Chemical and Biomolecular Engineering - Research Publications

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    Engineering Poly(ethylene glycol) Nanoparticles for Accelerated Blood Clearance Inhibition and Targeted Drug Delivery
    Tian, Y ; Gao, Z ; Wang, N ; Hu, M ; Ju, Y ; Li, Q ; Caruso, F ; Hao, J ; Cui, J (AMER CHEMICAL SOC, 2022-10-12)
    Surface modification with poly(ethylene glycol) (PEGylation) is an effective strategy to improve the colloidal stability of nanoparticles (NPs) and is often used to minimize cellular uptake and clearance of NPs by the immune system. However, PEGylation can also trigger the accelerated blood clearance (ABC) phenomenon, which is known to reduce the circulation time of PEGylated NPs. Herein, we report the engineering of stealth PEG NPs that can avoid the ABC phenomenon and, when modified with hyaluronic acid (HA), show specific cancer cell targeting and drug delivery. PEG NPs cross-linked with disulfide bonds are prepared by using zeolitic imidazolate framework-8 NPs as templates. The reported templating strategy enables the simultaneous removal of the template and formation of PEG NPs under mild conditions (pH 5.5 buffer). Compared to PEGylated liposomes, PEG NPs avoid the secretion of anti-PEG antibodies and the presence of anti-PEG IgM and IgG did not significantly accelerate the blood clearance of PEG NPs, indicating the inhibition of the ABC effect for the PEG NPs. Functionalization of the PEG NPs with HA affords PEG NPs that retain their stealth properties against macrophages, target CD44-expressed cancer cells and, when loaded with the anticancer drug doxorubicin, effectively inhibit tumor growth. The innovation of this study lies in the engineering of PEG NPs that can circumvent the ABC phenomenon and that can be functionalized for the improved and targeted delivery of drugs.
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    Polyphenol-Functionalized Cubosomes as Thrombolytic Drug Carriers
    Yu, H ; Palazzolo, JS ; Ju, Y ; Niego, B ; Pan, S ; Hagemeyer, CE ; Caruso, F (WILEY, 2022-11)
    The safe administration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid-based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes are examined as nanocarriers for the encapsulation of thrombolytic drugs. The lipid cubosomes are loaded with the thrombolytic drug urokinase-type plasminogen activator (uPA) and coated with a low-fouling peptide that is incorporated within a metal-phenolic network (MPN). The peptide-containing MPN (pep-MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep-MPN-coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane-dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA-loaded pep-MPN-coated cubosomes demonstrate significantly reduced nonspecific cell association (<10% of the uncoated cubosomes) in the whole blood assay, a prolonged circulating half-life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane-dependent release of uPA within pep-MPN-coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs.
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    Influence of protein corona on the interaction of glycogen-siRNA constructs with ex vivo human blood immune cells
    Wojnilowicz, M ; Laznickova, P ; Ju, Y ; Ang, C-S ; Tidu, F ; Bendickova, K ; Forte, G ; Plebanski, M ; Caruso, F ; Cavalieri, F ; Fric, J (ELSEVIER, 2022-09)
    Glycogen-nucleic acid constructs i.e., glycoplexes are emerging promising platforms for the alteration of gene expression and transcription. Understanding the interaction of glycoplexes with human blood components, such as serum proteins and peripheral blood mononuclear cells (PBMCs), is important to overcome immune cell activation and control biodistribution upon administration of the glycoplexes in vivo. Herein, we investigated the interactions of polyethylene glycol (PEG)ylated and non-PEGylated glycoplexes carrying siRNA molecules with PBMCs isolated from the blood of healthy donors. We found that both types of glycoplexes were non-toxic and were primarily phagocytosed by monocytes without triggering a pro-inflammatory interleukin 6 cytokine production. Furthermore, we investigated the role of the protein corona on controlling the internalization efficiency in immune cells - we found that the adsorption of serum proteins, in particular haptoglobin, alpha-1-antitrypsin and apolipoprotein A-II, onto the non-PEGylated glycoplexes, significantly reduced the uptake of the glycoplexes by PBMCs. Moreover, the non-PEGylated glycoplexes were efficient in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) knockdown in monocytic THP-1 cell line. This study provides an insight into the rational design of glycogen-based nanocarriers for the safe delivery of siRNA without eliciting unwanted immune cell activation and efficient siRNA activity upon its delivery.
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    Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine
    Ju, Y ; Lee, WS ; Pilkington, EH ; Kelly, HG ; Li, S ; Selva, KJ ; Wragg, KM ; Subbarao, K ; Nguyen, THO ; Rowntree, LC ; Allen, LF ; Bond, K ; Williamson, DA ; Truong, NP ; Plebanski, M ; Kedzierska, K ; Mahanty, S ; Chung, AW ; Caruso, F ; Wheatley, AK ; Juno, JA ; Kent, SJ (AMER CHEMICAL SOC, 2022-08-23)
    Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle (LNP) mRNA vaccines for SARS-CoV-2 contain small amounts of PEG, but it is not known whether PEG antibodies are enhanced by vaccination and what their impact is on particle-immune cell interactions in human blood. We studied plasma from 130 adults receiving either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) mRNA vaccines or no SARS-CoV-2 vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was significantly boosted a mean of 13.1-fold (range 1.0-70.9) following mRNA-1273 vaccination and a mean of 1.78-fold (range 0.68-16.6) following BNT162b2 vaccination. Anti-PEG IgM increased 68.5-fold (range 0.9-377.1) and 2.64-fold (0.76-12.84) following mRNA-1273 and BNT162b2 vaccination, respectively. The rise in PEG-specific antibodies following mRNA-1273 vaccination was associated with a significant increase in the association of clinically relevant PEGylated LNPs with blood phagocytes ex vivo. PEG antibodies did not impact the SARS-CoV-2 specific neutralizing antibody response to vaccination. However, the elevated levels of vaccine-induced anti-PEG antibodies correlated with increased systemic reactogenicity following two doses of vaccination. We conclude that PEG-specific antibodies can be boosted by LNP mRNA vaccination and that the rise in PEG-specific antibodies is associated with systemic reactogenicity and an increase of PEG particle-leukocyte association in human blood. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA vaccines should be monitored. It may be useful to identify suitable alternatives to PEG for developing next-generation LNP vaccines to overcome PEG immunogenicity in the future.
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    Protein precoating modulates biomolecular coronas and nanocapsule-immune cell interactions in human blood
    Li, S ; Ju, Y ; Zhou, J ; Faria, M ; Ang, C-S ; Mitchell, AJ ; Zhong, Q-Z ; Zheng, T ; Kent, SJ ; Caruso, F (ROYAL SOC CHEMISTRY, 2022-09-28)
    The biomolecular corona that forms on particles upon contact with blood plays a key role in the fate and utility of nanomedicines. Recent studies have shown that precoating nanoparticles with serum proteins can improve the biocompatibility and stealth properties of nanoparticles. However, it is not fully clear how precoating influences biomolecular corona formation and downstream biological responses. Herein, we systematically examine three precoating strategies by coating bovine serum albumin (single protein), fetal bovine serum (FBS, mixed proteins without immunoglobulins), or bovine serum (mixed proteins) on three nanoparticle systems, namely supramolecular template nanoparticles, metal-phenolic network (MPN)-coated template (core-shell) nanoparticles, and MPN nanocapsules (obtained after template removal). The effect of protein precoating on biomolecular corona compositions and particle-immune cell interactions in human blood was characterized. In the absence of a pre-coating, the MPN nanocapsules displayed lower leukocyte association, which correlated to the lower amount (by 2-3 fold) of adsorbed proteins and substantially fewer immunoglobulins (more than 100 times) in the biomolecular corona relative to the template and core-shell nanoparticles. Among the three coating strategies, FBS precoating demonstrated the most significant reduction in leukocyte association (up to 97% of all three nanoparticles). A correlation analysis highlights that immunoglobulins and apolipoproteins may regulate leukocyte recognition. This study demonstrates the impact of different precoating strategies on nanoparticle-immune cell association and the role of immunoglobulins in bio-nano interactions.
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    Nanostructured particles assembled from natural building blocks for advanced therapies
    Ju, Y ; Liao, H ; Richardson, JJ ; Guo, J ; Caruso, F (ROYAL SOC CHEMISTRY, 2022-06-06)
    Advanced treatments based on immune system manipulation, gene transcription and regulation, specific organ and cell targeting, and/or photon energy conversion have emerged as promising therapeutic strategies against a range of challenging diseases. Naturally derived macromolecules (e.g., proteins, lipids, polysaccharides, and polyphenols) have increasingly found use as fundamental building blocks for nanostructured particles as their advantageous properties, including biocompatibility, biodegradability, inherent bioactivity, and diverse chemical properties make them suitable for advanced therapeutic applications. This review provides a timely and comprehensive summary of the use of a broad range of natural building blocks in the rapidly developing field of advanced therapeutics with insights specific to nanostructured particles. We focus on an up-to-date overview of the assembly of nanostructured particles using natural building blocks and summarize their key scientific and preclinical milestones for advanced therapies, including adoptive cell therapy, immunotherapy, gene therapy, active targeted drug delivery, photoacoustic therapy and imaging, photothermal therapy, and combinational therapy. A cross-comparison of the advantages and disadvantages of different natural building blocks are highlighted to elucidate the key design principles for such bio-derived nanoparticles toward improving their performance and adoption. Current challenges and future research directions are also discussed, which will accelerate our understanding of designing, engineering, and applying nanostructured particles for advanced therapies.
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    Template-Assisted Antibody Assembly: A Versatile Approach for Engineering Functional Antibody Nanoparticles
    Hu, Y ; Li, J ; Ju, Y ; Houston, ZH ; Fletcher, NL ; De Rose, R ; Fernandes, S ; Hagemeyer, CE ; Alt, K ; Thurecht, KJ ; Cortez-Jugo, C ; Caruso, F (American Chemical Society, 2022-04-26)
    The clinical success of monoclonal antibody therapy has inspired research in understanding the fundamental molecular basis of antibody-antigen interactions and the engineering of antibodies and antibody assemblies with enhanced or novel properties. In particular, colloidally stable antibody assemblies can enhance dosing strategies and enable combined therapy of a mixture of antibodies or biologics. Herein, nanoassemblies of therapeutic antibodies were fabricated with controlled physicochemical properties using a versatile template-mediated assembly method. The antibody nanoparticles (AbNPs) cross-linked with poly(ethylene glycol)-N-hydroxysuccinimide were monodispersed, with particle diameters consistent with the template size (250 nm). When assembled using Herceptin or Kadcyla as a model antibody and antibody-drug conjugate, respectively, the nanoparticles retained the selectivity of the monoclonal antibody and recognized >98% of cells expressing the target receptors on cell membranes. Unlike the free Herceptin antibody, which was predominantly localized at the surface, the AbNPs were internalized via receptor-mediated endocytosis, presenting opportunities for delivering monoclonal antibodies intracellularly at high concentrations and/or against intracellular targets. With the vast array of antibodies that could be applied and different cross-linking chemistries possible, the reported antibody assembly strategy provides a versatile platform for the development of antibody assemblies for therapeutic, diagnostic, and clinical applications.
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    Bioresponsive Polyphenol-Based Nanoparticles as Thrombolytic Drug Carriers
    Yu, H ; Palazzolo, JS ; Zhou, J ; Hu, Y ; Niego, B ; Pan, S ; Ju, Y ; Wang, T-Y ; Lin, Z ; Hagemeyer, CE ; Caruso, F (AMER CHEMICAL SOC, 2022-01-12)
    Thrombolytic (clot-busting) therapies with plasminogen activators (PAs) are first-line treatments against acute thrombosis and ischemic stroke. However, limitations such as narrow therapeutic windows, low success rates, and bleeding complications hinder their clinical use. Drug-loaded polyphenol-based nanoparticles (NPs) could address these shortfalls by delivering a more targeted and safer thrombolysis, coupled with advantages such as improved biocompatibility and higher stability in vivo. Herein, a template-mediated polyphenol-based supramolecular assembly strategy is used to prepare nanocarriers of thrombolytic drugs. A thrombin-dependent drug release mechanism is integrated using tannic acid (TA) to cross-link urokinase-type PA (uPA) and a thrombin-cleavable peptide on a sacrificial mesoporous silica template via noncovalent interactions. Following drug loading and template removal, the resulting NPs retain active uPA and demonstrate enhanced plasminogen activation in the presence of thrombin (1.14-fold; p < 0.05). Additionally, they display lower association with macrophage (RAW 264.7) and monocytic (THP-1) cell lines (43 and 7% reduction, respectively), reduced hepatic accumulation, and delayed blood clearance in vivo (90% clearance at 60 min vs 5 min) compared with the template-containing NPs. Our thrombin-responsive, polyphenol-based NPs represent a promising platform for advanced drug delivery applications, with potential to improve thrombolytic therapies.
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    Macromolecular Engineering of Thermoresponsive Metal-Phenolic Networks
    Kim, C-J ; Ercole, F ; Chen, J ; Pan, S ; Ju, Y ; Quinn, JF ; Caruso, F (AMER CHEMICAL SOC, 2022-01-01)
    Dynamic nanostructured materials that can react to physical and chemical stimuli have attracted interest in the biomedical and materials science fields. Metal-phenolic networks (MPNs) represent a modular class of such materials: these networks form via coordination of phenolic molecules with metal ions and can be used for surface and particle engineering. To broaden the range of accessible MPN properties, we report the fabrication of thermoresponsive MPN capsules using FeIII ions and the thermoresponsive phenolic building block biscatechol-functionalized poly(N-isopropylacrylamide) (biscatechol-PNIPAM). The MPN capsules exhibited reversible changes in capsule size and shell thickness in response to temperature changes. The temperature-induced capsule size changes were influenced by the chain length of biscatechol-PNIPAM and catechol-to-FeIII ion molar ratio. The metal ion type also influenced the capsule size changes, allowing tuning of the MPN capsule mechanical properties. AlIII-based capsules, having a lower stiffness value (10.7 mN m-1), showed a larger temperature-induced size contraction (∼63%) than TbIII-based capsules, which exhibit a higher stiffness value (52.6 mN m-1) and minimal size reduction (<1%). The permeability of the MPN capsules was controlled by changing the temperature (25-50 °C)─a reduced permeability was obtained as the temperature was increased above the lower critical solution temperature of biscatechol-PNIPAM. This temperature-dependent permeability behavior was exploited to encapsulate and release model cargo (500 kDa fluorescein isothiocyanate-tagged dextran) from the capsules; approximately 70% was released over 90 min at 25 °C. This approach provides a synthetic strategy for developing dynamic and thermoresponsive-tunable MPN systems for potential applications in biological science and biotechnology.
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    Synthesis of Customizable Macromolecular Conjugates as Building Blocks for Engineering Metal–Phenolic Network Capsules with Tailorable Properties
    Kim, C-J ; Ercole, F ; Ju, Y ; Pan, S ; Chen, J ; Qu, Y ; Quinn, JF ; Caruso, F (American Chemical Society (ACS), 2021)
    Metal–phenolic networks (MPNs), formed through coordination bonding between phenolic molecules and metal ions, are a promising class of materials for engineering particle systems for diverse applications. However, the properties of such MPNs are inherently restricted due to the finite properties of naturally occurring phenolic molecules. Herein, we report a simple and robust approach to incorporate phenolic moieties into polymers, thereby providing customizable phenolic ligand building blocks that can be used to assemble capsules with a range of tailorable properties. The phenolic ligand building blocks were synthesized via carbonic anhydride coupling to terminal amines, a conjugation approach typically used for peptide coupling but applied herein for functionalizing polymers. The chemistry enabled optimized end-group purity, thus affording a robust and efficient strategy to generate a library of macromolecular poly(ethylene glycol) (PEG) catechol building blocks with different architectures (i.e., 2-, 4-, and 8-arm) and molecular weights (from 2.5 to 20 kDa). The resulting phenolic building blocks were applied to fabricate capsules with shell thickness, permeability, and cell association properties that were controlled via the variation of the macromolecular catechol architecture and molecular weight. Specifically, the shell thickness was varied more than 19-fold (i.e., between ∼9 and 169 nm) by judicious selection of the polymer molecular weight, arm number, and template. Similarly, the permeability of the resulting MPN capsules to 500 kDa dextran was tuned from >90 to <5% by varying the number of arms in the polymer structure while maintaining a constant PEG Mn-to-catechol group ratio. Furthermore, the cell association was reduced by a factor of 2.5 by employing 20 kDa 8-arm PEG instead of 2.5 kDa 2-arm PEG during film assembly. These results demonstrate that the applied macromolecular conjugation approach can be used to customize particle properties, potentially facilitating applications in therapeutic delivery, imaging, separations, and catalysis.