Bone-Targeting Exosome Mimetics Engineered by Bioorthogonal Surface Functionalization for Bone Tissue Engineering.

Extracellular vesicles have received a great interest as safe biocarriers in biomedical engineering. There is a need to develop more efficient delivery strategies to improve localized therapeutic efficacy and minimize off-target adverse effects. Here, exosome mimetics (EMs) are reported for bone targeting involving the introduction of hydroxyapatite-binding moieties through bioorthogonal functionalization. Bone-binding ability of the engineered EMs is verified with hydroxyapatite-coated scaffolds and an ex vivo bone-binding assay. The EM-bound construct provided a biocompatible substrate for cell adhesion, proliferation, and osteogenic differentiation. Particularly, the incorporation of Smoothened agonist (SAG) into EMs greatly increased the osteogenic capacity through the activation of hedgehog signaling. Furthermore, the scaffold integrated with EM/SAG significantly improved in vivo reossification. Lastly, biodistribution studies confirmed the accumulation of systemically administered EMs in bone tissue. This facile engineering strategy could be a versatile tool to promote bone regeneration, offering a promising nanomedicine approach to the sophisticated treatment of bone diseases.

Stem Cell-Derived Extracellular Vesicles for Cancer Therapy and Tissue Engineering Applications.

Recently, stem cells and their secretomes have attracted great attention in biomedical applications, particularly extracellular vesicles (EVs). EVs are secretomes of cells for cell-to-cell communication. They play a role as intercellular messengers as they carry proteins, nucleic acids, lipids, and therapeutic agents. They have also been utilized as drug-delivery vehicles due to their biocompatibility, low immunogenicity, stability, targetability, and engineerable properties. The therapeutic potential of EVs can be further enhanced by surface engineering and modification using functional molecules such as aptamers, peptides, and antibodies. As a consequence, EVs hold great promise as effective delivery vehicles for enhancing treatment efficacy while avoiding side effects. Among various cell types that secrete EVs, stem cells are ideal sources of EVs because stem cells have unique properties such as self-renewal and regenerative potential for transplantation into damaged tissues that can facilitate their regeneration. However, challenges such as immune rejection and ethical considerations remain significant hurdles. Stem cell-derived EVs have been extensively explored as a cell-free approach that bypasses many challenges associated with cell-based therapy in cancer therapy and tissue regeneration. In this review, we summarize and discuss the current knowledge of various types of stem cells as a source of EVs, their engineering, and applications of EVs, focusing on cancer therapy and tissue engineering.

Extracellular Vesicles as Potential Therapeutics for Inflammatory Diseases.

Extracellular vesicles (EV) deliver cargoes such as nucleic acids, proteins, and lipids between cells and serve as an intercellular communicator. As it is revealed that most of the functions associated to EVs are closely related to the immune response, the important role of EVs in inflammatory diseases is emerging. EVs can be functionalized through EV surface engineering and endow targeting moiety that allows for the target specificity for therapeutic applications in inflammatory diseases. Moreover, engineered EVs are considered as promising nanoparticles to develop personalized therapeutic carriers. In this review, we highlight the role of EVs in various inflammatory diseases, the application of EV as anti-inflammatory therapeutics, and the current state of the art in EV engineering techniques.

Inspired by nature: facile design of nanoclay-organic hydrogel bone sealant with multifunctional properties for robust bone regeneration.

Bone repair is a complex process involving the sophisticated interplay of osteogenic stem cells, extracellular matrix, and osteoinductive factors, and it is affected by bacterial toxins and oxidative stress. Inspired by the nature of plant-derived phytochemicals and inorganic-organic analogues of the bone extracellular matrix, we report herein the facile design of a nanoclay-organic hydrogel bone sealant (NoBS) that integrates multiple physico-chemical cues for bone regeneration into a single system. Assembly of phytochemical-modified organic chitosan and silica-rich inorganic nanoclay serves as highly biocompatible and osteoconductive extracellular matrix mimics. The decorated phytochemical exerts inherent bactericidal and antioxidant activities, and acts as an intermolecular networking precursor for gelation with injectable and self-healing capabilities. Moreover, the NoBS exerts osteoinductive effects mediated by the nanoclay, which regulates the Wnt/ß-catenin pathway, along with the addition of osteoinductive signals, resulting in bone regeneration in a non-healing cranial defect. Engineering of this integrated bone graft substitute with multifunctional properties inspired by natural materials may suggest a promising and effective approach for creating a favorable microenvironment for optimal bone healing.

Immense Insulin Intestinal Uptake and Lymphatic Transport Using Bile Acid Conjugated Partially Uncapped Liposome.

We provide immense insulin absorption from the gastrointestinal tract, combining apical sodium-dependent bile acid transporter-mediated intestinal uptake and the lymphatic transport pathway. This strategy has proven to employ chondroitin sulfate- g-taurocholic acid coated, insulin-loaded partially uncapped liposome (IPUL-CST) for type 1 diabetes mellitus (T1DM) treatment. The loading efficiency of insulin in IPUL-CST increased significantly from 33% to 75% via the partially uncapped liposome preparation method. Moreover, the IPUL-CST revealed an improved insulin protection efficacy in GIT simulated pH and digestive enzyme conditions. The high dose of IPUL-CST in the small intestine was detected 4 h post-oral administration using ex vivo optical imaging and fluorescence intensity. The IPUL-CST exhibited significantly enhanced intestinal absorption (oral bioavailability, 34%; Tmax, 9 h) and reduced blood glucose levels for 16 h in T1DM. The results demonstrated that the new investigated IPUL-CST is a promising carrier for oral insulin delivery.

Photoresponsive Micelle-Incorporated Doxorubicin for Chemo-Photodynamic Therapy to Achieve Synergistic Antitumor Effects.

A combination of chemo-photodynamic therapy has been manifested as a promising strategy for efficient cancer treatment due to the enhanced therapeutic efficacy. Here, we designed doxorubicin (DOX)-loaded photoresponsive micelles (DPRMs) based on a combination of chlorin e6 (Ce6) and lipoic acid (LA) conjugated methoxy-poly(ethylene) glycol (mPEG-Ce6, mPEG-LA) to achieve effective drug delivery using a single system. DPRMs were optimized with different molar ratios of mPEG-Ce6 and mPEG-LA which showed uniformly spherical morphology of size ∼130 nm and approximately 9% of DOX loading contents. Photoresponsive lipoyl ring of mPEG-LA was incorporated in DPRMs in order to induce photomediated reduction resulting in 2-3-fold accelerated DOX release according to higher molar ratio of mPEG-LA and enhancement of light dose. The photoresponsive DOX release and ROS generation by Ce6 mediated cytotoxic effect of DPRMs were demonstrated in vitro using CT-26 (mouse colon cancer) and HCT-116 (human colon cancer) cells. We observed both the photosensitizer and the anticancer drug are colocalized in the tumor cells to achieve effective enhancement. Additionally, the DPRMs with laser irradiation successfully inhibited tumor growth in CT-26 tumor bearing mouse model and immunohistochemical staining verified apoptosis-mediated tumor growth inhibition. These observations demonstrated that the DPRMs showed a higher therapeutic effect than the other systems and PDT maximized the antitumor effect. Thus, DPRMs confirmed the advantages as a chemo-photodynamic dual-therapy with a synergistic therapeutic effect and great potential for cancer treatment.

Role of polymeric endosomolytic agents in gene transfection: a comparative study of poly(L-lysine) grafted with monomeric L-histidine analogue and poly(L-histidine).

Endosomal entrapment is one of the main barriers that must be overcome for efficient gene expression along with cell internalization, DNA release, and nuclear import. Introducing pH-sensitive ionizable groups into the polycationic polymers to increase gene transfer efficiency has proven to be a useful method; however, a comparative study of introducing equal numbers of ionizable groups in both polymer and monomer forms, has not been reported. In this study, we prepared two types of histidine-grafted poly(L-lysine) (PLL), a stacking form of poly(L-histidine) (PLL-g-PHis) and a mono-L-histidine (PLL-g-mHis) with the same number of imidazole groups. These two types of histidine-grafted PLL, PLL-g-PHis and PLL-g-mHis, showed profound differences in hemolytic activity, cellular uptake, internalization, and transfection efficiency. Cy3-labeled PLL-g-PHis showed strong fluorescence in the nucleus after internalization, and high hemolytic activity upon pH changes was also observed from PLL-g-PHis. The arrangement of imidazole groups from PHis also provided higher gene expression than mHis due to its ability to escape the endosome. mHis or PHis grafting reduced the cytotoxicity of PLL and changed the rate of cellular uptake by changing the quantity of free ε-amines available for gene condensation. The subcellular localization of PLL-g-PHis/pDNA measured by YOYO1-pDNA intensity was highest inside the nucleus, while the lysotracker, which stains the acidic compartments was lowest among these polymers. Thus, the polymeric histidine arrangement demonstrate the ability to escape the endosome and trigger rapid release of polyplexes into the cytosol, resulting in a greater amount of pDNA available for translocation to the nucleus and enhanced gene expression.

Bioreducible polymers as a determining factor for polyplex decomplexation rate and transfection.

Polyplex formation (complexation) and gene release from the polyplexes (decomplexation) are major events in polymeric gene delivery; however, the effect of the decomplexation rate on transfection has been rarely investigated. This study employed mixed polymers of poly((L)-lysine) (PLL: MW ~7.4 kDa) and reducible PLL (RPLL) (MW ~6.7 kDa) to design decomplexation rate-controllable PLL(100-x)RPLL(x)/pDNA complexes (PRL(x) polyplexes). The transfection efficiency of a model gene (luciferase) in MCF7 and HEK293 cell lines increased with increasing x (RPLL content) in the PRL(x) polyplexes until peaking at x = 2.5 and 10, respectively, after which point transfection efficiency declined rapidly. In MCF7 cells, PRL(2.5) polyplex produced 3 or 223 times higher gene expression than PLL or RPLL polyplexes, respectively. Similarly, the transfection efficiency of PRL(10) polyplex-transfected HEK293 cells was 3.8 or 67 times higher than that of PLL or RPLL polyplexes, respectively. The transfection results were not apparently related to the particle size, surface charge, complexation/compactness, cellular uptake, or cytotoxicity of the tested polyplexes. However, the decomplexation rate varied by RPLL content in the polyplexes, which in turn influenced the gene transfection. The nuclear localization of pDNA delivered by PRL(x) polyplexes showed a similar trend to their transfection efficiencies. This study suggests that an optimum decomplexation rate may result in high nuclear localization of pDNA and transfection. Understanding in decomplexation and intracellular localization of pDNA may help develop more effective polyplexes.

Recent Progress in Hyaluronic-Acid-Based Hydrogels for Bone Tissue Engineering.

Hydrogel-based bone tissue engineering is a potential strategy for treating bone abnormalities and fractures. Hyaluronic acid (HA) is a natural polymer that is widely distributed in the human body and plays a significant role in numerous physiological processes such as cell migration, tissue hydration, and wound healing. Hydrogels based on HA and its derivatives have gained popularity as potential treatments for bone-related diseases. HA-based hydrogels have been extensively studied for their ability to mimic the natural extracellular matrix of bone tissue and provide a suitable microenvironment for cell support and tissue regeneration. The physical and chemical properties of HA can be modified to improve its mechanical strength, biocompatibility, and osteogenic potential. Moreover, HA-based hydrogels combined with other biomaterials in the presence or absence of bioactive agents have been investigated as a means of improving the mechanical properties and bioactivity of the hydrogel scaffold. Therefore, HA-based hydrogels have shown great promise in bone tissue engineering due to their biocompatibility, osteogenic activity, and ability to mimic the natural extracellular matrix of bone tissue. Overall, this review provides a comprehensive overview of the current state of the art in HA-based hydrogels for bone tissue engineering, highlighting the key advances, challenges, and future directions in this rapidly evolving field.

Starch-Based Hydrogels as a Drug Delivery System in Biomedical Applications.

Starch-based hydrogels have gained significant attention in biomedical applications as a type of drug delivery system due to their biocompatibility, biodegradability, and ability to absorb and release drugs. Starch-based hydrogels can serve as effective carriers for pharmaceutical compounds such as drugs and proteins to develop drug-loaded hydrogel systems, providing controlled release over an extended period. The porous structure of a hydrogel allows for the diffusion of drugs, ensuring sustained and localized delivery to the target site. Moreover, starch-based hydrogels have been used as a powerful option in various biomedical fields, including cancer and infectious disease treatment. In addition, starch-based hydrogels have shown promise in tissue engineering applications since hydrogels can be used as scaffolds or matrices to support cell growth and tissue regeneration. Depending on techniques such as chemical crosslinking or physical gelation, it can create a three-dimensional network structure that tunes its mechanical properties and mimics the extracellular matrix. Starch-based hydrogels can also provide a supportive environment for cell attachment, proliferation, and differentiation to promote specific cellular responses and tissue regeneration processes with the loading of growth factors, cytokines, or other bioactive molecules. In this review, starch-based hydrogels as a versatile platform for various biomedical applications are discussed.

Silver-Composited Polydopamine Nanoparticles: Antibacterial and Antioxidant Potential in Nanocomposite Hydrogels.

(1) Background: Infections of pathogenic microorganisms can be life-threatening due to delayed healing or even worsening conditions in tissue engineering and regenerative medicine. The excessive presence of reactive oxygen species in damaged and infected tissues causes a negative inflammatory response, resulting in failed healing. Thus, the development of hydrogels with antibacterial and antioxidant abilities for the treatment of infectious tissues is in high demand. (2) Methods: We herein describe the development of green-synthesized silver-composited polydopamine nanoparticles (AgNPs), which are fabricated by the self-assembly of dopamine as a reducing and antioxidant agent in the presence of silver ions. (3) Results: The facile and green-synthesized AgNPs have a nanoscale diameter with mostly spherical shapes, with various shapes coexisting. The particles are stable in an aqueous solution for up to 4 weeks. In addition, remarkable antibacterial activity against Gram-positive and -negative bacterial strains and antioxidant capabilities were evaluated by in vitro assays. When incorporated into biomaterial hydrogels at concentrations above 2 mg L-1, the hydrogels produced powerful antibacterial effects. (4) Conclusions: This study describes a biocompatible hydrogel with antibacterial and antioxidant activities from the introduction of facile and green-synthesized AgNPs as a safer tool for the treatment of damaged tissues.

Mesenchymal Stem Cell-Mediated Deep Tumor Delivery of Gold Nanorod for Photothermal Therapy.

Gold nanoparticles (AuNPs) with various sizes and morphologies have been extensively investigated for effective photothermal therapy (PTT) against multiple cancer types. However, a highly dynamic and complex tumor microenvironment (TME) considerably reduces the efficacy of PTT by limiting deep tumor penetration of AuNPs. Herein, we propose a mesenchymal stem cell (MSC)-mediated deep tumor delivery of gold nanorod (AuNR) for a potent PTT. First, MSCs are treated with tetraacylated N-azidomannosamine (Ac4ManNAz) to introduce modifiable azide (N3) groups on the cell surface via metabolic glycoengineering. Then, AuNRs modified with bio-orthogonal click molecules of bicyclo[6.1.0]nonyne (AuNR@BCN) are chemically conjugated to the N3 groups on the MSC surface by copper-free click chemistry reaction, resulting in AuNR@MSCs. In cultured MSCs, the appropriate condition to incorporate the AuNR into the MSCs is optimized; in addition, the photothermal efficiency of AuNR-MSCs under light irradiation are assessed, showing efficient heat generation in vitro. In colon tumor-bearing mice, intravenously injected AuNR@MSCs efficiently accumulate within the tumor tissues by allowing deep tissue penetration owing to the tumor homing effect by natural tumor tropism of AuNR@MSCs. Upon localized light irradiation, the AuNR@MSCs significantly inhibit colon tumor growth by the enhanced photothermal effect compared to conventional AuNRs. Collectively, this study shows a promising approach of MSCs-mediated deep tumor delivery of AuNR for effective PTT.

Hemagglutinin Nanoparticulate Vaccine with Controlled Photochemical Immunomodulation for Pathogenic Influenza-Specific Immunity.

Recently, viral infectious diseases, including COVID-19 and Influenza, are the subjects of major concerns worldwide. One strategy for addressing these concerns focuses on nasal vaccines, which have great potential for achieving successful immunization via safe, easy, and affordable approaches. However, conventional nasal vaccines have major limitations resulting from fast removal when pass through nasal mucosa and mucociliary clearance hindering their effectiveness. Herein a nanoparticulate vaccine (NanoVac) exhibiting photochemical immunomodulation and constituting a new self-assembled immunization system of a photoactivatable polymeric adjuvant with influenza virus hemagglutinin for efficient nasal delivery and antigen-specific immunity against pathogenic influenza viruses is described. NanoVac increases the residence period of antigens and further enhances by spatiotemporal photochemical modulation in the nasal cavity. As a consequence, photochemical immunomodulation of NanoVacs successfully induces humoral and cellular immune responses followed by stimulation of mature dendritic cells, plasma cells, memory B cells, and CD4+ and CD8+ T cells, resulting in secretion of antigen-specific immunoglobulins, cytokines, and CD8+ T cells. Notably, challenge with influenza virus after nasal immunization with NanoVacs demonstrates robust prevention of viral infection. Thus, this newly designed vaccine system can serve as a promising strategy for developing vaccines that are active against current hazardous pathogen outbreaks and pandemics.

Rediscovery of nanoparticle-based therapeutics: boosting immunogenic cell death for potential application in cancer immunotherapy.

Immunogenic cell death (ICD) occurring by chemical and physical stimuli has shown the potential to activate an adaptive immune response in the immune-competent living body through the release of danger-associated molecular patterns (DAMPs) into the tumor microenvironment (TME). However, limitations to the long-term immune responses and systemic toxicity of conventional ICD inducers have led to unsatisfactory therapeutic efficacy in ICD-based cancer immunotherapy. Until now, various nanoparticle-based ICD-inducers have been developed to induce an antitumor immune response without severe toxicity, and to efficiently elicit an anticancer immune response against target cancer cells. In this review, we introduce a recent advance in the designs and applications of nanoparticle-based therapeutics to elicit ICD for effective cancer immunotherapy. In particular, combination strategies of nanoparticle-based ICD inducers with typical theranostic modalities are introduced intensively. Subsequently, we discuss the expected challenges and future direction of nanoparticle-based ICD inducers to provide strategies for boosting ICD in cancer immunotherapy. These versatile designs and applications of nanoparticle-based therapeutics for ICD can provide advantages to improve the therapeutic efficacy of cancer immunotherapy.

Visible-Light-Triggered Prodrug Nanoparticles Combine Chemotherapy and Photodynamic Therapy to Potentiate Checkpoint Blockade Cancer Immunotherapy.

Immune checkpoint blockade is a promising approach for cancer immunotherapy, but many patients do not respond due to the immunosuppressive tumor microenvironment (ITM). Herein, we propose visible-light-triggered prodrug nanoparticles (LT-NPs) for reversing ITM into high immunogenic tumors to potentiate checkpoint blockade immunotherapy. The photosensitizer (verteporfin; VPF), cathepin B-specific cleavable peptide (FRRG), and doxorubicin (DOX) conjugates are self-assembled into LT-NPs without any additional carrier material. The LT-NPs are specifically cleaved to VPF and DOX in cathepsin B-overexpressing cancer cells, thereby inducing cancer-specific cytotoxicity and immunogenic cell death (ICD) upon visible light irradiation. In tumor models, LT-NPs highly accumulate within tumors via the enhanced permeability and retention effect, and photochemotherapy of VPF and DOX induces effective ICD and maturation of dendritic cells to stimulate cross-presentation of cancer-antigens to T cells. Furthermore, LT-NPs with PD-L1 blockade greatly inhibit tumor growth, tumor recurrence, and lung metastasis by initiating a strong antitumor immune response. The photochemotherapy by LT-NPs provides a promising strategy for effective checkpoint blockade immunotherapy.

Smoothened agonist sterosome immobilized hybrid scaffold for bone regeneration.

Biomaterial delivery of bioactive agents and manipulation of stem cell fate are an attractive approach to promote tissue regeneration. Here, smoothened agonist sterosome is developed using small-molecule activators [20S-hydroxycholesterol (OHC) and purmorphamine (PUR)] of the smoothened protein in the hedgehog pathway as carrier and cargo. Sterosome presents inherent osteoinductive property even without drug loading. Sterosome is covalently immobilized onto three-dimensional scaffolds via a bioinspired polydopamine intermediate to fabricate a hybrid scaffold for bone regeneration. Sterosome-immobilized hybrid scaffold not only provides a favorable substrate for cell adhesion and proliferation but also delivers bioactive agents in a sustained and spatially targeted manner. Furthermore, this scaffold significantly improves osteogenic differentiation of bone marrow stem cells through OHC/PUR-mediated synergistic activation of the hedgehog pathway and also enhances bone repair in a mouse calvarial defect model. This system serves as a versatile biomaterial platform for many applications, including therapeutic delivery and endogenous regenerative medicine.

Controlling complexation/decomplexation and sizes of polymer-based electrostatic pDNA polyplexes is one of the key factors in effective transfection.

The delivery of plasmid DNA (pDNA) using polycations has been investigated for several decades; however, obstacles that limit efficient gene delivery still hinder the clinical application of gene therapy. One of the major limiting factors is controlling pDNA binding affinity with polymers to control the complexation and decomplexation of polyplexes. To address this challenge, polycations of α-poly(L-lysine) (APL) and ε-poly(L-lysine) (EPL) were used to prepare variable complexation/decomplexation polyplexes with binding affinities ranging from too tight to too loose and sizes ranging from small to large. APL-EPL/ATP-pDNA polyplexes were also prepared to compare the effects of endosomolytic ATP on complexation/decomplexation and the sizes of polyplexes. The results showed that smaller and tighter polyplexes delivered more pDNA into the cells and into the nucleus than the larger and looser polyplexes. Larger polyplexes exhibited slower cytosolic transport and consequently less nuclear delivery of pDNA than smaller polyplexes. Tighter polyplexes exhibited poor pDNA release in the nucleus, leading to no improvement in transfection efficiency. Thus, polyplexes should maintain a balance between complexation and decomplexation and should have optimal sizes for effective cellular uptake, cytosolic transport, nuclear import, and gene expression. Understanding the effects of complexation/decomplexation and size is important when designing effective polymer-based electrostatic gene carriers.

TRAIL-secreting human mesenchymal stem cells engineered by a non-viral vector and photochemical internalization for pancreatic cancer gene therapy.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic protein to selectively induce cancer cell apoptosis. However, TRAIL exhibits low stability and short half-life due to its denaturation. Thus, delivering the TRAIL gene for stem cell-mediated gene therapy was conducted by using non-viral vectors (a less efficient but safer method). To overcome the limitation of non-viral vectors, photochemical internalization (PCI) was utilized for enhanced transfection efficiency of secreting TRAIL from human mesenchymal stem cells (hMSCs). To explore a more effective approach for cancer treatment, polyplexes were formed by using TRAIL plasmid (pTRAIL) and branched polyethyleneimine (bPEI). PCI is applied to improve polyplex entrapping in hMSCs and enhance the transfection efficiency of TRAIL into hMSCs for secretion in tumors via a homing effect. We demonstrate that PCI-mediated polyplex loading significantly enhanced TRAIL expression in stem cells and that homing ability magnified cancer targeting. The xenograft mouse model shows that polyplex loaded hMSCs (pTRAIL/bPEI@hMSCs) under laser irradiation results in a beneficial therapeutic antitumor effect compared to unloaded polyplexes and pTRAIL/bPEI@hMSCs. Taken together, the delivery of PCI-pTRAIL/bPEI@hMSCs offers exciting potential treatments in pancreatic cancer gene therapy via the enhanced the transfection efficiency of TRAIL by PCI system and the tumor homing properties of hMSCs.

Theranostics and contrast agents for magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging is one of the diagnostic tools that uses magnetic particles as contrast agents. It is noninvasive methodology which provides excellent spatial resolution. Although magnetic resonance imaging offers great temporal and spatial resolution and rapid in vivo images acquisition, it is less sensitive than other methodologies for small tissue lesions, molecular activity or cellular activities. Thus, there is a desire to develop contrast agents with higher efficiency. Contrast agents are known to shorten both T1 and T2. Gadolinium based contrast agents are examples of T1 agents and iron oxide contrast agents are examples of T2 agents. In order to develop high relaxivity agents, gadolinium or iron oxide-based contrast agents can be synthesized via conjugation with targeting ligands or functional moiety for specific interaction and achieve accumulation of contrast agents at disease sites. MAIN BODY: This review discusses the principles of magnetic resonance imaging and recent efforts focused on specificity of contrast agents on specific organs such as liver, blood, lymph nodes, atherosclerotic plaque, and tumor. Furthermore, we will discuss the combination of theranostic such as contrast agent and drug, contrast agent and thermal therapy, contrast agent and photodynamic therapy, and neutron capture therapy, which can provide for cancer diagnosis and therapeutics. CONCLUSION: These applications of magnetic resonance contrast agents demonstrate the usefulness of theranostic agents for diagnosis and treatment.

Galactosylated iodine-based small molecule I.V. CT contrast agent for bile duct imaging.

Computed tomography (CT) with contrast plays an important role as a clinical diagnostic tool but still has a limited diagnostic range. In this work, we developed a novel injectable iodine-based small molecule CT contrast agent, even can be used for bile duct diagnostics. The bile duct diagnosable CT contrast agent (BDICA) is synthesized with 5-amino-2,4,6-triiodoisophthaloyl dichloride (ATIPC), tromethamine and lactobionic acid (LBA) for asialoglycoprotein receptor (ASGPR) targeted delivery via receptor-mediated endocytosis and transport to the bile canaliculi. Specific binding to the ASGPRs was confirmed by in vitro cellular uptake in HepG2 cells (ASGPR positive) and HCT 116 cells (ASGPR negative). Compared to iohexol, BDICA has equal in vivo distribution and a 13-fold iodine increase in content was observed in bile juice after BDICA injection. The radiopaque contrast effect in the bile duct has been clearly shown in in vivo CT scans. Furthermore, within 36 h, 91.3% of the BDICA was eliminated without organ damage, which verified the overall safety of the contrast agent. BDICA not only provides sufficient contrast images similar to iohexol, but also provides superior images of the bile duct. Based on recent studies, it has been shown that BDICA is a promising, safe and effective contrast agent for CT imaging of the organs and soft tissues, including the bile duct.