Chemical and Biomedical Engineering - Research Publications
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ItemUnderstanding the Uptake of Nanomedicines at Different Stages of Brain Cancer Using a Modular Nanocarrier Platform and Precision Bispecific Antibodies(American Chemical Society (ACS), 2020-05-27)Increasing accumulation and retention of nanomedicines within tumor tissue is a significant challenge, particularly in the case of brain tumors where access to the tumor through the vasculature is restricted by the blood–brain barrier (BBB). This makes the application of nanomedicines in neuro-oncology often considered unfeasible, with efficacy limited to regions of significant disease progression and compromised BBB. However, little is understood about how the evolving tumor–brain physiology during disease progression affects the permeability and retention of designer nanomedicines. We report here the development of a modular nanomedicine platform that, when used in conjunction with a unique model of how tumorigenesis affects BBB integrity, allows investigation of how nanomaterial properties affect uptake and retention in brain tissue. By combining different in vivo longitudinal imaging techniques (including positron emission tomography and magnetic resonance imaging), we have evaluated the retention of nanomedicines with predefined physicochemical properties (size and surface functionality) and established a relationship between structure and tissue accumulation as a function of a new parameter that measures BBB leakiness; this offers significant advancements in our ability to relate tumor accumulation of nanomedicines to more physiologically relevant parameters. Our data show that accumulation of nanomedicines in brain tumor tissue is better correlated with the leakiness of the BBB than actual tumor volume. This was evaluated by establishing brain tumors using a spontaneous and endogenously derived glioblastoma model providing a unique opportunity to assess these parameters individually and compare the results across multiple mice. We also quantitatively demonstrate that smaller nanomedicines (20 nm) can indeed cross the BBB and accumulate in tumors at earlier stages of the disease than larger analogues, therefore opening the possibility of developing patient-specific nanoparticle treatment interventions in earlier stages of the disease. Importantly, these results provide a more predictive approach for designing efficacious personalized nanomedicines based on a particular patient’s condition.
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ItemInjectable and Sprayable Polyphenol-Based Hydrogels for Controlling Hemostasis(American Chemical Society, 2020-02-17)Injectable and sprayable hydrogels have attracted considerable attention for application in the biomedical field owing to their high moldability and efficiency in encapsulating therapeutics and cells. Herein, we report the spontaneous assembly of injectable and sprayable hydrogels via a one-step mixing of solutions of tannic acid (TA) and O-carboxymethyl chitosan (CMCS) without an external stimulus. The presence of 1,4-benzenediboronic acid (BDBA) improves the mechanical properties and reduces the gelation time of the resulting hydrogels. The hydrogels assemble via hydrogen bonds between TA and CMCS as well as via dynamic boronate ester bonds between TA and BDBA, as confirmed by Fourier transform infrared spectroscopy. Balancing the interactions between the three components (CMCS/TA/BDBA) is essential for the construction of the hydrogels. The moduli of the CMCS-TA-BDBA hydrogels initially increase as the amount of BDBA increases and decrease after reaching a maximum value at a BDBA-to-TA molar ratio of 3:1. The CMCS-TA-BDBA hydrogels with interconnected porous morphologies display rapid gelation (∼10 s), biocompatibility, self-healing, injectable, and sprayable abilities. In addition, the hydrogels can be used for hemostasis. The extent of bleeding in mouse livers treated with the hydrogels could be reduced extensively from 240 (nontreated mouse livers) to 55 mg (77% reduction). The reported hydrogels coupled with the combination of functionality and biological activity make them promising hemostatic materials for biomedical applications.
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ItemNanoengineering of Poly(ethylene glycol) Particles for Stealth and Targeting(AMER CHEMICAL SOC, 2018-09-18)The assembly of particles composed solely or mainly of poly(ethylene glycol) (PEG) is an emerging area that is gaining increasing interest within bio-nano science. PEG, widely considered to be the "gold standard" among polymers for drug delivery, is providing a platform for exploring fundamental questions and phenomena at the interface between particle engineering and biomedicine. These include the targeting and stealth behaviors of synthetic nanomaterials in biological environments. In this feature article, we discuss recent work in the nanoengineering of PEG particles and explore how they are enabling improved targeting and stealth performance. Specific examples include PEG particles prepared through surface-initiated polymerization, mesoporous silica replication via postinfiltration, and particle assembly through metal-phenolic coordination. This particle class exhibits unique in vivo behavior (e.g., biodistribution and immune cell interactions) and has recently been explored for drug delivery applications.
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ItemLigand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.(American Chemical Society, 2019)Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.
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ItemCellular Targeting of Bispecific Antibody-Functionalized Poly(ethylene glycol) Capsules: Do Shape and Size Matter?(American Chemical Society, 2019-08-01)In the present study, a capsule system that consists of a stealth carrier based on poly(ethylene glycol) (PEG) and functionalized with bispecific antibodies (BsAbs) is introduced to examine the influence of the capsule shape and size on cellular targeting. Hollow spherical and rod-shaped PEG capsules with tunable aspect ratios (ARs) of 1, 7, and 18 were synthesized and subsequently functionalized with BsAbs that exhibit dual specificities to PEG and epidermal growth factor receptor (EGFR). Dosimetry (variation between the concentrations of capsules present and capsules that reach the cell surface) was controlled through "dynamic" incubation (i.e., continuously mixing the incubation medium). The results obtained were compared with those obtained from the "static" incubation experiments. Regardless of the incubation method and the capsule shape and size studied, BsAb-functionalized PEG capsules showed >90% specific cellular association to EGFR-positive human breast cancer cells MDA-MB-468 and negligible association with both control cell lines (EGFR negative Chinese hamster ovary cells CHO-K1 and murine macrophages RAW 264.7) after incubation for 5 h. When dosimetry was controlled and the dose concentration was normalized to the capsule surface area, the size or shape had a minimal influence on the cell association behavior of the capsules. However, different cellular internalization behaviors were observed, and the capsules with ARs 7 and 18 were, respectively, the least and most optimal shape for achieving high cell internalization under both dynamic and static conditions. Dynamic incubation showed a greater impact on the internalization of rod-shaped capsules (∼58-67% change) than on the spherical capsules (∼24-29% change). The BsAb-functionalized PEG capsules reported provide a versatile particle platform for the evaluation and comparison of cellular targeting performance of capsules with different sizes and shapes in vitro.
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ItemModulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies(WILEY, 2019-05)Low-fouling or "stealth" particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG-BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs-one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)-is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.
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ItemLow-Fouling and Biodegradable Protein-Based Particles for Thrombus Imaging(AMER CHEMICAL SOC, 2018-07)Nanomedicine holds great promise for vascular disease diagnosis and specific therapy, yet rapid sequestration by the mononuclear phagocytic system limits the efficacy of particle-based agents. The use of low-fouling polymers, such as poly(ethylene glycol), efficiently reduces this immune recognition, but these nondegradable polymers can accumulate in the human body and may cause adverse effects after prolonged use. Thus, new particle formulations combining stealth, low immunogenicity and biocompatible features are required to enable clinical use. Here, a low-fouling particle platform is described using exclusively protein material. A recombinant protein with superior hydrophilic characteristics provided by the amino acid repeat proline, alanine, and serine (PAS) is designed and cross-linked into particles with lysine (K) and polyglutamic acid (E) using mesoporous silica templating. The obtained PASKE particles have low-fouling behavior, have a prolonged circulation time compared to albumin-based particles, and are rapidly degraded in the cell's lysosomal compartment. When labeled with near-infrared fluorescent molecules and functionalized with an anti-glycoprotein IIb/IIIa single-chain antibody targeting activated platelets, the particles show potential as a noninvasive molecular imaging tool in a mouse model of carotid artery thrombosis. The PASKE particles constitute a promising biodegradable and versatile platform for molecular imaging of vascular diseases.
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ItemNo Preview AvailableRole of the Protein Corona Derived from Human Plasma in Cellular Interactions between Nanoporous Human Serum Albumin Particles and Endothelial Cells(AMER CHEMICAL SOC, 2017-08)The presence of a protein corona on various synthetic nanomaterials has been shown to strongly influence how they interact with cells. However, it is unclear if the protein corona also exists on protein particles, and if so, its role in particle-cell interactions. In this study, pure human serum albumin (HSA) particles were fabricated via mesoporous silica particle templating. Our data reveal that various serum proteins adsorbed on the particles, when exposed to human blood plasma, forming a corona. In human umbilical vein endothelial cells (HUVECs), the corona was shown to decrease particle binding to the cell membrane, increase the residence time of particles in early endosomes, and reduce the amount of internalized particles within the first hours of exposure to particles. These findings reveal important information regarding the mechanisms used by vascular endothelial cells to internalize protein-based particulate materials exposed to blood plasma. The ability to control the cellular recognition of these organic particles is expected to aid the advancement of HSA-based materials for intravenous drug delivery.
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ItemOne-Step Assembly of Coordination Complexes for Versatile Film and Particle Engineering(AMER ASSOC ADVANCEMENT SCIENCE, 2013-07-12)The development of facile and versatile strategies for thin-film and particle engineering is of immense scientific interest. However, few methods can conformally coat substrates of different composition, size, shape, and structure. We report the one-step coating of various interfaces using coordination complexes of natural polyphenols and Fe(III) ions. Film formation is initiated by the adsorption of the polyphenol and directed by pH-dependent, multivalent coordination bonding. Aqueous deposition is performed on a range of planar as well as inorganic, organic, and biological particle templates, demonstrating an extremely rapid technique for producing structurally diverse, thin films and capsules that can disassemble. The ease, low cost, and scalability of the assembly process, combined with pH responsiveness and negligible cytotoxicity, makes these films potential candidates for biomedical and environmental applications.
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ItemTuning the Mechanical Properties of Nanoporous Hydrogel Particles via Polymer Cross-Linking(AMER CHEMICAL SOC, 2013-08-06)Soft hydrogel particles with tunable mechanical properties are promising for next-generation therapeutic applications. This is due to the increasingly proven role that physicochemical properties play in particulate-based delivery vectors, both in vitro and in vivo. The ability to understand and quantify the mechanical properties of such systems is therefore essential to optimize function and performance. We report control over the mechanical properties of poly(methacrylic acid) (PMA) hydrogel particles based on a mesoporous silica templating method. The mechanical properties of the obtained particles can be finely tuned through variation of the cross-linker concentration, which is hereby quantified using a cross-linking polymer with a fluorescent tag. We demonstrate that the mechanical properties of the particles can be elucidated using an atomic force microscopy (AFM) force spectroscopy method, which additionally allows for the study of hydrogel material properties at the nanoscale through high-resolution force mapping. Young's modulus and stiffness of the particles were tuned between 0.04 and 2.53 MPa and between 1.6 and 28.4 mN m(-1), respectively, through control over the cross-linker concentration. The relationship between the concentration of the cross-linker added and the amount of adsorbed polymer was observed to follow a Langmuir isotherm, and this relationship was found to correlate linearly with the particle mechanical properties.