Bioconjugate Chemistry最新文献

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). CT imaging with contrast agents is commonly used for visualizing the gastrointestinal (GI) tract in UC patients. Contrast agents that provide enhanced imaging performance are highly valuable in this field. Recent studies have made significant progress in developing better contrast agents for imaging the gastrointestinal tract using nanoparticles. However, the impact of nanoparticle size on this application remains unexplored. Gold nanoparticles (AuNPs) serve as an ideal model to investigate the effect of nanoparticle size on imaging of the gastrointestinal tract due to their controllable synthesis across a broad size range. In this study, we synthesized AuNPs with core sizes ranging from 5 to 75 nm to examine the effect of the size in this setting. AuNPs were coated with poly(ethylene glycol) (PEG) to enhance stability and biocompatibility. In vitro tests show that gold nanoparticles are cytocompatible with macrophage cells (∼100% cell viability) and remain stable under acidic conditions, with no significant size changes over time. Phantom imaging studies using a clinical CT scanner indicated that there was no effect of nanoparticle size on CT contrast production, as previously demonstrated. In vivo imaging using a mouse model of acute colitis revealed a strong contrast generation throughout the GI tract for all agents tested. For the most part, in vivo contrast was independent of AuNP size, although AuNP outperformed iopamidol (a clinically approved control agent). In addition, differences in attenuation trends were observed between healthy and colitis mice. We also observed almost complete clearance at 24 h of all formulations tested (less than 0.7% ID/g was retained), supporting their value as a model platform for studying nanoparticle behavior in imaging. In conclusion, this study highlights the potential of nanoparticles as effective contrast agents for CT imaging of the gastrointestinal tract (GIT) in the UC. Further systemic research is needed to explore contrast agents that can specifically image disease processes in this disease setting.

Traumatic brain injuries (TBIs) result in significant morbidity and mortality due to the cascade of secondary injuries involving oxidative stress and neuroinflammation. The development of effective therapeutic strategies to mitigate these effects is critical. This study explores the fabrication and characterization of polyurethane nanocapsules for the sustained delivery of Tempol, a potent antioxidant. The nanocapsules were designed to extend the release of Tempol over a 30-day period, addressing the prolonged oxidative stress observed post-TBI. Tempol-loaded polyurethane nanocapsules were synthesized using interfacial polymerization and nanoemulsion techniques. Two generations of nanocapsules were produced, differing in Tempol loading and PEGylation levels. The first generation, with lower Tempol loading, exhibited an average size of 159.8 ± 12.61 nm and a Z-average diameter of 771.9 ± 87.95 nm. The second generation, with higher Tempol loading, showed an average size of 141.4 ± 6.13 nm and a Z-average diameter of 560.7 ± 171.1 nm. The zeta potentials were -18.9 ± 5.02 mV and -11.9 ± 3.54 mV for the first and second generations, respectively. Both generations demonstrated the presence of urethane linkages, confirmed by Fourier Transform Infrared Spectroscopy (FTIR). Loading studies revealed Tempol concentrations of 61.94 ± 3.04 μg/mg for the first generation and 77.61 ± 3.04 μg/mg for the second generation nanocapsules. Release profiles indicated an initial burst followed by a sustained, nearly linear release over 30 days. The higher PEGylation in the second generation nanocapsules is advantageous for intravenous administration, potentially enhancing their therapeutic efficacy in TBI treatment. This study demonstrates the feasibility of using polyurethane nanocapsules for the prolonged delivery of Tempol, offering a promising approach to manage oxidative stress and improve outcomes in TBI patients. Future work will include testing these nanocapsules in vivo to determine their potential at modulating recovery from TBI.

l-Asparaginase (l-ASNase) catalyzes the hydrolysis of l-asparagine, leading to its depletion and subsequent effects on the cellular proliferation and survival. In contrast to normal cells, malignant cells that lack asparagine synthase are extremely susceptible to asparagine deficiency. l-ASNase has been successfully employed in treating pediatric leukemias and non-Hodgkin lymphomas; however, its usage in adult patients and other types of cancer is limited due to significant side effects and drug resistance. Recent research has explored alternative formulations and delivery methods to enhance its efficacy and minimize adverse effects. One promising approach involves the immobilization of l-ASNase onto nanostructured materials, offering improved enzymatic activity and biocompatibility of the support. We harnessed an E. coli l-ASNase type II preparation to develop a novel strategy of enzyme immobilization on graphene oxide (GO)-based support. We compared GO and nanographene oxide (nGO) in terms of their biocompatibility and influence on enzyme parameters. The obtained l-ASNase on the nGO nanobiocatalyst maintains enzymatic activity and increases its stability, selectively acting on K562 leukemia cells without cytotoxic influence on normal endothelial cells. In the case of treated K562 cells, we confirmed enlargement in the cell and nucleus size, disturbance in the cell cycle (interphase and metaphase), and increased apoptosis rate. The potential therapeutic possibilities of immobilized l-ASNase on leukemia cell damage are also discussed, highlighting the importance of further research in this area for advancing cancer therapy.

The Wnt signaling pathway has a significant regulatory part in tissue development and homeostasis. Dysregulation of the Wnt signaling pathway has been associated with many diseases including cancers and various brain diseases, making this signaling pathway a promising therapeutic target for these diseases. In this review, we describe the roles of the Wnt signaling pathway in the blood-brain barrier (BBB) in intracranial tumors and peripheral tumors, from preclinical and clinical perspectives, introduce Wnt-regulated therapeutics including various types of drugs and nanomedicines as BBB modulators for brain-oriented drug delivery and as therapeutic drugs for cancer treatments, and finally discuss limitations and future perspectives for Wnt-regulated therapeutics.

Drug delivery systems (DDSs) are crucial for the controlled release and targeted delivery of therapeutic agents, enhancing the stability and specificity of small molecules, nucleic acids, or peptides and addressing challenges such as drug instability and poor tissue targeting, particularly in oncology. Over the past few decades, liposomes have become one of the most widely used DDSs due to their unique physicochemical properties and biocompatibility. In the 1990s, liposomes were approved by the FDA as the first nanomedicine for disease treatment. Ferritin, a natural protein with a hollow nanocage structure, shares many similarities in architecture and functionality with liposomes. As an innovative DDS, ferritin offers distinct advantages including inherent tumor-targeting capabilities and exceptional biocompatibility. Liposomes and ferritin represent, respectively, established and emerging approaches in drug delivery, both excelling in key features like encapsulation efficiency and biocompatibility, which align with the standards for pharmaceutical carriers. While liposomal formulations have been clinically used, challenges such as precision targeting remain unresolved. In contrast, although ferritins hold considerable promise for drug delivery, they have not yet been implemented in clinical practice. In this review, we provide a comprehensive analysis of ferritins and liposomes as drug delivery vehicles, evaluating their drug-loading capacities, tumor-targeting capabilities, biocompatibility, and therapeutic potential. On the basis of a comparison of their intended applications and inherent limitations in the context of current treatment strategies, ferritin is expected to be an ideal delivery vehicle for tumor-targeted therapy and a strong candidate for clinical translation in the near future.

Aldehyde represents an extremely useful bio-orthogonal group in chemical biology and has promoted the generation of high-quality bioconjugates in therapeutics development. However, the installation of an aldehyde group on a protein and subsequent conjugation remains technically inadequate in the aspect of site choice, substrate availability, and linkage stability. Herein, we take efforts to advance the genetic incorporation of an aldehyde-containing noncanonical amino acid in E. coli and then show that reductive amination could be a useful reaction in introducing various amine-containing molecules, including peptides, into a specific site of proteins.

In order to effectively replicate within a host cell, the Legionella pneumophila bacterium secretes effector enzymes into the cytoplasm in order to manipulate cellular host pathways including host ubiquitination. Some of these effectors, the so-called SidE-family, mediate noncanonical phosphoribosyl serine ubiquitination (PR-ubiquitination) of host substrate proteins, contributing to the recruitment of ER-remodeling proteins and the formation of a Legionella-containing vacuole, which is crucial in the early stages of bacterial infection. PR-ubiquitination is a dynamic process that is reversed by other Legionella effectors called deubiquitinases for PR-ubiquitination (Dups). We recently discovered a reactive allosteric cysteine in close proximity to the catalytic triad of DupA, which can be exploited as a target for covalent probe development. We here report on the synthesis of vinyl-sulfonate and fluoro-sulfonate warhead-containing phosphoribosyl ubiquitin probes, where the Arg42 position of ubiquitin is linked to the C1 of ribose via a native guanidinium group, and compare them to triazole-linked probes. In vitro tests on recombinant DupA and SdeA_PDE revealed that these probes are able to capture the enzymes covalently. In a pull-down proteomics experiment, DupA and DupB enzymes are enriched from Legionella-infected cell lysates, highlighting the potential of native Arg-riboside linked probes to capture Legionella effector enzymes in a complex proteome.

Toll-like receptors (TLR) are phylogenetically conserved mediators of innate immunity that are essential for establishing adaptive immune responses against invading pathogens. TLR7 is an endosomal receptor expressed predominantly in myeloid and B cells. Activation of TLR7 induces Type I interferon and proinflammatory responses; therefore, targeting TLR7 is a promising strategy for antitumor therapy. Although the use of bacterial components to trigger innate immune responses in cancer patients started a century ago, the effectiveness of systemic TLR agonists has been rather underwhelming in clinical trials, partly due to nonspecific immune activation leading to safety and tolerability issues. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality amenable to systemic administration with limited toxicity concerns via a targeted delivery platform. We generated TLR7 agonist-antibody conjugates that recognize tumor antigens expressed on the surface of tumor cells. Generated ADCs demonstrated robust activity in in vitro tumor antigen-presenting cell (APC) coculture systems as indicated by dose-dependent upregulation of PD-L1 and CD86 on macrophages. TLR7 agonist-ADC provided superior tumor growth control compared to intravenously (IV) administrated free TLR7 agonist. Treatment with TLR7 agonist-ADC led to prolonged activation of myeloid cells in the tumor microenvironment (TME) with minimum immune activation in the periphery. Systemic and tissue exposure studies demonstrated tumor-specific free drug release by targeted ADC treatment. In summary, the TLR7 agonist-ADC can potentially activate immune cells in the TME to generate tumor antigen-specific T-cell responses, making it an attractive approach for precision cancer therapy.

Brain tumors, particularly glioblastomas, represent the most complicated cancers to treat and manage due to their highly invasive nature and the protective barriers of the brain, including the blood-brain barrier (BBB). The efficacy of currently available treatments, viz., radiotherapy, chemotherapy, and immunotherapy, are frequently limited by major side effects, drug resistance, and restricted drug penetration into the brain. Lipid nanoparticles (LNPs) have emerged as a promising and targeted delivery system for brain tumors. Lipid nanocarriers have gained tremendous attention for brain tumor therapeutics due to multiple drug encapsulation abilities, controlled release, better biocompatibility, and ability to cross the BBB. Herein, a detailed analysis of the design, mechanisms, and therapeutic benefits of LNPs in brain tumor treatment is discussed. Moreover, we also discuss the safety issues and clinical developments of LNPs and their current and future challenges. Further, we also focused on the clinical transformation of LNPs in brain tumor therapy by eliminating side effects and engineering the LNPs to overcome the related biological barriers, which provide personalized, affordable, and low-risk treatment options.

Nonhealing chronic bacterial infections are very challenging to both patients and the healthcare-providing system. Multimodal therapy enhances the antibiotic efficacy to treat infections via combating multidrug resistance through cumulative therapeutic effects. Functionalized polydopamine (PDA)-coated Bi particles having a core-shell structure may treat such chronic infections. We fabricated a new advanced material based on Tris-functionalized PDA and Bi using a facile three-step protocol for healing drug-resistant bacterial infections. The fabrication of Bi particles, PDA coating on Bi particles, and their Tris functionalization were confirmed by X-ray diffraction, and spectroscopic and thermogravimetric analyses. Tris-functionalized PDA-coated Bi particles, abbreviated as Bi/PDA-Tris, exhibited a higher average diameter, improved hydrophilicity, aqueous dispersity, and colloidal stability. Bi/PDA-Tris showed a delicate surface morphology, narrow size distribution, spherical shape, and core-shell structure. In vitro bovine serum albumin and hemolysis assays showed minimal protein adsorption and the desirable hemocompatibility of Bi/PDA-Tris. Antibacterial gentamicin (GM)-immobilized Bi/PDA-Tris showed pH-mediated sustained drug release kinetics under acidic conditions. The in vitro study of GM-loaded Bi/PDA-Tris particles exhibited significant bacterial growth inhibition and bactericidal activity. Tris functionalization effectively enhances the antibacterial efficacy of the PDA shell under acidic conditions to target and heal bacterial infections. This approach has introduced economic, nontoxic, easy-to-use, relatively more biocompatible Bi particles as a substituent for precise metals like Pt, Au, and Ag for the development of core-shell composite materials.