Turning foes to friends: Advanced "in situ nanovaccine" with dual immunoregulation for enhanced immunotherapy of metastatic triple-negative breast cancer.

As a "cold tumor", triple-negative breast cancer (TNBC) exhibits limited responsiveness to current immunotherapy. How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a formidable challenge. Herein, an "in situ nanovaccine" Au/CuNDs-R848 was designed for imaging-guided photothermal therapy (PTT)/chemodynamic therapy (CDT) synergistic therapy to trigger dual immunoregulatory effects on TNBC. On the one hand, Au/CuNDs-R848 served as a promising photothermal agent and nanozyme, achieving PTT and photothermal-enhanced CDT against the primary tumor of TNBC. Meanwhile, the released antigens and damage-associated molecular patterns (DAMPs) promoted the maturation of dendritic cells (DCs) and facilitated the infiltration of T lymphocytes. Thus, Au/CuNDs-R848 played a role as an "in situ nanovaccine" to enhance the immunogenicity of TNBC by inducing immunogenic cell death (ICD). On the other hand, the nanovaccine suppressed the myeloid-derived suppressor cells (MDSCs), thereby reversing the immunosuppressive microenvironment. Through the dual immunoregulation, "cold tumor" was transformed into a "hot tumor", not only implementing a "turning foes to friends" therapeutic strategy but also enhancing immunotherapy against metastatic TNBC. Furthermore, Au/CuNDs-R848 acted as an excellent nanoprobe, enabling high-resolution near-infrared fluorescence and computed tomography imaging for precise visualization of TNBC. This feature offers potential applications in clinical cancer detection and surgical guidance. Collectively, this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.

Mussel-inspired antimicrobial hydrogel with cellulose nanocrystals/tannic acid modified silver nanoparticles for enhanced calvarial bone regeneration.

Bacterial infection is a serious challenge in the treatment of open bone defects, and reliance on antibiotic therapy may contribute to the emergence of drug-resistant bacteria. To solve this problem, this study developed a mineralized hydrogel (PVA-Ag-PHA) with excellent antibacterial properties and osteogenic capabilities. Silver nanoparticles (CNC/TA@AgNPs) were greenly synthesized using natural macromolecular cellulose nanocrystals (CNC) and plant polyphenolic tannins (TA) as stabilizers and reducing agents respectively, and then introduced into polyvinyl alcohol (PVA) and polydopamine-modified hydroxyapatite (PDA@HAP) hydrogel. The experimental results indicate that the PVA-Ag-PHA hydrogel, benefiting from the excellent antibacterial properties of CNC/TA@AgNPs, can not only eliminate Staphylococcus aureus and Escherichia coli, but also maintain a sustained sterile environment. At the same time, the HAP modified by PDA is uniformly dispersed within the hydrogel, thus releasing and maintaining stable concentrations of Ca2+ and PO43- ions in the local environment. The porous structure of the hydrogel with excellent biocompatibility creates a suitable bioactive environment that facilitates cell adhesion and bone regeneration. The experimental results in the rat critical-sized calvarial defect model indicate that the PVA-Ag-PHA hydrogel can effectively accelerate the bone healing process. Thus, this mussel-inspired hydrogel with antibacterial properties provides a feasible solution for the repair of open bone defects, demonstrating the considerable potential for diverse applications in bone repair.

Lipid sulfoxide polymers as potential inhalable drug delivery platforms with differential albumin binding affinity.

Inhalable nanomedicines are increasingly being developed to optimise the pharmaceutical treatment of respiratory diseases. Large lipid-based nanosystems at the forefront of the inhalable nanomedicines development pipeline, though, have a number of limitations. The objective of this study was, therefore, to investigate the utility of novel small lipidated sulfoxide polymers based on poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA) as inhalable drug delivery platforms with tuneable membrane permeability imparted by differential albumin binding kinetics. Linear PMSEA (5 kDa) was used as a hydrophilic polymer backbone with excellent anti-fouling and stealth properties compared to poly(ethylene glycol). Terminal lipids comprising single (1C2, 1C12) or double (2C12) chain diglycerides were installed to provide differing affinities for albumin and, by extension, albumin trafficking pathways in the lungs. Albumin binding kinetics, cytotoxicity, lung mucus penetration and cellular uptake and permeability through key cellular barriers in the lungs were examined in vitro. The polymers showed good mucus penetration and no cytotoxicity over 24 h at up to 1 mg ml-1. While 1C2-showed no interaction with albumin, 1C12-PMSEA and 2C12-PMSEA bound albumin with KD values of approximately 76 and 10 µM, respectively. Despite binding to albumin, 2C12-PMSEA showed reduced cell uptake and membrane permeability compared to the smaller polymers and the presence of albumin had little effect on cell uptake and membrane permeability. While PMSEA strongly shielded these lipids from albumin, the data suggest that there is scope to tune the lipid component of these systems to control membrane permeability and cellular interactions in the lungs to tailor drug disposition in the lungs.

Advancing Spinal Cord Injury Bioimaging and Repair with Multifunctional Gold Nanodots Tracking.

High levels of reactive oxygen species (ROS) are known to play a critical role in the secondary cascade of spinal cord injury (SCI). The scavenging of ROS has emerged as a promising approach for alleviating acute SCI. Moreover, identifying the precise location of the SCI site remains challenging. Enhancing the visualization of the spinal cord and improving the ability to distinguish the lesion site are crucial for accurate and safe treatment. Therefore, there is an urgent clinical need to develop a biomaterial that integrates diagnosis and treatment for SCI. Herein, ultra-small-sized gold nanodots (AuNDs) were designed for dual-mode imaging-guided precision treatment of SCI. The designed AuNDs demonstrate two important functions. First, they effectively scavenge ROS, inhibit oxidative stress, reduce the infiltration of inflammatory cells, and prevent apoptosis. This leads to a significant improvement in SCI repair and promotes a functional recovery after injury. Second, leveraging their excellent dual-mode imaging capabilities, the AuNDs enable rapid and accurate identification of SCI sites. The high contrast observed between the injured and adjacent uninjured areas highlights the tremendous potential of AuNDs for SCI detection. Overall, by integrating ROS scavenging and dual-mode imaging in a single biomaterial, our work on functionalized AuNDs provides a promising strategy for the clinical diagnosis and treatment of SCI.

Reactive Oxygen Species Amplifier for Apoptosis-Ferroptosis Mediated High-Efficiency Radiosensitization of Tumors.

Insufficient reactive oxygen species (ROS) production and radioresistance have consistently contributed to the failure of radiotherapy (RT). The development of a biomaterial capable of activating ROS-induced apoptosis and ferroptosis is a potential strategy to enhance RT sensitivity. To achieve precision and high-efficiency RT, the theranostic nanoplatform Au/Cu nanodots (Au/CuNDs) were designed for dual-mode imaging, amplifying ROS generation, and inducing apoptosis-ferroptosis to sensitize RT. A large amount of ROS is derived from three aspects: (1) When exposed to ionizing radiation, Au/CuNDs effectively absorb photons and emit various electrons, which can interact with water to produce ROS. (2) Au/CuNDs act as a catalase-like to produce abundant ROS through Fenton reaction with hydrogen peroxide overexpressed of tumor cells. (3) Au/CuNDs deplete overexpressed glutathione, which causes the accumulation of ROS. Large amounts of ROS and ionizing radiation further lead to apoptosis by increasing DNA damage, and ferroptosis by enhancing lipid peroxidation, significantly improving the therapeutic efficiency of RT. Furthermore, Au/CuNDs serve as an excellent nanoprobe for high-resolution near-infrared fluorescence imaging and computed tomography of tumors. The promising dual-mode imaging performance shows their potential application in clinical cancer detection and imaging-guided precision RT, minimizing damage to adjacent normal tissues during RT. In summary, our developed theranostic nanoplatform integrates dual-mode imaging and sensitizes RT via ROS-activated apoptosis-ferroptosis, offering a promising prospect for clinical cancer diagnosis and treatment.

Lipidated brush-PEG polymers as low molecular weight pulmonary drug delivery platforms.

OBJECTIVES: Nanomedicines are being actively developed as inhalable drug delivery systems. However, there is a distinct utility in developing smaller polymeric systems that can bind albumin in the lungs. We therefore examined the pulmonary pharmacokinetic behavior of a series of lipidated brush-PEG (5 kDa) polymers conjugated to 1C2, 1C12 lipid or 2C12 lipids. METHODS: The pulmonary pharmacokinetics, patterns of lung clearance and safety of polymers were examined in rats. Permeability through monolayers of primary human alveolar epithelia, small airway epithelia and lung microvascular endothelium were also investigated, along with lung mucus penetration and cell uptake. RESULTS: Polymers showed similar pulmonary pharmacokinetic behavior and patterns of lung clearance, irrespective of lipid molecular weight and albumin binding capacity, with up to 30% of the dose absorbed from the lungs over 24 h. 1C12-PEG showed the greatest safety in the lungs. Based on its larger size, 2C12-PEG also showed the lowest mucus and cell membrane permeability of the three polymers. While albumin had no significant effect on membrane transport, the cell uptake of C12-conjugated PEGs were increased in alveolar epithelial cells. CONCLUSION: Lipidated brush-PEG polymers composed of 1C12 lipid may provide a useful and novel alternative to large nanomaterials as inhalable drug delivery systems.

Thermoresponsive Helical Dendronized Poly(phenylacetylene)s: Remarkable Stabilization of Their Helicity via Photo-Dimerization of the Dendritic Pendants.

Dynamic helical polymers can change their helicity according to external stimuli due to the low helix-inversion barriers, while helicity stabilization for polymers is important for applications in chiral recognition or chiral separations. Here, we present a convenient methodology to stabilize dynamic helical conformations of polymers through intramolecular cross-linking. Thermoresponsive dendronized poly(phenylacetylene)s (PPAs) carrying 3-fold dendritic oligoethylene glycol pendants containing cinnamate moieties were synthesized. These polymers exhibit typical features of dynamic helical structures in different solvents, that is, racemic contracted conformations in less polar organic solvents and predominantly one-handed stretched helical conformations in highly polar solvents. This dynamic helicity can be enhanced through selective solvation by increasing the polarity of the organic solvents or simply via their thermally mediated dehydration in water. However, through photocycloaddition of the cinnamate moieties between the neighboring pendants via UV irradiation, these dendronized PPAs adopt stable helical conformations either below or above their phase transition temperatures in water, and their helical conformations can even be retained in less polar organic solvents. Spectroscopic and atomic force microscopy measurements demonstrate that photocycloaddition between the cinnamate moieties occurs on the individual molecular level, and this is found to be helpful in restraining the photodegradation of the PPA backbones. Molecular dynamics simulations reveal that the spatial orientation of the pendants along the rigid polyene backbone is crucial for the photodimerization of cinnamates within one helix pitch.

Utilization of endogenous albumin trafficking pathways in the lungs has potential to modestly increase the lung interstitial access and absorption of drug delivery systems after inhaled administration.

OBJECTIVES: Drug delivery systems typically show limited access to the lung interstitium and absorption after pulmonary delivery. The aim of this work was to undertake a proof-of-concept investigation into the potential of employing endogenous albumin and albumin absorption mechanisms in the lungs to improve lung interstitial access and absorption of inhaled drug delivery systems that bind albumin. METHODS: The permeability of human albumin (HSA) through monolayers of primary human alveolar epithelia, small airway epithelia, and microvascular endothelium were investigated. The pulmonary pharmacokinetics of bovine serum albumin (BSA) was also investigated in efferent caudal mediastinal lymph duct-cannulated sheep after inhaled aerosol administration. RESULTS: Membrane permeability coefficient values (Papp) of HSA increased in the order alveolar epithelia

Fluoropolymer-MOF Hybrids with Switchable Hydrophilicity for 19F MRI-Monitored Cancer Therapy.

Cancer theranostics that combines cancer diagnosis and therapy is a promising approach for personalized cancer treatment. However, current theranostic strategies suffer from low imaging sensitivity for visualization and an inability to target the diseased tissue site with high specificity, thus hindering their translation to the clinic. In this study, we have developed a tumor microenvironment-responsive hybrid theranostic agent by grafting water-soluble, low-fouling fluoropolymers to pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoparticles by surface-initiated RAFT polymerization. The conjugation of the fluoropolymers to ZIF-8 nanoparticles not only allows sensitive in vivo visualization of the nanoparticles by 19F MRI but also significantly prolongs their circulation time in the bloodstream, resulting in improved delivery efficiency to tumor tissue. The ZIF-8-fluoropolymer nanoparticles can respond to the acidic tumor microenvironment, leading to progressive degradation of the nanoparticles and release of zinc ions as well as encapsulated anticancer drugs. The zinc ions released from the ZIF-8 can further coordinate to the fluoropolymers to switch the hydrophilicity and reverse the surface charge of the nanoparticles. This transition in hydrophilicity and surface charge of the polymeric coating can reduce the "stealth-like" nature of the agent and enhance specific uptake by cancer cells. Hence, these hybrid nanoparticles represent intelligent theranostics with highly sensitive imaging capability, significantly prolonged blood circulation time, greatly improved accumulation within the tumor tissue, and enhanced anticancer therapeutic efficiency.

Magnetic iron oxide nanoparticles for brain imaging and drug delivery.

Central nervous system (CNS) disorders affect as many as 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment of CNS disorders. With the advent of nanotechnologies, controlled delivery of drugs with nanoparticles holds great promise in CNS disorders for overcoming the blood-brain barrier (BBB) and improving delivery efficacy. In recent years, magnetic iron oxide nanoparticles (MIONPs) have stood out as a promising theranostic nanoplatform for brain imaging and drug delivery as they possess unique physical properties and biodegradable characteristics. In this review, we summarize the recent advances in MIONP-based platforms as imaging and drug delivery agents for brain diseases. We firstly introduce the methods of synthesis and surface functionalization of MIONPs with emphasis on the inclusion of biocompatible polymers that allow for the addition of tailored physicochemical properties. We then discuss the recent advances in in vivo imaging and drug delivery applications using MIONPs. Finally, we present a perspective on the remaining challenges and possible future directions for MIONP-based brain delivery systems.

Efficient Removal of Perfluorinated Chemicals from Contaminated Water Sources Using Magnetic Fluorinated Polymer Sorbents.

Efficient removal of per- and polyfluoroalkyl substances (PFAS) from contaminated waters is urgently needed to safeguard public and environmental health. In this work, novel magnetic fluorinated polymer sorbents were designed to allow efficient capture of PFAS and fast magnetic recovery of the sorbed material. The new sorbent has superior PFAS removal efficiency compared with the commercially available activated carbon and ion-exchange resins. The removal of the ammonium salt of hexafluoropropylene oxide dimer acid (GenX) reaches >99 % within 30 s, and the estimated sorption capacity was 219 mg g-1 based on the Langmuir model. Robust and efficient regeneration of the magnetic polymer sorbent was confirmed by the repeated sorption and desorption of GenX over four cycles. The sorption of multiple PFAS in two real contaminated water matrices at an environmentally relevant concentration (1 ppb) shows >95 % removal for the majority of PFAS tested in this study.

In Situ Bonding Regulation of Surface Ligands for Efficient and Stable FAPbI3 Quantum Dot Solar Cells.

Quantum dots (QDs) of formamidinium lead triiodide (FAPbI3 ) perovskite hold great potential, outperforming their inorganic counterparts in terms of phase stability and carrier lifetime, for high-performance solar cells. However, the highly dynamic nature of FAPbI3 QDs, which mainly originates from the proton exchange between oleic acid and oleylamine (OAm) surface ligands, is a key hurdle that impedes the fabrication of high-efficiency solar cells. To tackle such an issue, here, protonated-OAm in situ to strengthen the ligand binding at the surface of FAPbI3 QDs, which can effectively suppress the defect formation during QD synthesis and purification processes is selectively introduced. In addition, by forming a halide-rich surface environment, the ligand density in a broader range for FAPbI3 QDs without compromising their structural integrity, which significantly improves their optoelectronic properties can be modulated. As a result, the power conversion efficiency of FAPbI3 QD solar cells (QDSCs) is enhanced from 7.4% to 13.8%, a record for FAPbI3 QDSCs. Furthermore, the suppressed proton exchange and reduced surface defects in FAPbI3 QDs also enhance the stability of QDSCs, which retain 80% of the initial efficiency upon exposure to ambient air for 3000 hours.

Anti-Fouling Surfaces for Extracorporeal Membrane Oxygenation by Surface Grafting of Hydrophilic Sulfoxide Polymers.

Non-thrombogenic surfaces for extracorporeal membrane oxygenation (ECMO) devices are important to increase their duration of usage and to enable long-term life support. However, the contact of blood with the hydrophobic synthetic ECMO membrane materials such as poly(4-methyl-1-pentene) (PMP) can activate the coagulation cascade, causing thrombosis and a series of consequent complications during ECMO operation. Targeting this problem, we proposed to graft highly hydrophilic sulfoxide polymer brushes onto the PMP surfaces via gamma ray irradiation-initiated polymerization to improve the hemocompatibility of the membrane. Through this chemical modification, the surface of the PMP film is altered from hydrophobic to hydrophilic. The extent of plasma protein adsorption and platelet adhesion, the prerequisite mediators of the coagulation cascade and thrombus formation, are drastically reduced compared with those of the unmodified PMP film. Therefore, the method provides a facile approach to modify PMP materials with excellent antifouling properties and improved hemocompatibility demanded by the applications in ECMO and other blood-contacting medical devices.

Elucidating the Impact of Hydrophilic Segments on 19F MRI Sensitivity of Fluorinated Block Copolymers.

A major challenge in the preparation of polymeric 19F magnetic resonance imaging (MRI) contrast agents (CAs) is signal attenuation caused by reduced segmental mobility of partly fluorinated polymers possessing large numbers of fluorine atoms. Previous studies have thus mainly focused on the development of fluorinated segments for improved 19F MRI; however, detailed investigations of the role of hydrophilic segments on imaging performance remain scarce. In this study, three hydrophilic and biocompatible monomers, i.e., 2-(methylsulfinyl)ethyl acrylate (MSEA), oligo(ethylene glycol) methyl ether acrylate (OEGA), and oligo(2-methyl-2-oxazoline) acrylate (OMOXA), were used to prepare perfluoropolyether (PFPE)-containing amphiphilic block polymers through reversible addition-fragmentation chain-transfer (RAFT) polymerization. The effect of the different hydrophilic segments on 19F imaging performance was explored. The three polymers could be readily dissolved in aqueous solutions, forming assemblies with the hydrophobic PFPE as the core and the hydrophilic chains as the shell. Molecular dynamics simulations demonstrate that the POMOXA chains adopt a rigid, extended conformation, leading to a relatively short 19F NMR spin-spin relaxation time (T2), lower NMR detectable 19F spins (i.e., visibility), and the least intense 19F MRI signal. In contrast, although PMSEA-PFPE has a shorter 19F NMR T2 than POEGA-PFPE, the much higher 19F spin visibility enhances its MRI signal intensity. The result confirms the importance of maintaining both high fluorine visibility and long T2 relaxation time to prepare effective CAs and highlight the key role of the nonfluorinated hydrophilic segments in determining these parameters.

Low-Fouling Gold Nanorod Theranostic Agents Enabled by a Sulfoxide Polymer Coating.

Gold nanorods (GNRs) are widely used in various biomedical applications such as disease imaging and therapy due to their unique plasmonic properties. To improve their bioavailability, GNRs often need to be coated with hydrophilic polymers so as to impart stealth properties. Poly(ethylene glycol) (PEG) has been long used as such a coating material for GNRs. However, there is increasing acknowledgement that the amphiphilic nature of PEG facilitates its interaction with protein molecules, leading to immune recognition and consequent side effects. This has motivated the search for new classes of low-fouling polymers with high hydrophilicity as alternative low-fouling surface coating materials for GNRs. Herein, we report the synthesis, characterization, and application of GNRs coated with highly hydrophilic sulfoxide-containing polymers. We investigated the effect of the sulfoxide polymer coating on the cellular uptake and in vivo circulation time of the GNRs and compared these properties with pegylated GNR counterparts. The photothermal effect and photoacoustic imaging of these polymer-coated GNRs were also explored, and the results show that these GNRs are promising as nanotheranostic particles for the treatment of cancer.

Antifouling and Antibacterial Surfaces Grafted with Sulfur-Containing Copolymers.

Antifouling and antibacterial surfaces that can prevent nonspecific biological adhesion are important to support a myriad of biomedical applications. In this study, we have used an innovative photopolymerization technology to develop sulfur-containing polymer-grafted antifouling and antibacterial surfaces. The relationship between the hydrophilic property and the capability to resist protein and macrophage adsorption of the surface copolymer brushes was investigated. The sulfide monomer incorporated into the surface copolymer brushes can be further ionized to carry positive charges and impart antibacterial activity, leading to surfaces with dual antifouling and antibacterial functions. We believe that the reported sulfur-containing polymer brushes can be considered an emerging and important polymer for antifouling and antibacterial applications.

Ultra-stable all-solid-state sodium metal batteries enabled by perfluoropolyether-based electrolytes.

Rechargeable batteries paired with sodium metal anodes are considered to be one of the most promising high-energy and low-cost energy-storage systems. However, the use of highly reactive sodium metal and the formation of sodium dendrites during battery operation have caused safety concerns, especially when highly flammable liquid electrolytes are used. Here we design and develop solvent-free solid polymer electrolytes (SPEs) based on a perfluoropolyether-terminated polyethylene oxide (PEO)-based block copolymer for safe and stable all-solid-state sodium metal batteries. Compared with traditional PEO SPEs, our results suggest that block copolymer design allows for the formation of self-assembled nanostructures leading to high storage modulus at elevated temperatures with the PEO domains providing transport channels even at high salt concentration (ethylene oxide/sodium = 8/2). Moreover, it is demonstrated that the incorporation of perfluoropolyether segments enhances the Na+ transference number of the electrolyte to 0.46 at 80 °C and enables a stable solid electrolyte interface. The new SPE exhibits highly stable symmetric cell-cycling performance at high current density (0.5 mA cm-2 and 1.0 mAh cm-2, up to 1,000 h). Finally, the assembled all-solid-state sodium metal batteries demonstrate outstanding capacity retention, long-term charge/discharge stability (Coulombic efficiency, 99.91%; >900 cycles with Na3V2(PO4)3 cathode) and good capability with high loading NaFePO4 cathode (>1 mAh cm-2).

Supramolecular Chiral Assembly of Symmetric Molecules with an Extended Conjugated Core.

C3-symmetric molecules carrying a conjugated diacetylene (DA) core are found to self-assemble into well-defined supramolecular fibers with enhanced supramolecular chirality in both organic and aqueous solutions. The conjugated core affords these amphiphiles characteristic fluorescence properties, which can be quenched partially due to the aggregation. Integration of the C3-symmetry with the conjugation provides these novel molecules strong aggregation tendency through solvent-mediated π-π stacking with preferential supramolecular chirality, which is predominately related to steric hindrance from their dipeptide pendants. Highly uniform supramolecular fibers of P and M handedness with thickness consistent in the dimensions of individual C3 molecules are obtained. The increase of concentrations induces these fibers to wrap together to form supramolecular fibrous bundles. Topochemical polymerization of the DA moieties can transform these supramolecular fibers into stable covalent polymers. We therefore believe that self-assembly of these C3-symmetric molecules with extended conjugated DA cores provides new prospects for the construction of supramolecular helical fibers through enhanced π-π stacking and creates a convenient strategy to furnish covalent chiral polymers of hierarchical structures through supramolecular assembly.

Investigation of heparin-loaded poly(ethylene glycol)-based hydrogels as anti-thrombogenic surface coatings for extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO), a critical life-sustaining tool, faces significant challenges for the maintenance of normal haemostasis due to the large volume of circulating blood continuously in contact with artificial surfaces, hyperoxia and excessive shear stresses of the extracorporeal circuit. From a biomaterials perspective, it has been hypothesised that drug eluting coatings composed of haemocompatible hydrogels loaded with an anticoagulant drug could potentially enhance the haemocompatibility of the circuit. Poly(ethylene glycol) (PEG) has been well established as a biocompatible and anti-fouling material with wide biomedical application. Unfractionated heparin is the most commonly used anticoagulant for ECMO. In the present study, the feasibility of using heparin-loaded PEG-based hydrogels as anti-thrombogenic surface coatings for ECMO was investigated. The hydrogels were synthesised by photopolymerisation using poly(ethylene glycol) diacrylate (PEGDA) as the crosslinking monomer and poly(ethylene glycol) methacrylate (PEGMA) as the hydrophilic monomer, with heparin loaded into the pre-gel solution. Factors which could affect the release of heparin were investigated, including the ratio of PEGDA/PEGMA, water content, loading level of heparin and the flow of fluid past the hydrogel. Our results showed that increased crosslinker content and decreased water content led to slower heparin release. The hydrogels with water contents of 60 wt% and 70 wt% could achieve a sustained heparin release by adjusting the ratio of PEGDA/PEGMA. The anticoagulation efficacy of the released heparin was evaluated by measuring the activated clotting time of whole blood. The hydrogels with desirable heparin release profiles were prepared onto poly(4-methyl-1-pentene) (PMP) films with the same chemical composition as the PMP ECMO membranes. The coatings showed sustained heparin release with a cumulative release of 70-80% after 7 days. Haemocompatibility tests demonstrated that PEG hydrogel coatings significantly reduced platelet adhesion and prolonged plasma recalcification time. These results suggest that heparin-loaded PEG hydrogels are potential anti-thrombogenic coatings for ECMO.

Liposomes are Poorly Absorbed via Lung Lymph After Inhaled Administration in Sheep.

Enhancing the delivery of therapeutic agents to the lung lymph, including drugs, transfection agents, vaccine antigens and vectors, has the potential to significantly improve the treatment and prevention of a range of lung-related illnesses. One way in which lymphatic delivery can be optimized is via the use of nanomaterial-based carriers, such as liposomes. After inhaled delivery however, there is conflicting information in the literature regarding whether nanomaterials can sufficiently access the lung lymphatics to have a therapeutic benefit, in large part due to a lack of reliable quantitative pharmacokinetic data. The aim of this work was to quantitatively evaluate the pulmonary lymphatic pharmacokinetics of a model nanomaterial-based drug delivery system (HSPC liposomes) in caudal mediastinal lymph duct cannulated sheep after nebulized administration to the lungs. Liposomes were labelled with 3H-phosphatidylcholine to facilitate evaluation of pharmacokinetics and biodistribution in biological samples. While nanomaterials administered to the lungs may access the lymphatics via direct absorption from the airways or after initial uptake by alveolar macrophages, only 0.3 and 0.001% of the 3H-lipid dose was recovered in lung lymph fluid and lymph cell pellets (containing immune cells) respectively over 5 days. This suggests limited lymphatic access of liposomes, despite apparent pulmonary bioavailability of the 3H-lipid being approximately 17%, likely a result of absorption of liberated 3H-lipid after breakdown of the liposome in the presence of lung surfactant. Similarly, biodistribution of 3H in the mediastinal lymph node was insignificant after 5 days. These data suggest that liposomes, that are normally absorbed via the lymphatics after interstitial administration, do not access the lung lymphatics after inhaled administration. Alternate approaches to maximize the lung lymphatic delivery of drugs and other therapeutics need to be identified.