Chengchao Chu

Metal–Organic Framework-Based Nanomedicine Platforms for Drug Delivery and Molecular Imaging

Metal-organic frameworks (MOFs), which are a unique class of hybrid porous materials built from metal ions and organic linkers, have attracted significant research interest in recent years. Compared with conventional porous materials, MOFs exhibit a variety of advantages, including a large surface area, a tunable pore size and shape, an adjustable composition and structure, biodegradability, and versatile functionalities, which enable MOFs to perform as promising platforms for drug delivery, molecular imaging, and theranostic applications. In this article, the recent research progress related to nanoscale metal-organic frameworks (NMOFs) is summarized with a focus on synthesis strategies and drug delivery, molecular imaging, and theranostic applications. The future challenges and opportunities of NMOFs are also discussed in the context of translational medical research. More effort is warranted to develop clinically translatable NMOFs for various applications in nanomedicine.

Engineering Phototheranostic Nanoscale Metal–Organic Frameworks for Multimodal Imaging-Guided Cancer Therapy

Many photoresponsive dyes have been utilized as imaging and photodynamic/photothermal therapy agents. Indocyanine green (ICG) is the only near-infrared region (NIR) organic dye for clinical applications approved by the United States Food and Drug Administration; however, the clinical application of ICG is limited by its poor aqueous solubility, low cancer specificity, and low sensitivity in cancer theranostics. To overcome these issues, a multifunctional nanoplatform based on hyaluronic acid (HA) and ICG-engineered metal-organic framework MIL-100(Fe) nanoparticles (MOF@HA@ICG NPs) was successfully developed for imaging-guided, anticancer photothermal therapy (PTT). The synthesized NPs showed a high loading content of ICG (40%), strong NIR absorbance, and photostability. The in vitro and in vivo imaging showed that the MOF@HA@ICG NPs exhibited greater cellular uptake in CD44-positive MCF-7 cells and enhanced tumor accumulation in xenograft tumors due to their targeting capability, compared to MOF@ICG NPs (non-HA-targeted) and free ICG. The in vitro photothermal toxicity and in vivo PTT treatments demonstrated that MOF@HA@ICG NPs could effectively inhibit the growth of MCF-7 cells/xenograft tumors. These results suggest that MOF@HA@ICG NPs could be served as a new promising theranostic nanoplatform for improved anticancer PTT through cancer-specific and image-guided drug delivery.

Tumor Microenvironment-Triggered Supramolecular System as an In Situ Nanotheranostic Generator for Cancer Phototherapy

The efficacy of photosensitizers in cancer phototherapy is often limited by photobleaching, low tumor selectivity, and tumor hypoxia. Assembling photosensitizers into nanostructures can improve photodynamic therapy efficacy and the safety profile of photosensitizers. Herein by employing supramolecular assembly, enhanced theranostic capability of Mn2+ -assisted assembly of a photosensitizer (sinoporphyrin sodium, DVDMS) is demonstrated. A tumor environment-triggered coassembly strategy is further developed to form Mn/DVDMS nanotheranostics (nanoDVD) for cancer phototherapy. MnO2 nanosheets serve as a highly effective DVDMS carrier and in situ oxygen and nanoDVD generator. In MCF-7 cells and xenograft tumors, MnO2 /DVDMS is reduced by glutathione (GSH) and H2 O2 and reassembled into nanoDVD, which can be monitored by activated magnetic resonance/fluorescence/photoacoustic signals. Intriguingly, the decrease of GSH, the production of O2 , and the formation of nanoDVD are shown to be synergistic with phototherapy to improve antitumor efficacy in vitro and in vivo, offering a new avenue for cancer theranostics.

Virus-mimetic nanovesicles as a versatile antigen-delivery system

Significance The previously unidentified virus-mimetic nanovesicles (VMVs) described in this manuscript consist of phospholipid derived from mammalian cell plasma membrane, recombinant protein anchored to cell membrane via the route of signal peptide sorting, and surfactants capable of controlling the VMV size and strength, which allows the VMVs to display functional polypeptides or maintain the correct conformation of protein antigen. The protein integrated into VMV by its hydrophobic transmembrane peptide has more modifications, such as glycosylation, than proteins in conventional subunit vaccines. Moreover, many viral envelope glycoproteins can be genetically engineered onto VMV liposomal surface so as to mimic the properties and conformational epitopes of natural virus. VMV provides an effective, straightforward, and tunable approach against a wide range of emerging enveloped viruses. It is a critically important challenge to rapidly design effective vaccines to reduce the morbidity and mortality of unexpected pandemics. Inspired from the way that most enveloped viruses hijack a host cell membrane and subsequently release by a budding process that requires cell membrane scission, we genetically engineered viral antigen to harbor into cell membrane, then form uniform spherical virus-mimetic nanovesicles (VMVs) that resemble natural virus in size, shape, and specific immunogenicity with the help of surfactants. Incubation of major cell membrane vesicles with surfactants generates a large amount of nano-sized uniform VMVs displaying the native conformational epitopes. With the diverse display of epitopes and viral envelope glycoproteins that can be functionally anchored onto VMVs, we demonstrate VMVs to be straightforward, robust and tunable nanobiotechnology platforms for fabricating antigen delivery systems against a wide range of enveloped viruses.

Genetically Engineered Liposome‐like Nanovesicles as Active Targeted Transport Platform

Ligand-targeted delivery of drug molecules to various types of tumor cells remains a major challenge in precision medicine. Inspired by the secretion process and natural cargo delivery functions of natural exosomes, biomimetic synthetic strategies are exploited to prepare biofunctionalized liposome-like nanovesicles (BLNs) that can artificially display a wide variety of targeting protein/peptide ligands and directly encapsulate medical agents for enhanced drug delivery. Here, as a proof of concept, genetically engineered BLNs, which display human epidermal growth factor (hEGF) or anti-HER2 Affibody as targeting moieties, are developed to, respectively, target two types of tumor cells. Notably, in comparison to synthetic liposomes covalently coupled with hEGF, it is demonstrated in this work that biosynthetically displayed hEGF ligands on BLNs possess higher biological activities and targeting capabilities. Additionally, treatments with doxorubicin-loaded BLNs displaying Affibody ligands exhibit much better antitumor therapeutic outcomes than clinically approved liposomal doxorubicin (Doxil) in HER2-overexpressing BT474 tumor xenograft models. These data suggest that BLN is suitable as a potent surrogate for conventional proteoliposomes or immunoliposomes as a result of excellent targeting capacities and facile production of BLNs.

Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging

The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

Photo-excitable hybrid nanocomposites for image-guided photo/TRAIL synergistic cancer therapy

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells without toxicity to normal cells. However, the efficiency is greatly limited by its short half-life and wild resistance in various cancer cells. In this study, we reported a micellar hybrid nanoparticle to carry TRAIL ligand (denoted as IPN@TRAIL) for a novel photo-excited TRAIL therapy. These IPN@TRAIL offered increased TRAIL stability, prolonged half-life and enhanced tumor accumulation, monitored by dual mode imaging. Furthermore, IPN@TRAIL nanocomposites enhanced wrapped TRAIL therapeutic efficiency greatly towards resistant cancer cells by TRAIL nanovectorization. More importantly, when upon external laser, these nanocomposites not only triggered tumor photothermal therapy (PTT), but also upregulated the expression of death receptors (DR4 and DR5), resulting in a greater apoptosis mediated by co-delivered TRAIL ligand. Such photo/TRAIL synergistic effect showed its great killing effects in a controllable manner on TRAIL-resistant A549 tumor model bearing mice. Finally, these nanocomposites exhibited rapid clearance without obvious systemic toxicity. All these features rendered our nanocomposites a promising theranostic platform in cancer therapy.

Novel Intrapolymerization Doped Manganese‐Eumelanin Coordination Nanocomposites with Ultrahigh Relaxivity and Their Application in Tumor Theranostics

Abstract While magnetic resonance imaging contrast agents have potential in noninvasive image‐guided tumor treatment, further developments are needed to increase contrast, biodegradability, and safety. Here, novel engineered manganese‐eumelanin coordination nanocomposites (MnEMNPs) are developed via a facile one‐pot intrapolymerization doping (IPD) approach in aqueous solution, through simple chemical oxidation–polymerization of the 3,4‐dihydroxy‐DL‐phenylalanine precursor with potassium permanganate serving as the Mn source and an oxidant. The resulting MnEMNPs possess ultrahigh longitudinal relaxivity (r 1 value up to 60.8 mM−1 s−1 at 1.5 T) attributed to the high manganese doping efficiency (>10%) and geometrically confined conformation. Due to their high manganese chelation stability, excellent biocompatibility, and strong near‐infrared absorption, high‐performance longitudinal‐transverse (T 1 ‐T 2) dual‐modal magnetic resonance/photoacoustic imaging and photothermal tumor ablation are achieved. Furthermore, the hydrogen peroxide‐triggered decomposition behavior of MnEMNPs circumvents the poor biodegradation issue of many nanomaterials. This facile, convenient, economical, and efficient IPD strategy will open up new avenues for the development of high‐performance multifunctional theranostic nanoplatforms in bionanomedicine.

Enzyme-free colorimetric determination of EV71 virus using a 3D-MnO2-PEG nanoflower and 4-MBA-MA-AgNPs

We present a simple colorimetric assay for EV71 virus detection based on the aggregation of 4-mercaptobenzoic acid (4-MBA) and melamine (MA) modified silver nanoparticles (4-MBA-MA-AgNPs) in the presence of Mn2+. The EV71-Ab1 was incubated on a 96-well plate and the EV71-Ab2 was labeled on the surface of three-dimensional nanoflower-like MnO2-PEG (3D-MnO2-PEG). After layer-by-layer immunoreactions, the EV71 virus and the corresponding 3D-MnO2-PEG-Ab2 were captured on the plate. With the addition of Vitamin C (Vc), Mn2+ was released from the 3D-MnO2-PEG and then the aggregation of the 4-MBA-MA-AgNPs was induced, allowing a naked-eye detection limit of EV71 virus to be as low as 5 × 104 particles per mL, which is about three orders of magnitude lower than the conventional enzyme-linked immunosorbent assay (ELISA). This enzyme-free immunoassay based on a hybrid 3D-MnO2 features signal amplification strategies via a simple reduction reaction.

A Single-step Multi-level Supramolecular System for Cancer Sonotheranostics

A multi-level supramolecular system produced by single-step Fe3+-mediated ionic crosslinking self-assembly can overcome the critical issues of current sonodynamic therapy (SDT) and address the need to monitor therapeutic effects in vivo with a non-invasive approach. This rational design of organic sonosensitizer-based formulation shows great potential for clinical SDT against deep-seated cancer.