Bioconjugate Chemistry最新文献

Heat-induced cancer therapies such as magnetic hyperthermia-based cancer therapy (MHCT) and photothermal tumor ablation (PTT) have garnered significant attention as minimally invasive new-generation cancer therapy modalities. However, solid tumors associated with hypoxia present a considerable challenge to effective cancer therapy. In this study, we took up the challenge of mitigating the limiting penetration ability of nanoparticles by integrating polydopamine-coated magnetic nanoparticles and motile anaerobic bacteria (PDBs) to function as a smart thermo-vector. The developed PDBs are capable of self-navigating hypoxic tumors and as thermo-therapy agents with the ability to induce heat through exposure to an alternating magnetic field or near-infrared laser light. The thermo-vector system exhibited a dual-functioning synergistic antitumor effect of MHCT and PTT and an outstanding tumor targeting efficiency, outperforming the conventional ‘nanoparticles only’ approach. The heat-induced cellular oxidative stress and disrupted mitochondrial function led to 80% cellular cytotoxicity within 24 h of treatment. The PDB-based approach led to complete tumor regression in c57BL/6 mice within 21 days of treatment and a tumor-free survival for 60 days without recurrence, proving the capability of the developed PDBs in combatting solid tumors.

Historically, RNA delivery via nanoparticles has primarily relied on encapsulation, as demonstrated by lipid nanoparticles in SARS-CoV-2 vaccines. Concerns about RNA degradation on nanoparticle surfaces initially limited the exploration of adsorption-based approaches. However, recent advancements have renewed interest in adsorption as a viable alternative. This Viewpoint explores the approaches of RNA incorporation in nanoparticles, comparing encapsulation, adsorption, and the combination of encapsulation and adsorption, and presents a framework to guide the selection of the most suitable strategy based on general characteristics.

Glioblastoma (GBM) is a highly invasive tumor with poorly defined boundaries, often leaving residual tissue after surgery, which contributes to the recurrence and poor prognosis. A critical challenge in GBM treatment is the precise identification of tumor boundaries during surgery to achieve a safe and complete resection. In this study, we present a novel near-infrared fluorescent agent, IR-PEG-cRGD, that is designed to accurately delineate GBM boundaries for surgical navigation of tumor resection. IR-PEG-cRGD is successfully prepared from the cyanine dye IR-820, which is conjugated to poly(ethylene glycol) (PEG) to prolong circulation time and enhance tumor accumulation. Additionally, a glioma-targeting peptide (cRGD, cyclo(Arg-Gly-Asp-d-Phe-Cys)) is conjugated to PEG to selectively target GBM. IR-PEG-cRGD demonstrates effective targeting and enrichment in subcutaneous human-derived GBM mice models, enabling specific distinguishing of the GBM margin from the surrounding parenchyma with a high signal-to-background ratio (SBR) of 4.79. Moreover, IR-PEG-cRGD can pass across the blood-brain barrier (BBB) efficiently. These findings indicate that IR-PEG-cRGD can serve as a valuable tool for the precise intraoperative delineation of GBM boundaries, aiding in safe and complete tumor resection.

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.

Cu(II) coordination complexes are emerging as promising anticancer agents due to their ability to induce oxidative stress through reactive oxygen species (ROS) generation. In this study, we synthesized and characterized two novel Cu(II) metallopeptide systems, 1/Cu(II) and 2/Cu(II), derived from the oligocationic bipyridyl cyclopeptides 1 and 2, and designed to enhance the transport of Cu(II) into cells and increase ROS levels. Spectroscopic and electrochemical analyses confirmed the formation of stable metallopeptide species in aqueous media. Inductively coupled plasma mass spectrometry (ICP-MS) studies demonstrated that both metallopeptides significantly increase intracellular Cu(II) accumulation in NCI/ADR-RES cancer cells, highlighting their role as efficient Cu(II) transporters. Additionally, ROS generation assays revealed that 1/Cu(II) induces a substantial increase in intracellular ROS levels, supporting the hypothesis of oxidative stress-induced cytotoxicity. Cell-viability assays further confirmed that both 1/Cu(II) and 2/Cu(II) exhibit strong anticancer activity in a number of cancer cell lines, with IC₅₀ values significantly lower than those of their free cyclopeptide counterparts or Cu(II) alone, showing an order of activity higher than that of cisplatin. Finally, molecular modeling studies provided further insights into the structural stability and coordination environment of Cu(II) within the metallopeptide complexes. These findings suggest that these Cu(II) cyclometallopeptide systems hold potential as novel metal-based therapeutic agents, leveraging Cu(II) transport and ROS increase as key strategies for cancer treatment.

The dsDNA-selective fluorescent-dye-based DNA damage assay was developed for DNA-encoded library (DEL) synthesis. For the various DEL synthesis conditions, the assay was validated through cross-checking with high-performance liquid chromatography (HPLC) analysis, and the fact was confirmed that the usage of a specific ratio of organic solvent can critically induce DNA damage. Also, the applicability of the assay was confirmed through the screening of the DNA-damaging condition of the on-DNA amide coupling reaction and Pd-catalyzed on-DNA N-arylation reaction.

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.

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.

Lysosomal enzyme replacement therapy (ERT) holds potential for treating lysosomal storage disorders, but achieving targeted delivery of deficient therapeutic enzymes remains a significant challenge. This study presents a novel approach for the lysosome-specific delivery of the β-glucosidase (B8CYA8) enzyme by covalently conjugating lysosome-targeting mannose-6-phosphate functionalized glycopolypeptides (M6P-GP). We used a protein-glycopolypeptide conjugate developed through advanced protein engineering and bioconjugation techniques. By conjugating β-glucosidase to M6P-GP that has a high affinity for the cation-independent mannose-6-phosphate receptors (CI-MPR) and lysosomal receptors, we enhance the enzyme's selective intracellular uptake and lysosome-specific localization. To attain maximum activity of the near-native enzyme after delivery, we have designed and synthesized an acetal linkage containing the pH-responsive linker maleimide-acetal-azide (MAA), which will cleave in the lysosomal acidic pH to detach the glycopolypeptide from the protein backbone. We demonstrated the efficient cellular uptake of the protein-glycopolypeptide conjugate and showed targeted lysosome delivery, leading to increased enzymatic activity compared to untreated cells. Our results proved that the approach mainly improves the specificity and efficiency of enzyme delivery, particularly into lysosomes, which may enable new methods for ERT. These findings suggest that protein-glycopolypeptide conjugates could represent a class of bioconjugates to design targeted enzyme therapies, offering a pathway to the effective treatment of Gaucher disease (GD) and potentially other related lysosomal storage disorders.

Nucleic acid nanoparticles (NANPs) fabricated by using the DNA origami method have broad utility in materials science and bioengineering. Their site-specific, heterovalent functionalization with secondary molecules such as proteins or fluorophores is a unique feature of this technology that drives its utility. Currently, however, there are few chemistries that enable fast, efficient covalent functionalization of NANPs with a broad conjugate scope and heterovalency. To address this need, we introduce synthetic methods to access inverse electron-demand Diels-Alder chemistry on NANPs. We demonstrate a broad conjugate scope, characterize application-relevant kinetics, and integrate this new chemistry with strain-promoted azide-alkyne cycloaddition chemistry to enable heterovalent click reactions on NANPs. We applied these chemistries to formulate a prototypical chemical countermeasure against chemical nerve agents. We envision this additional chemistry finding broad utility in the synthetic toolkit accessible to the nucleic acid nanotechnology community.