Polyethylene Glycol Research Articles

Improvement of Bone Metabolism in Prepubertal Girls with Turner Syndrome Following Long-term Pegylated Growth Hormone Treatment.

The study aims to assess the improvement in bone metabolism in prepubertal girls with Turner Syndrome (TS) after long-term polyethylene glycol recombinant human Growth Hormone (PEG-rhGH) treatment. A 12-month longitudinal prospective study was conducted with 28 prepubertal girls diagnosed with TS. Participants were divided into two groups: 18 received PEG-rhGH therapy (0.1-0.25 mg/kg/week) and 10 did not. Anthropometric measurements, bone turnover markers (BTMs), and serum levels of IGF-1, calcium, and phosphate were collected at baseline and after 12 months. BTMs included bone alkaline phosphatase (BAP), Type I collagen propeptide (CICP), Type I collagen telopeptide (CTX), and fibroblast growth factor 23 (FGF23). After 12 months of PEG-rhGH therapy, the treatment group showed significant increases in growth velocity (GV) and height standard deviation scores (HtSDS). Serum IGF-1 levels increased rapidly within one month and remained elevated. BTMs indicated enhanced bone formation, significantly increasing BAP and CICP, while CTX levels remained low. FGF23 levels initially rose slightly but declined below baseline by 12 months. Elevated blood phosphate levels were observed. PEG-rhGH therapy in children with TS significantly improves linear growth and enhances bone formation markers, benefiting bone metabolism.

In vitro and in vivo performance of amorphous solid dispersions of ursolic acid as a function of polymer type and excipient addition.

The objective of this research was to enhance the bioavailability of ursolic acid (UA) by preparing multielement amorphous solid dispersion (ASD) systems comprising excipients. The ASDs were prepared via the solvent evaporation method, characterized by a range of techniques, and investigated with respect to permeability of human colorectal adenocarcinoma cell line (Caco-2) cells monolayers and pharmacokinetics, with comparisons made to the physical mixture and the pure drug. The (UA-choline)-Polyethylcaprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer (Soluplus)-Vitamin E polyethylene glycol succinate (TPGS) ASD demonstrated superior dissolution properties compared to the corresponding binary solid dispersions and ternary solid dispersions (P<.05). The permeability studies of Caco-2 cell monolayers revealed that the ASD exhibited moderate permeability, with an efflux rate that was significantly lower than that of the UA raw material (P<.05). Pharmacokinetic studies in rats demonstrated that the oral bioavailability of the ASD was 19.0 times higher than that of UA (P<.01). The research indicated that the multielement ASD could be employed as an efficacious drug delivery system for UA. Furthermore, the Soluplus/TPGS/choline combination represents a promising candidate for the fabrication of ASDs that can load weakly acidic and poorly soluble drugs.

Disulfide stoppered polyrotaxanes with enhanced cellular uptake and intracellular cyclodextrin release

Background and AimPolyrotaxanes are molecular necklaces composed of polymers, threaded macrocycles, and bulky stopper molecules to inhibit the decomposition of the first two. These supramolecular assemblies are promising active ingredients for treating lysosomal storage disorders. This study aimed to synthesize such polyrotaxanes with a novel, simple method, resulting in high threading efficacy, enhanced cellular uptake, and intracellular cyclodextrin (CD) release. MethodsIn this study, we developed two novel poly(ethylene glycol) (PEG) based polyrotaxanes, with threaded α-cyclodextrin (α-CD) or its mixture with 2-hydroxypropyl-α-CD (HP-α-CD) and glutathione sensitive disulfide connected stopper molecules. The structure and composition of these polyrotaxanes were determined by 1H NMR spectroscopy and gel permeation chromatography, while the cellular uptake was investigated by flow cytometry and confocal microscopy. ResultsHigh threading efficacy, as well as molar mass of 17.9 and 13.1 kDa, was found for the polymeric supramolecules with threaded α-CD and α-CD/HP-α-CD, respectively. Glutathion-triggered reductive removal of the stopper molecules showed potential decomposition of these polyrotaxanes in target cells. Flow cytometry revealed an up to 52-fold enhancement in cellular uptake of α- and HP-α-CD by the polyrotaxanes compared to free CD, which was also visualized by confocal microscopy. Conclusion and scope of applicationPolyrotaxanes based on α-CD and its derivative were tested in vitro for application in the treatment of lysosomal storage disease for the first time. Based on these results, polyrotaxanes with disulfide stopper molecules might be promising supramolecular excipients for cellular delivery of α-CDs.

Linker Chemistry and Connectivity Fine-Tune the Immune Response and Kinetic Solubility of Conjugated NOD2/TLR7 Agonists.

There is a growing interest in developing novel immune potentiators capable of eliciting a cellular immune response. We tackle this challenge by harnessing the synergistic cross-activation between two innate immune receptors─the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 7 (TLR7). Herein, we investigate the structure-activity relationship of a series of novel conjugated NOD2/TLR7 agonists incorporating a variety of flexible aliphatic, poly(ethylene glycol)-based and triazole-featuring linkers. Our findings reveal potent immune-enhancing properties of conjugates in human primary peripheral blood mononuclear cells, characterized by a Th1/Th17 polarized cytokine response. Importantly, we demonstrate that both the chemistry of the linker and the site of linkage affect the immune fingerprint and the kinetic solubility of these conjugated agonists. These results shed further light on the immunostimulatory potential of NOD2/TLR7 cross-activation and provide insights for designing innovative immune potentiators.

Photo and pH dual stimuli-responsive block copolymer micelles with defined incorporation of o-nitrobenzyl units in poly(ɛ-caprolactone) block for controlled release

A series of dual stimuli-responsive block copolymers with varying content of photocleavable o-nitrobenzyl (ONB) ester group pendent in the hydrophobic poly(ɛ-caprolactone) block and pH-cleavable acetal linkage at the junction with hydrophilic poly(ethylene glycol) block is synthesized. The hydrophobic block is a random copolymer synthesized by ring-opening copolymerization of ɛ-caprolactone and ONB-substituted ɛ-caprolactone containing varying compositions of the two monomers. Kinetics of polymerization shows that ONB-functionalized monomer has lower reactivity than that of the unsubstituted monomer. The series of block copolymers shows self-assembly into well-defined spherical micelles of average size of 150–200 nm in aqueous solution. Photocleavage of ONB groups is studied by NMR and UV–vis spectroscopy, and its extent is determined. The two stimuli viz. UV light and pH are used individually as well as simultaneously to study the controlled release of the encapsulated drug Camptothecin and the synergistic effect of the two stimuli is demonstrated. The effect of varying content of ONB groups is observed on drug release profile. MTT assay showed non-cytotoxic nature of the polymer. Cell uptake and photoinduced release of doxorubicin (DOX) from the micelles in MDA-MB-231 cells is demonstrated.

Magnesium Nanocomposite Hydrogel Reverses the Pathologies to Enhance Mandible Regeneration.

The healing of bone defects after debridement in medication-related osteonecrosis of the jaw (MRONJ) is a challenging medical condition with impaired angiogenesis, susceptible infection, and pro-inflammatory responses. Magnesium (Mg) nanocomposite hydrogel is developed to specifically tackle multiple factors involved in MRONJ. Mg-oxide nanoparticles tune the gelation kinetics in the reaction between N-hydroxysuccinimide-functionalized hyperbranched poly (ethylene glycol) and proteins. This reaction allows an enhanced mechanical property after instant solidification and, more importantly, also stable gelation in challenging environments such as wet and hemorrhagic conditions. The synthesized hydrogel guides mandible regeneration in MRONJ rats by triggering the formation of type H vessels, activating Osterix+ osteoprogenitor cells, and generating anti-inflammatory microenvironments. Additionally, this approach demonstrates its ability to suppress infection by inhibiting specific pathogens while strengthening stress tolerance in the affected alveolar bone. Furthermore, the enhanced osteogenic properties and feasibility of implantation of the hydrogel are validated in mandible defect and iliac crest defect created in minipigs, respectively. Collectively, this study offers an injectable and innovative bone substitute to enhance mandible defect healing by tackling multiple detrimental pathologies.

Low-Foaming Nonionic Gemini Surfactants Containing Hydrophilic Poly(oxyethylene) Chain and Hydrophobic Di-tert-pentylbenzenes Groups.

Low-foaming nonionic gemini surfactants have a wide range of applications in industrial cleaning and photoresist development. In this study, three low-foaming nonionic gemini surfactants (S1, S2, and S3) with different poly(oxyethylene) chain lengths have been synthesized by using methoxy poly(ethylene glycol) and 2,5-di-tert-pentylhydroquinone. The chemical structures of the novel surfactants are confirmed by 1H NMR, Fourier transform infrared, and gel permeation chromatography (GPC), and their properties such as surface tension, wetting properties, emulsifying properties, and foaming properties are investigated. The surface tension values of S1, S2, and S3 at the critical micelle concentration are 40.29, 37.14, and 41.64 mN/m, exhibiting good surface activity. When the surfactant concentration is higher than 2 mM, the contact angles of S1 and S2 no longer change and can maintain 62 and 64°, showing good wetting properties. In addition, S3 can keep an emulsion state for 2 months at high concentrations, exhibiting good emulsion stability. Furthermore, all the prepared surfactants show good low-foaming properties. The initial foaming volumes of S1 are very low, less than 0.1 mL at various concentrations, less than 2% of the conventional surfactant sodium dodecyl sulfate. For S2, the initial foaming volumes at the concentration of 0.1, 1, 2, and 3 g/L are 1, 0.5, 0.55, and 0.45 mL, respectively. For S3, the initial foaming volumes show a general trend of increasing with concentration. The surfactants with longer poly(oxyethylene) chains possess more initial foaming volumes at the same concentration, which is because the greater cohesion between the surfactant molecules can increase the elasticity of the bubble film. Our study enriches the design rationales for low-foaming surfactants and motivates researchers to develop more advanced surfactants for industrial cleaning and photoresist development.

Development and characterization of novel fast-dissolving pentobarbital suppositories for pediatric procedural sedation and comparison with lipophilic formulations

For pediatric radiological procedures (RP), pentobarbital sodium (PNa) can be used orally or rectally to replace intravenous anesthesia. Since no commercial PNa suppositories exist, they must be prepared by compounding pharmacies. This study aims to develop fast-dissolving PNa suppositories for fast pharmacological activity during RP. We prepared gelatin (G), gelatin/polyethylene glycol 4000 (GP), and polyethylene glycol 4000 (P) suppositories, with and without pH adjustment, and assessed their dosage uniformity (DU), softening time, rupture resistance, and in-vitro dissolution. An optimal formulation was selected, and PNa release was compared to that of fat-based suppositories using dissolution tests. Additionally, the quality control process (analytical performance, safety/eco-friendliness and productivity/practical effectiveness) of these formulas were compared using a RGB method. All hydrophilic formulas (HF) met the DU requirement (AV < 8 %) except for P (AV 15.62 ± 4 %). pH adjustment enhanced G and GP suppositories resistance to 2.2 ± 0.2 kg and 2.0 ± 0.3 kg, respectively, and allowed 100 % release of PNa in under 10 min. In contrast, lipophilic formulas released less than 80 % of PNa at best after 120 min. These results show the biopharmaceutical suitability of HF for RP compared to lipophilic ones, but a pharmacokinetic study is needed to confirm data.

Semi-Interpenetrating Hydrogel with Long-Term Intrinsic Antibacterial Properties Promotes Healing of Infected Wounds In Vivo.

Bacterial infections significantly deteriorate the process of wound healing. The wound dressings loaded with antimicrobials are widely used to reduce bacterial infections. However, release-based sterilization may increase the risk of drug resistance of bacteria and complicate translation. Thus, the development of long-term intrinsic antibacterial wound dressings is highly desirable. In this study, an intrinsic antibacterial hydrogel (PVA/PPG-HBPL) consisting of poly(vinyl alcohol) (PVA), poly(polyethylene glycol methyl ether methacrylate-co-glycidyl methacrylate) (PPG), and hyperbranched poly-l-lysine (HBPL) was designed and fabricated. The mechanical properties of the PVA/PPG-HBPL hydrogel were enhanced by hydrogen bonding and semi-interpenetrating networks. It also possessed a favorable ability to absorb the wound exudates. The release of antibacterial HBPL was significantly decreased by the methods of cyclic freeze-thawing and covalent cross-linking during hydrogel fabrication, enabling the PVA/PPG-HBPL hydrogel with intrinsic and long-term antibacterial performance. The PVA/PPG-HBPL hydrogel dressing killed 99.9% of methicillin-resistant Staphylococcus aureus (MRSA) cultured on its surface without observable cytotoxicity in vitro. It observably shortened the healing process by 2 orders of magnitude of MRSA colonies compared with the control in the MRSA-infected full-thickness skin wound of rats in vivo even after being soaked in phosphate-buffered saline (PBS) for 21 days (PBS was changed every 3 days). The antibacterial hydrogels could kill wound bacteria in a timely manner, significantly reduce inflammatory cell infiltration, and promote neovascularization and collagen deposition.

Cytocompatible Hyperbranched Polyesters Capable of Altering the Ca2+ Signaling in Neuronal Cells In Vitro.

Synthetic hyperbranched polyesters with potential therapeutic properties were synthesized using the bifunctional polyethylene glycol or PEG with different molecular weights, ca., 4000, 6000, and 20,000 g/mol, and the trifunctional trans-aconitic acid or TAA. During polycondensation, a fixed amount of PEG was allowed to react with varying amounts of TAA (1:1 and 1:3) to control the branching extents. It was found that the synthetic polyesters had a considerable yield and were highly water soluble. Spectroscopic data (Fourier transform infrared and 1H NMR) confirmed the polyester formation; the branching percentages were determined from 1H NMR spectroscopy which varied from 73% to 22% among the synthesized samples. As the molecular weight of PEG was increased, the branching percentage drastically dropped. All polyesters were found to be negatively charged due to the ionization of unreacted -COOH in the branched ends at the working pH (7.4). Both the hydrodynamic size and intrinsic viscosity were found to reduce as the branching extent increased. Among the sets of polyesters, the one with the highest branching percentage (73%) showed the core-shell morphology (evident from field emission scanning electron microscopy and transmission electron microscopy studies). It also exhibited the highest efficiency toward Ca2+ influx in neuronal cells due to the unique morphology and the negatively charged surface. Nevertheless, this particular grade of polyester along with all the other grades was cytocompatible and induced reactive oxygen species generation. Since the maximally branched grade was highly efficient in altering the Ca2+ signaling through stronger influx, it may well be tested for treating neuronal disorders in vivo in future.

Highly thermally conductive and shape-stabilized phase change materials with desirable solar/electric-to-thermal conversion performance based on high-modulus graphite/PVA foam

The widespread utilization of phase change materials (PCMs) has been impeded by challenges such as leakage, low thermal/electrical conductivity, and inadequate light absorption. Although constructing interconnected three-dimensional (3D) carbon networks within PCMs can mitigate these issues, their complex and energy-intensive fabrication processes, coupled with insufficient mechanical strength causing significant leakage and collapse of liquefied PCMs under external loads or impacts, hinder their practical application. Herein, we present a novel approach for the preparation of 3D graphite/polyvinyl alcohol foam (GPF) through a simple vacuum foaming combined with air-drying method. The obtained GPF-5 exhibits impressive compression strength (4.46 MPa) and compression modulus (93.1 MPa) at low density of 0.30 g/cm3. Upon impregnation with polyethylene glycol (PEG), GPF-5/PEG exhibits notable mechanical strength (7.62 MPa), contributing to its thermal shape stability and resistance to leakage. Even when subjected to temperatures above the melting point of PEG under external loads, GPF-5/PEG maintains its original shape without any liquid leakage. Due to the efficient construction of 3D thermal conductivity pathways within GPF, GPF-5/PEG demonstrates a high thermal conductivity of up to 3.48 W/m K−1 with graphite contents of 21.1 wt%, representing an increase of 136 % and 1640 % compared to graphite/PEG (with equivalent graphite content) and pure PEG, respectively. Additionally, GPF-5/PEG displays high latent heat of melting (136.8 J/g) and superior thermal cycling stability. Moreover, GPF-5/PEG demonstrates high solar-to-thermal and electric-to-thermal energy conversion capabilities, highlighting their potential for diverse applications. The work offers a rational strategy for fabricating high-modulus carbon foam, which can be used for PCMs-based multi energy conversion and storage systems with high thermo-mechanical properties.

Microbial Degradation of Polyester Microfibers Using Indigenously Isolated Bacterial Strain Exiguobacterium Sp.

ABSTRACTSynthetic microfibers are emerging environmental microplastic pollutants released from different industrial and domestic sources. The present investigation describes the isolation of potential bacterial strains from microplastic‐contaminated sites of Bhubaneswar city of Odisha, India. Four morphologically distinct bacterial strains were isolated using 2% polyethylene glycol (PEG) supplemented nutrient agar (NA) medium and were screened for their polymer tolerance ability by growing them on 2%–8% PEG. A single microorganism capable of growing on 8% PEG was selected for biodegradation experiment. Through 16S rRNA sequencing, the selected bacterial strain was identified as Exiguobacterium sp. with gene bank accession number ON318396. The microbial strain's microfiber biodegradation ability was assessed in a laboratory setting over a period of 28 ± 2 days, utilizing optimized conditions with an initial pH of 7, 2 mL inoculum volume, an incubation temperature of 30°C ± 2°C, and 150 rpm, using 2 g of polyester microfiber. In optimum conditions, the weight loss of the treated sample with the selected microbial strain was 19.2%. The polyester degradation was confirmed through scanning electron microscopic images viewing the degradation of the polyester microfiber surfaces. Variation in functional groups confirmed through Fourier transform infrared spectrophotometry. Detection of carbonyl (C═O) group stretching band at 1711 cm−1 through ATR‐FTIR analysis in the treated sample confirmed the polymer biodegradation. The potential isolate can efficiently degrade polyester and, in the future, can be employed as a promising solution for the sustainable treatment of synthetic microfiber pollution.

Bacterial cellulose/polyethylene glycol composite aerogel with incorporated graphene and metal oxides for VOCs detection

It is important to monitor and detect volatile organic compounds (VOCs) for environmental protection, occupational safety and human health. Portable and compact VOC sensing devices with a fast response are needed for real-time monitoring and simple analysis. Using solvent exchange and freeze-drying techniques, an ultralight 3D bacterial cellulose (BC) aerogel is prepared and modified by polyethylene glycol with the functionalization of graphene and metal oxides to detect VOC gases. Unlike commercially available flat VOC sensors, the 3D structure of our VOC sensor with high permeability of BC composite provides superior sensing characteristics for acetone, formaldehyde and ethanol in a wider range of scenarios. The portable BC composite sensor exhibits remarkable sensitivity and selectivity toward VOCs detection. The BC composite with TiO2 has a response time of about 20 s to 1 ppm acetone and can detect as low as 1.43 ppm at room temperature. In addition, BC composites with ZnO are suitable for detecting formaldehyde in indoor air.

Limitations of Limulus amebocyte lysate test for endotoxin control in raw materials for liposomal nanoformulations.

Aim: To evaluate the applicability of Limulus amebocyte lysate (LAL) assay for endotoxin determination in lipid compounding liposomal nanoformulations.Materials & methods: Spiked cholesterol, hydrogenated soy phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG 2000) samples with endotoxins, simulating contaminated samples or in-process contamination were analyzed by chromogenic LAL assay.Results: Recovery of spiked endotoxins was achieved from DSPE-PEG 2000 suspended in water, whereas recovery was not achieved from spiked cholesterol and hydrogenated soy phosphatidylcholine suspended in methanol, and from multilamellar vesicles. Conclusion: Endotoxins, when in contact with organic solvents, no longer react in the LAL assay as they do in aqueous media. This indicates limitations of the LAL assay for endotoxin control in raw materials for liposomal nanoformulations.

Plasmonic semi shells derived from simultaneous in situ gold growth and anisotropic acid etching of ZIF-8 for photothermal ablation of metastatic breast tumor

Open nanoshells such as nanobowls or nanocups collectively described as ‘semi shells’ have unique plasmonic properties due to their lack of symmetry. So far, their fabrication was based on multistep and laborious methods such as solid state sputter coating or selective deposition/etching using sacrificial templates. In this work, we report a rapid one step colloidal synthetic protocol for PEGylated semi-shell (SS) fabrication by simultaneous facet specific anisotropic chemical etching of rhombic dodecahedral ZIF-8 and heterogenous nucleation & growth of gold. The SS possesses a strong localized surface plasmon resonance in the near-infrared region, which is retained after surface passivation with polyethylene glycol and subsequent cryopreservation for extended shelf-life. Freshly reconstituted PEGylated SS was found to be safe & non-toxic in healthy C57BL/6 mice post intravenous administration. The PEGylated SS displayed significant photothermal efficiency of ~37% with 808 nm laser irradiation. Preclinical assessment of intra-tumoral photothermal efficacy indicated complete remission of primary breast tumor mass with insignificant metastasis to vital organs in 4T1 FL2 tumor bearing CD1 nude mice. Further, PEGylated SS mediated photothermal therapy also yielded morbidity free survivael of 75% for up to 90 days, indicating their potential to significantly improve outcomes in advanced breast tumors.

Investigation of Rheological Properties of Molten Materials for Dripping Pills Based on Imaging Monitoring.

Rheological properties, as critical material attributes (CMAs) of solid dispersion drugs such as dripping pills, affect the melting, dispersion, and solidification. Therefore, characterization and assessments of rheological properties in the pharmaceutical process are important in enhancing drug stability and bioavailability. The study aimed to develop a method for analyzing the rheology of molten materials, assessing their consistency and how rheological properties affect the dripping process and pills quality. The rheological behavior of molten materials composed of Ginkgo biloba leaf extract (GBE) and polyethylene glycol (PEG) 4000 was characterized. Batch consistency of molten materials was evaluated. Image monitoring technology was utilized to capture and process images of the droplet formation process. We established the relationship between the rheological properties of molten materials and various attributes. The quality consistency of molten materials was evaluated, with 12 batches showing similarity above 0.8. The MLR models showed strong correlations (R2 > 0.80) between rheological properties and evaluation attributes. The rheological properties, including consistency coefficient, flow index, and viscosity at 80°C, were identified as critical rheological properties of the molten materials. Rheological property differences of molten materials have an impact on the morphology of droplet and quality performance. A rheological method was established, enabling quality consistency evaluation of molten materials in dripping pills. This study revealed the influence of rheological properties on droplet formation process and dripping pills quality, providing a reference for researches on material attributes control of other traditional Chinese medicine dripping pills.

Preparation of dual drug-loaded polymer nanoconjugate to enhance treatment efficacy for ovarian cancer cells

Ovarian cancer is the deadliest gynecological malignancy, representing 2.5 % of all female cancers and accounting for 5 % of female cancer-related fatalities. Despite numerous strategies in its treatment, the disease shows a high recurrence rate and a low survival rate. Consequently, there is a growing focus on targeted therapies in ovarian cancer treatment. It is well-known that VEGFR and LPA pathways undergo alterations in ovarian cancer and stimulate survival, adhesion, migration, invasion, tumor growth and angiogenesis. Cabozantinib (CBZ) is a multi-receptor tyrosine kinase inhibitor that effectively targets MET, VEGFR-1, 2, 3, FLT3, c-KIT, and RET. Ki16425 is a selective inhibitor of LPA receptors 1, 2, and 3. Therefore, targeting LPA receptors and combining with VEGFR inhibitor is a strategic approach for ovarian cancer treatment. In this study, it was aimed to prepare polymer-drug nanoconjugate for both VEGFR and LPAR inhibition. For this, O-(2-Carboxyethyl) polyethylene glycol (PEG5000) which advantages are known in cancer studies, was chosen as the carrier system, and a nanoconjugate containing Ki16425 and CBZ (Ki-PEG-CBZ) was synthesized and its potential was evaluated. Initially, CBZ and Ki16425 were conjugated to the PEG5000 through pH-sensitive hydrazone and ester bonds. After nanoconjugate characterization, in vitro release and its ovarian cancer treatment potential were evaluated on A2780, OVCAR3 and SKOV3 ovarian cancer cell lines. A nanoconjugate was obtained with a particle size of 169 ± 15.23 nm, a zeta potential of −13.5 ± 1.21 mV, and a release profile lasting 48 h, containing CBZ and Ki16425 with drug loading efficiencies of 73.71 ± 0.53 % and 77.72 ± 2.51 %, respectively. In vitro studies have demonstrated that Ki-PEG-CBZ is highly effective against ovarian cancer. We suggest that the developed polymer-drug nanoconjugate is an effective and safe nanoconjugate for the treatment of ovarian cancer.

Microfluidic post-insertion of polyethylene glycol lipids and KK or RGD high functionality and quality lipids in milk-derived extracellular vesicles

To achieve the desired delivery effect, extracellular vesicles (EVs) must bypass rapid clearance from circulation and exhibit affinity for target cells; however, it is difficult to simultaneously incorporate two materials into EVs. Post-insertion is a general modification method that can be performed by simply mixing different solutions. Previously, we have developed a microfluidic post-insertion method that supported fast and upscaled modification of EVs using KK-modified high-functionality and -quality (HFQ) lipids. Here, we used microfluidic post-insertion to achieve simultaneous incorporation of polyethylene glycol (PEG) lipids and KK or RGD-modified HFQ lipids into milk-derived EVs to avoid uptake from the reticuloendothelial system and increase the uptake into target cells. PEG lipid and HFQ lipids were formulated to produce micelles and subsequently mixed with EV solution using a microfluidic device. Compared to bulk mixing, microfluidic post-insertion showed higher cellular association. Altered cellular association capacities and endocytic pathways indicated simultaneous incorporation. The cellular association of modified EVs can be adjusted by altering the ratio of (EK)4-KK in micelles with slight changes in physicochemical properties. Furthermore, microfluidic post-insertion is also suitable for (SG)5-RGD, which is insoluble in phosphate-buffered saline (PBS). Our results may be valuable for the development and manufacture of functional EVs as drug delivery systems for clinical applications.

Facile fabrication of degradable, serrated polyethylene diacrylate microneedles using stereolithography

Microneedles have the potential for minimally invasive drug delivery. However, they are constrained by absence of rapid, scalable fabrication methods to produce intricate arrays and serrations for enhanced adhesion. 3D printing techniques like stereolithography (SLA) are fast, scalable modalities but SLAs require non-degradable and stiff resins. This work attempts to overcome this limitation by utilizing a poly (ethylene glycol diacrylate) (PEGDA, F3) resin and demonstrating its compatibility with a commercial SLA printer. FESEM images showed high printing efficiency of customized bioinks (F3) similar to commercial resins using SLA 3D printer. Mechanical endurance tests of whole MNA showed that MNs array printed from F3 resin (485 ± 5.73 N) required considerably less force than commercial F1 resin (880 ± 32.4 N). Penetration performance of F1 and F3 was found to be 10.8 ± 2.06 N and 0.705 ± 0.03 N. In-vitro degradation study in PBS showed that MNs fabricated from F3 resin exhibited degradation after 7 days, which was not observed with the commercial F1 resin provided by the manufacturer. The histology of porcine skin exhibited formation of triangular pores with pore length of 548 μm and efficient penetration into the deeper dermal layer. In conclusion, PEGDA can be used as for fabricating degradable, serrated solid MNs over commercial resin.

Patient-Specific Nanoparticle Targeting in Human Leukemia Blood.

Antibody-directed targeting of chemotherapeutic nanoparticles to primary human cancers holds promise for improving efficacy and reducing off-target toxicity. However, clinical responses to targeted nanomedicines are highly variable. Herein, we prepared and examined a matrix of 9 particles (organic and inorganic particles of three surface chemistries with and without antibody functionalization) and developed an ex vivo model to study the person-specific targeting of nanoparticles in whole blood of 15 patients with chronic lymphocytic leukemia (CLL). Generally, anti-CD20-functionalized poly(ethylene glycol) (PEG) nanoparticles efficiently targeted CLL cells, leading to low off-target phagocytosis by granulocytes and monocytes in the blood. However, there was up to 164-fold patient-to-patient variability in the CLL targeting. This was further exemplified through using clinically relevant PEGylated doxorubicin-encapsulated liposomes, which showed high interpersonal differences in CLL targeting (up to 234-fold differences) and off-target phagocytosis (up to 65- and 112-fold differences in granulocytes and monocytes, respectively). Off-target phagocytosis led to almost all monocytes being killed within 24 h of treatment. Variance of the off-target association of PEGylated liposomes with granulocytes and monocytes significantly correlated to anti-PEG immunoglobulin G levels in the blood of CLL patients. A negative correlation between CLL targeting of PEG particles and anti-PEG immunoglobulin M levels was found in the blood. Taken together, our study identifies anti-PEG antibodies as key proteins in modulating patient-specific targeting of PEGylated nanoparticles in human leukemia blood. Other factors, such as the antigen expression of targeted cells and fouling properties of nanoparticles, also play an important role in patient-specific targeting. The human leukemia blood assay we developed provides an ex vivo model to evaluate interpersonal variances in response to targeted nanomedicines.