219 research outputs found
Polymer-nanoparticle interactions in supramolecular hydrogels: Enabling long- term antibody delivery
Antibody drugs are a rapidly growing set of therapeutics that increasingly prove effective for clinical applications spanning from macular degeneration treatments, to targeted cancer therapies, and to passive immunization. These antibody treatments can be engineered to target almost any cell surface moiety and their production has since been scaled to an industrial level. Despite these advances, parenteral administration of antibodies is severely constrained by high viscosities at desirable doses, poor long-term antibody stability, high required frequency of administration, and therapeutically suboptimal pharmacokinetics. Herein, we demonstrate the development of supramolecular polymer-nanoparticle (PNP) interactions between poly(ethylene glycol)-poly(lactic acid) block copolymer nanoparticles (PEG-PLA) and modified hydroxypropylmethylcellulose (HPMC-x) polymers to engineer shear-thinning, self-healing hydrogels capable of stabilizing and delivering high concentrations of antibodies over prolonged timeframes (Figure 1). The PNP interactions underpinning the behavior of these materials afford injectability and tunable mechanical properties, while also controlling antibody release kinetics. In this work, we investigate how the thermodynamics of the PNP interaction affect in vitro and in vivo antibody release kinetics, pharmacokinetics, and bioavailability. Analysis of PEG-PLA surface density, HPMC-x hydrophobicity and modification extent, and hydrogel formulation reveal explicit design handles relating PNP thermodynamics to in vivo antibody release kinetics via subcutaneous injection. Differences in antibody release kinetics between in vitro and in vivo experiments were examined through mathematical modelling, revealing possible mechanisms of antibody uptake from subcutaneous space to the bloodstream when compared to literature. Overall, this work presents a robust set of design parameters to tune PNP interactions to develop a new nanotechnology-based platform for long-term, controlled antibody delivery.
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Towards brain-tissue-like biomaterials
Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered
Biomimetic non-ergodic aging by dynamic-to-covalent transitions in physical hydrogels
Hydrogels are soft materials engineered to suit a multitude of applications
that exploit their tunable mechanochemical properties. Dynamic hydrogels
employing noncovalent, physically crosslinked networks dominated by either
enthalpic or entropic interactions enable unique rheological and
stimuli-responsive characteristics. In contrast to enthalpy-driven interactions
that soften with increasing temperature, entropic interactions result in
largely temperature-independent mechanical properties. By engineering
interfacial polymer-particle interactions, we can induce a dynamic-to-covalent
transition in entropic hydrogels that leads to biomimetic non-ergodic aging in
the microstructure without altering the network mesh size. This transition is
tuned by varying temperature and formulation conditions such as H, which
allows for multivalent tunability in properties. These hydrogels can thus be
designed to exhibit either temperature-independent metastable dynamic
crosslinking or time-dependent stiffening based on formulation and storage
conditions, all while maintaining strucutural features critical for controlling
mass transport, akin to many biological tissues. Such robust materials with
versatile and adaptable properties can be utilized in applications such as
wildfire suppression, surgical adhesives, and depot-forming injectable drug
delivery systems.Comment: 23 pages, 12 figure
Self-assembled hydrogels utilizing polymer–nanoparticle interactions
Mouldable hydrogels that flow on applied stress and rapidly self-heal are increasingly utilized as they afford minimally invasive delivery and conformal application. Here we report a new paradigm for the fabrication of self-assembled hydrogels with shear-thinning and self-healing properties employing rationally engineered polymer–nanoparticle (NP) interactions. Biopolymer derivatives are linked together by selective adsorption to NPs. The transient and reversible interactions between biopolymers and NPs enable flow under applied shear stress, followed by rapid self-healing when the stress is relaxed. We develop a physical description of polymer–NP gel formation that is utilized to design biocompatible gels for drug delivery. Owing to the hierarchical structure of the gel, both hydrophilic and hydrophobic drugs can be entrapped and delivered with differential release profiles, both in vitro and in vivo. The work introduces a facile and generalizable class of mouldable hydrogels amenable to a range of biomedical and industrial applications.Wellcome Trust-MIT Postdoctoral FellowshipMisrock Foundation (Cancer Nanotechnology Postdoctoral Fellowship)United States. Dept. of Defense. Congressionally Directed Medical Research Programs (Postdoctoral Fellowship Award W81XWH-13-1-0215)National Institutes of Health (U.S.) (NIH-R01 DE016516
Synthesis of Conducting Polymer-Metal Nanoparticle Hybrids Exploiting RAFT Polymerization.
The direct covalent attachment of conducting polymers (CP) to nanoparticles (NP) to form CP-NP nanohybrids is of great interest for optoelectronic device applications. Hybrids formed by covalently anchoring CP to NP, rather than traditional blending or bilayer approaches, is highly desirable. CP-NP nanohybrids have increased interfacial surface area between the two components, facilitating rapid exciton diffusion at the p-n heterojunction. These materials take advantage of the facile solution processability, lightweight characteristics, flexibility, and mechanical strength associated with CPs, and the broad spectral absorption, photostability, and high charge carrier mobility of NPs. We demonstrate the ability to polymerize a hole transporting (HT) polymer utilizing reversible-addition-fragmentation chain transfer (RAFT) polymerization and its subsequent rapid aminolysis to yield a thiol-terminated HT polymer. Subsequent facile attachment to gold (Au) and silver (Ag) NPs and cadmium selenide (CdSe) quantum dots (QDs), to form a number of CP-NP systems is demonstrated and characterized. CP-NP nanohybrids show broad spectral absorptions ranging from UV through visible to the near IR, and their facile synthesis and purification could allow for large scale industrial applications.P.E.W. and S.T.J. contributed equally to this
work. E.A.A. thanks Schlumberger for financial support. This work
was supported in part by Atomic Weapons Establishment (AWE),
the Walters-Kundert foundation, and an ERC Starting Investigator
grant (ASPiRe, 240629).This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/mz500645c
Towards brain-tissue-like biomaterials
Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered
A Multiscale Model for Solute Diffusion in Hydrogels.
The number of biomedical applications of hydrogels is increasing rapidly on account of their unique physical, structural, and mechanical properties. The utility of hydrogels as drug delivery systems or tissue engineering scaffolds critically depends on the control of diffusion of solutes through the hydrogel matrix. Predicting or even modeling this diffusion is challenging due to the complex structure of hydrogels. Currently, the diffusivity of solutes in hydrogels is typically modeled by one of three main theories proceeding from distinct diffusion mechanisms: (i) hydrodynamic, (ii) free volume, and (iii) obstruction theory. Yet, a comprehensive predictive model is lacking. Thus, time and capital-intensive trial-and-error procedures are used to test the viability of hydrogel applications. In this work, we have developed a model for the diffusivity of solutes in hydrogels combining the three main theoretical frameworks, which we call the multiscale diffusion model (MSDM). We verified the MSDM by analyzing the diffusivity of dextran of different sizes in a series of poly(ethylene glycol) (PEG) hydrogels with distinct mesh sizes. We measured the subnanoscopic free volume by positron annihilation lifetime spectroscopy (PALS) to characterize the physical hierarchy of these materials. In addition, we performed a meta-analysis of literature data from previous studies on the diffusion of solutes in hydrogels. The model presented outperforms traditional models in predicting solute diffusivity in hydrogels and provides a practical approach to predicting the transport properties of solutes such as drugs through hydrogels used in many biomedical applications
Decoupled Associative and Dissociative Processes in Strong yet Highly Dynamic Host-Guest Complexes.
Kinetics and thermodynamics in supramolecular systems are intimately linked, yet both are independently important for application in sensing assays and stimuli-responsive switching/self-healing of materials. Host-guest interactions are of particular interest in many water-based materials, sensing, and drug delivery applications. Herein we investigate the binding dynamics of a variety of electron-rich aromatic moieties forming hetero-ternary complexes with the macrocycle cucurbit[8]uril (CB[8]) and an auxiliary guest, dimethyl viologen, with high selectivity and equilibrium binding constants (Keq up to 1014 M-2). Using stopped-flow spectrofluorimetry, association rate constants were observed to approach the diffusion limit and were found to be insensitive to the structure of the guest. Conversely, the dissociation rate constants of the ternary complexes varied dramatically with the guest structure and were correlated with the thermodynamic binding selectivity. Hence differing molecular features were found to contribute to the associative and dissociative processes, mimicking naturally occurring reactions and giving rise to a decoupling of these kinetic parameters. Moreover, we demonstrate the ability to exploit these phenomena and selectively perturb the associative process with external stimuli (e.g., viscosity and pressure). Significantly, these complexes exhibit increased binding equilibria with increasing pressure, with important implications for the application of the CB[8] ternary complex for the formation of hydrogels, as these gels exhibit unprecedented pressure-insensitive rheological properties. A high degree of flexibility therefore exists in the design of host-guest systems with tunable kinetic and thermodynamic parameters for tailor-made applications across a broad range of fields
Imaging of poly(α-hydroxy-ester) scaffolds with X-ray phase-contrast microcomputed tomography
Porous scaffolds based on poly(α-hydroxy-esters) are under investigation in many tissue engineering applications. A biological response to these materials is driven, in part, by their three-dimensional (3D) structure. The ability to evaluate quantitatively the material structure in tissue-engineering applications is important for the continued development of these polymer-based approaches. X-ray imaging techniques based on phase contrast (PC) have shown a tremendous promise for a number of biomedical applications owing to their ability to provide a contrast based on alternative X-ray properties (refraction and scatter) in addition to X-ray absorption. In this research, poly(α-hydroxy-ester) scaffolds were synthesized and imaged by X-ray PC microcomputed tomography. The 3D images depicting the X-ray attenuation and phase-shifting properties were reconstructed from the measurement data. The scaffold structure could be imaged by X-ray PC in both cell culture conditions and within the tissue. The 3D images allowed for quantification of scaffold properties and automatic segmentation of scaffolds from the surrounding hard and soft tissues. These results provide evidence of the significant potential of techniques based on X-ray PC for imaging polymer scaffolds
Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis
BACKGROUND AND OBJECTIVES: In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.
METHODS: Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 10
RESULTS: The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of -2.7 points per the ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of -10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.
DISCUSSION: Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS
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