of activity of the biomolecule following chemical manipulation. Perfluorophenyl azide bearing a N‐hydroxysuccinimide (PFPA-NHS) active ester group is a versatile tool for UV-initiated covalent coupling of amine-containing molecules to hydrocarbon-based polymers, such as polydioxanone or polycaprolactone (PCL). This study therefore explored the feasibility of PFPA-NHS functionalisation of electrospun PCL scaffolds with model biomolecules. Protein conjugation was extensively explored using fluorescence staining and attachment studies, confirming the retention of amine coupling capability following photografting of PFPA-NHS to the PCL surface. The effect of the washing method used to remove unreacted PFPA was explored in Caco-2 cell viability studies, and it was determined that sonication washing is required to avoid cell death. A model enzyme, catalase, was then successfully attached to the surface of PCL scaffolds for potential applications in oncological photodynamic therapy. Catalase retained its enzymatic activity following attachment to the fibres and the majority of the enzyme (~60%) remained bound to the fibre after incubation in an aqueous environment for six days. The anticipated prolonged presentation and sustained release of proteins as a result of PFPA-NHS conjugation could be advantageous in progressing protein-based therapies.

Aggregation, including the formation of fibrils, poses significant challenges for the development of therapeutic peptides. To prepare stable peptide formulations, some understanding of the mechanisms underpinning the fibrillation process is required. A thioflavin T fluorescence assay was first used to determine the fibrillation profile of a GLP-1-like peptide (G48) at conditions being considered to formulate the peptide. G48 concentrations ranged from 0 to 600 µM and three pH values (pH 3.7, 7.4 and 8.5) were evaluated. Kinetic data demonstrate that G48 displays a pH-dependent aggregation profile. At pH 3.7, which is below the isoelectric point of G48 (pI ~ 5), kinetics representative of amorphous aggregates forming via a nucleation-independent mechanism were seen. At pH 7.4 and 8.5 (pH > pI) typical nucleation-dependent aggregation kinetics were observed. The weight concentration of β-sheet rich aggregates (FLmax) correlated inversely with net charge, so lower FLmax values were observed at pH 3.7 and 8.5 than at pH 7.4. Incorporation of a non-ionic surfactant (polysorbate 80) into the peptide solution suppressed the fibrillation of G48 at all pH values and maintained the native peptide conformation, whereas a phenolic co-formulant (ferulic acid) had minimal effects on fibril growth. Peptide fibrillation, which can occur within a range of formulation concentrations and pH values, can hence be inhibited by the judicious use of excipients.

A series of 5-fluorouracil (5-FU) loaded core/shell electrospun fibers is reported. The fibers have shells made of Eudragit S100 (ES-100), and drug-loaded cores comprising poly(vinylpyrrolidone), ethyl cellulose, ES-100, or drug alone. Monolithic 5-FU loaded ES-100 fibers were also prepared for comparison. Electron microscopy showed all the fibers to have smooth cylindrical shapes, and clear core-shell structures were visible for all samples except the monolithic fibers. 5-FU was present in the amorphous physical form in all the materials prepared. Dissolution studies showed that the ES-100 shell was not able to prevent drug release at pH 1.0, even though the polymer is completely insoluble at this pH: around 30-80% of the maximum drug release was reached after 2h immersion at pH 1.0. These observations are ascribed to the low molecular weight of 5-FU permitting it to diffuse through pores in the ES-100 coating, and the relatively high acid solubility of the drug providing a thermodynamic impetus for this to happen. In addition, the fibers were observed to be broken or merged following 2h at pH 1.0, giving additional escape routes for the 5-FU.

Medicated shellac nanofibers providing colon-specific sustained release were fabricated using coaxial electrospinning. A solution of 7.5 g shellac and 1.5 g of ferulic acid (FA) in 10 mL ethanol was used as the core fluid, and a mixture of ethanol and N,N-dimethylformamide (8/10 v/v) as the shell. The presence of the shell fluid was required to prevent frequent clogging of the spinneret. The diameters of the fibers (D) can be manipulated by varying the ratio of shell to core flow rates (F), according to the equation D=0.52 F(-0.19). Scanning electron microscopy images revealed that fibers prepared with F values of 0.1 and 0.25 had linear morphologies with smooth surfaces, but when the shell fluid flow rate was increased to 0.5 the fiber integrity was compromised. FA was found to be amorphously distributed in the fibers on the basis of X-ray diffraction and differential scanning calorimetry results. This can be attributed to good compatibility between the drug and carrier: IR spectra indicated the presence of hydrogen bonds between the two. In vitro dissolution tests demonstrated that there was minimal FA release at pH 2.0, and sustained release in a neutral dissolution medium. The latter occurred through an erosion mechanism. During the dissolution processes, the shellac fibers were gradually converted into nanoparticles as the FA was freed into solution, and ultimately completely dissolved.

A series of polyvinylpyrrolidone fibers loaded with paracetamol (PCM) and caffeine (CAF) was fabricated by electrospinning and explored as potential oral fast-dissolving films. The fibers take the form of uniform cylinders with smooth surfaces, and contain the drugs in the amorphous form. Drug-polymer intermolecular interactions were evidenced by infrared spectroscopy and molecular modeling. The properties of the fiber mats were found to be highly appropriate for the preparation of oral fast dissolving films: their thickness is around 120-130 μm, and the pH after dissolution in deionized water lies in the range of 6.7-7.2. Except at the highest drug loading, the folding endurance of the fibers was found to be >20 times. A flavoring agent can easily be incorporated into the formulation. The fiber mats are all seen to disintegrate completely within 0.5s when added to simulated saliva solution. They release their drug cargo within around 150s in a dissolution test, and to undergo much more rapid dissolution than is seen for the pure drugs. The data reported herein clearly demonstrate that electrospun PCM/CAF fibers comprise excellent candidates for oral fast-dissolving films, which could be particularly useful for children and patients with swallowing difficulties.

Electrospinning was used to prepare core/shell fibers containing the active pharmaceutical ingredients indomethacin (IMC) or mebeverine hydrochloride (MB-HCl). The shell of the fibers was fabricated from the pH sensitive Eudragit S100 polymer, while the drug-loaded core was based on the mucoadhesive poly(ethylene oxide) (PEO). Three different drug loadings (from 9 to 23% (w/w) of the core mass) were prepared, and for MB-HCl two different molecular weights of PEO were explored. The resultant fibers generally comprise smooth cylinders, although in some cases defects such as surface particles or flattened or merged fibers were visible. Transmission electron microscopy showed all the systems to have clear core and shell compartments. The drugs are present in the amorphous physical form in the fibers. Dissolution tests found that the fibers can effectively prevent release in acidic conditions representative of the stomach, particularly for the acidic indomethacin. After transfer to a pH 7.4 medium, sustained release over between 6 and 22h is observed. Given the mucoadhesive nature of the PEO core, after dissolution of the shell the fibers will be able to adhere to the walls of the intestinal tract and give sustained local drug release. This renders them promising for the treatment of conditions such as irritable bowel disease and colon cancer.

In this study, drug-loaded nanofibers were prepared by electrospinning captopril (CPL) with aliphatic biodegradable polyesters. Poly(L-lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA), and poly(lactic-co-ε-caprolactone) (PLCL) were used as filament-forming matrix polymers, and the concentration of CPL in each fiber type was varied. Scanning electron microscopy indicated that the morphology and diameters of the fibers were influenced by the concentration of polymer in the spinning solution and the drug loading. CPL was found to be distributed in the polymer fibers in an amorphous manner using differential scanning calorimetry and X-ray diffraction. FTIR indicated that hydrogen bonding existed between the drug molecules and the carrier polymers. In vitro dissolution tests showed that drug release from the fibers was highly dependent on the release medium, temperature, and on the polymer used. A range of kinetic models were fitted to the drug-release data obtained, and indicated that release was diffusion controlled in all cases. The different polymer fibers have application in diverse areas of drug delivery, for instance as sub-lingual or sustained release systems. Furthermore, by combining different CPL-loaded fibers, it would be possible to produce a bespoke formulation with tailored drug-release properties.

To obtain wound dressings which could be removed easily without secondary injuries, we prepared thermoresponsive electrospun fiber mats containing poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA). Blend fibers of PDEGMA and poly(l-lactic acid-co-e-caprolactone) (P(LLA-CL) were fabricated via electrospinning, and analogous fibers containing the antibiotic ciprofloxacin (CIF) were also prepared. Smooth cylindrical fibers were obtained, albeit with a small amount of beading visible for the ciprofloxacin-loaded fibers. X-ray diffraction showed the drug to exist in the amorphous physical form post-electrospinning. The composite fibers showed distinct thermosensitive properties and gave sustained release of CIF over more than 160h in vitro. The fibers could promote the proliferation of fibroblasts, and by varying the temperature cells could easily be attached to and detached from the fibers. Antibacterial tests demonstrated that fibers loaded with ciprofloxacin were effective in inhibiting the growth of E. coli and S. aureus. In vivo investigations on rats indicated that the composite PDEGMA/P(LLA-CL) fibers loaded with CIF had much more potent wound healing properties than a commercial gauze and CIF-loaded fibers made solely of P(LLA-CL). These results demonstrate the potential of PDEGMA/P(LLA-CL)/ciprofloxacin fibers as advanced wound dressing materials.

Two series of fibers containing the active ingredients acyclovir, ciprofloxacin and cyanocobalamin, and combinations of these drugs, were prepared by electrospinning. One set used the hydrophilic poly(vinylpyrrolidone) (PVP) as the filament-forming polymer, while the other used the slow-dissolving poly(e-caprolactone) (PCL). The fibers were found to have cylindrical morphologies, although there was evidence for solvent occlusion with the PVP systems and for some drug particles in the PCL materials. The active ingredients were generally present in the amorphous physical form in the case of PVP, but evidence of crystallinity was observed with PCL. The existence of intermolecular interactions between the drugs and polymers was proven using simple molecular modeling calculations. Drug release from the various fibers was tested in a validated in vitro outflow model of the eye, and the fiber formulations found to be capable of extending drug release. We thus conclude that electrospun matrices such as those prepared in this work have potential for use as intravitreal implants.