Chemical and Biomolecular Engineering - Research Publications
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ItemEngineering poly(ethylene glycol) particles for targeted drug delivery(ROYAL SOC CHEMISTRY, 2024-02-29)Poly(ethylene glycol) (PEG) is considered to be the "gold standard" among the stealth polymers employed for drug delivery. Using PEG to modify or engineer particles has thus gained increasing interest because of the ability to prolong blood circulation time and reduce nonspecific biodistribution of particles in vivo, owing to the low fouling and stealth properties of PEG. In addition, endowing PEG-based particles with targeting and drug-loading properties is essential to achieve enhanced drug accumulation at target sites in vivo. In this feature article, we focus on recent work on the synthesis of PEG particles, in which PEG is the main component in the particles. We highlight different synthesis methods used to generate PEG particles, the influence of the physiochemical properties of PEG particles on their stealth and targeting properties, and the application of PEG particles in targeted drug delivery.
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ItemNo Preview AvailableParticle Engineering via Supramolecular Assembly of Macroscopic Hydrophobic Building Blocks(Wiley, 2024-01-22)Abstract Tailoring the hydrophobicity of supramolecular assembly building blocks enables the fabrication of well‐defined functional materials. However, the selection of building blocks used in the assembly of metal–phenolic networks (MPNs), an emerging supramolecular assembly platform for particle engineering, has been essentially limited to hydrophilic molecules. Herein, we synthesized and applied biscatechol‐functionalized hydrophobic polymers (poly(methyl acrylate) (PMA) and poly(butyl acrylate) (PBA)) as building blocks to engineer MPN particle systems (particles and capsules). Our method allowed control over the shell thickness (e.g., between 10 and 21 nm), stiffness (e.g., from 10 to 126 mN m−1), and permeability (e.g., 28–72 % capsules were permeable to 500 kDa fluorescein isothiocyanate‐dextran) of the MPN capsules by selection of the hydrophobic polymer building blocks (PMA or PBA) and by controlling the polymer concentration in the MPN assembly solution (0.25–2.0 mM) without additional/engineered assembly processes. Molecular dynamics simulations provided insights into the structural states of the hydrophobic building blocks during assembly and mechanism of film formation. Furthermore, the hydrophobic MPNs facilitated the preparation of fluorescent‐labeled and bioactive capsules through postfunctionalization and also particle–cell association engineering by controlling the hydrophobicity of the building blocks. Engineering MPN particle systems via building block hydrophobicity is expected to expand their use.
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ItemParticle Engineering via Supramolecular Assembly of Macroscopic Hydrophobic Building Blocks(WILEY-V C H VERLAG GMBH, 2024-01-22)Tailoring the hydrophobicity of supramolecular assembly building blocks enables the fabrication of well-defined functional materials. However, the selection of building blocks used in the assembly of metal-phenolic networks (MPNs), an emerging supramolecular assembly platform for particle engineering, has been essentially limited to hydrophilic molecules. Herein, we synthesized and applied biscatechol-functionalized hydrophobic polymers (poly(methyl acrylate) (PMA) and poly(butyl acrylate) (PBA)) as building blocks to engineer MPN particle systems (particles and capsules). Our method allowed control over the shell thickness (e.g., between 10 and 21 nm), stiffness (e.g., from 10 to 126 mN m-1 ), and permeability (e.g., 28-72 % capsules were permeable to 500 kDa fluorescein isothiocyanate-dextran) of the MPN capsules by selection of the hydrophobic polymer building blocks (PMA or PBA) and by controlling the polymer concentration in the MPN assembly solution (0.25-2.0 mM) without additional/engineered assembly processes. Molecular dynamics simulations provided insights into the structural states of the hydrophobic building blocks during assembly and mechanism of film formation. Furthermore, the hydrophobic MPNs facilitated the preparation of fluorescent-labeled and bioactive capsules through postfunctionalization and also particle-cell association engineering by controlling the hydrophobicity of the building blocks. Engineering MPN particle systems via building block hydrophobicity is expected to expand their use.
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ItemPoly(ethylene glycol) Cross-Linked Antibody Nanoparticles for Tunable Biointeractions(American Chemical Society (ACS), 2023)Liver accumulation of nanoparticles is a major challenge in nanoparticle-mediated delivery as it can reduce the delivery of the nanoparticles to their intended site and lead to liver damage and toxicity. Recent studies have shown that particle engineering, e.g., nanoparticle composition, can influence liver uptake and allow homing of nanoparticles to specific organs or tissues. Herein, we investigated the role of nanoparticle cross-linking on liver uptake. We developed a series of antibody nanoparticles (AbNPs) using various poly(ethylene glycol) (PEG) molecule (e.g., different arm numbers and arm lengths) cross-linkers. Specifically, AbNPs based on Herceptin were engineered with PEG cross-linker architectures ranging from 2-arm (at molecular weights of 600 Da, 2.5 kDa, and 5 kDa) to 4-arm and 8-arm via a mesoporous silica templating method. The molecular architecture of PEG modulated not only the targeting ability of the AbNPs in model cell lines but also their interaction with phagocytes in human blood. Increasing the PEG arm length from 600 Da to 5 kDa also reduced the uptake of the nanoparticles in the liver by 85%. Tumor accumulation of Herceptin AbNPs cross-linked with a 5 kDa 2-arm-PEG was 50% higher compared with control AbNPs and displayed similar liver uptake as free Herceptin. This study highlights the role of PEG cross-linking in receptor targeting and liver uptake, which influence tumor targeting, and combined with the versatility and multifunctionality of the antibody nanoparticle platform could lead to the development of organ-selective targeted antibody nanoparticle assemblies.
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ItemFunctional Ligand-Enabled Particle Assembly for Bio-Nano Interactions(AMER CHEMICAL SOC, 2023-05-24)Functional ligands consist of a wide range of small or large molecules that exhibit a spectrum of physical, chemical, and biological properties. A suite of small molecules (e.g., peptides) or macromolecular ligands (e.g., antibodies and polymers) have been conjugated to particle surfaces for specific applications. However, postfunctionalization of ligands often presents challenges in controlling the surface density and may require the chemical modification of ligands. As an alternative option to postfunctionalization, our work has focused on using functional ligands as building blocks to assemble particles while maintaining their intrinsic (functional) properties. Through self-assembly or template-mediated assembly strategies, we have developed a range of protein-, peptide-, DNA-, polyphenol-, glycogen-, and polymer-based particles. This Account discusses the assembly of such nanoengineered particles, which includes self-assembled nanoparticles, hollow capsules, replica particles, and core-shell particles, according to three categories of functional ligands (i.e., small molecules, polymers, and biomacromolecules) that are used as building blocks for their formation. We discuss a range of covalent and noncovalent interactions among ligand molecules that have been explored to facilitate the assembly of particles. The physicochemical properties of the particles, including size, shape, surface charge, permeability, stability, thickness, stiffness, and stimuli-responsiveness, can be readily controlled by varying the ligand building block or by tuning the assembly method. By selecting specific ligands as building blocks, the bio-nano interactions (i.e., stealth, targeting, and cell trafficking) can also be modulated. For instance, particles composed mainly of low-fouling polymers (i.e., poly(ethylene glycol)) exhibit an extended blood circulation time (half-life > 12 h), while antibody-based nanoparticles demonstrate that a trade-off between stealth and targeting may be required when designing targeting nanoparticle systems. Small molecular ligands, such as polyphenols, have been used as building blocks for particle assembly as they can interact with various biomacromolecules through multiple noncovalent interactions, retain the function of biomacromolecules within the assembly, enable pH-responsive disassembly when coordinating with metal ions, and facilitate endosomal escape of nanoparticles. A perspective is provided on the current challenges associated with the clinical translation of ligand-based nanoparticles. This Account is also expected to serve as a reference to guide the fundamental research and development of functional particle systems assembled from various ligands for diverse applications.
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ItemNo Preview AvailableSupramolecular Polyphenol‐DNA Microparticles for In Vivo Adjuvant and Antigen Co‐Delivery and Immune Stimulation(Wiley, 2023-03-13)Abstract DNA‐based materials have attracted interest due to the tunable structure and encoded biological functionality of nucleic acids. A simple and general approach to synthesize DNA‐based materials with fine control over morphology and bioactivity is important to expand their applications. Here, we report the synthesis of DNA‐based particles via the supramolecular assembly of tannic acid (TA) and DNA. Uniform particles with different morphologies are obtained using a variety of DNA building blocks. The particles enable the co‐delivery of cytosine‐guanine adjuvant sequences and the antigen ovalbumin in model cells. Intramuscular injection of the particles in mice induces antigen‐specific antibody production and T cell responses with no apparent toxicity. Protein expression in cells is shown using capsules assembled from TA and plasmid DNA. This work highlights the potential of TA as a universal material for directing the supramolecular assembly of DNA into gene and vaccine delivery platforms.
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ItemSupramolecular Polyphenol-DNA Microparticles for In Vivo Adjuvant and Antigen Co-Delivery and Immune Stimulation(WILEY-V C H VERLAG GMBH, 2023-03-13)DNA-based materials have attracted interest due to the tunable structure and encoded biological functionality of nucleic acids. A simple and general approach to synthesize DNA-based materials with fine control over morphology and bioactivity is important to expand their applications. Here, we report the synthesis of DNA-based particles via the supramolecular assembly of tannic acid (TA) and DNA. Uniform particles with different morphologies are obtained using a variety of DNA building blocks. The particles enable the co-delivery of cytosine-guanine adjuvant sequences and the antigen ovalbumin in model cells. Intramuscular injection of the particles in mice induces antigen-specific antibody production and T cell responses with no apparent toxicity. Protein expression in cells is shown using capsules assembled from TA and plasmid DNA. This work highlights the potential of TA as a universal material for directing the supramolecular assembly of DNA into gene and vaccine delivery platforms.
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ItemEngineering Poly(ethylene glycol) Nanoparticles for Accelerated Blood Clearance Inhibition and Targeted Drug Delivery(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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ItemPolyphenol-Functionalized Cubosomes as Thrombolytic Drug Carriers(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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ItemInfluence of protein corona on the interaction of glycogen-siRNA constructs with ex vivo human blood immune cells(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.