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Targeted Delivery of TLR7 Agonists to the Tumor Microenvironment Enhances Tumor Immunity via Activation of Tumor-Resident Myeloid Cells.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-13 DOI: 10.1021/acs.bioconjchem.4c00534
Emanuela Sega, Srikanth Kotapati, Yam B Poudel, Qinqin Cheng, Keerthi Sadanala, Bridget Schneider, Eugene P Chekler, Chetana Rao, Sanjeev Gangwar, Tim Sproul, Deborah Law, Miranda Broz, Pavel Strop, Sayumi Yamazoe

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.

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引用次数: 0
Lipid Nanocarriers as Precision Delivery Systems for Brain Tumors.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-12 DOI: 10.1021/acs.bioconjchem.5c00007
Roshan Keshari, Mahima Dewani, Navneet Kaur, Girijesh Kumar Patel, Sumit Kumar Singh, Pranjal Chandra, Rajendra Prasad, Rohit Srivastava

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.

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引用次数: 0
Functionalization of Biomimetic Polydopamine Shells Constructed onto Bismuth-Core Particles for pH-Mediated Drug Targeting to Heal Bacterial Infections.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-12 DOI: 10.1021/acs.bioconjchem.5c00003
Md Abdur Rahman, Pinky Akter, Md Rowshanul Habib, Md Ataur Rahman, Md Mahiuddin, Md Mahbubor Rahman, Md Shahidul Islam, M A Jalil Miah, Hasan Ahmad

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.

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引用次数: 0
Ferritin versus Liposomes: A Comparative Analysis of Protein- and Lipid-Based Drug Delivery Systems.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-10 DOI: 10.1021/acs.bioconjchem.4c00576
Yang Liu, Feiyan Zhu, Jiuyang He, Minmin Liang

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.

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引用次数: 0
Delivery of Tempol from Polyurethane Nanocapsules to Address Oxidative Stress Post-Injury.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-08 DOI: 10.1021/acs.bioconjchem.4c00360
Temitope Ale, Tolulope Ale, Kimberly J Baker, Kameel M Zuniga, Jack Hutcheson, Erin Lavik

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.

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引用次数: 0
Method for Screening Sodium Cyanoborohydride for Free Cyanide Content and Its Impact on Bioconjugation Chemistry.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-06 DOI: 10.1021/acs.bioconjchem.4c00514
Jarrod P Cohen, Adam DiCaprio, Jian He, Mikhail Reibarkh, James Small, Matthew Schombs

Sodium cyanoborohydride (CBH) is commonly used as a mild reducing agent in the reductive amination of aldehydes and free amines. Within the pharmaceutical industry, this reaction is employed in the bioconjugation of proteins and peptides. Free cyanide species such as HCN and NaCN are known residual impurities in CBH that can contribute to the formation of undesired side products including cyanoamines and cyanohydrins. In commercial processes, the potential for bound cyanated species requires an analytical control strategy to monitor and mitigate any risk to human health. Given these concerns, minimization of cyanated side products is of utmost priority and can be achieved through a robust control strategy of quantitative screening of starting materials for free cyanide. Alternative risk mitigation strategies such as purification of bound cyanide containing species to pure species are less effective due to minor chemical differences between the expected product and bound cyanide species. Herein, we present a simple chromatographic assay for the quantitation of free cyanide in the raw material sodium cyanoborohydride. Method development, robustness evaluation, and scientific soundness assessment are reported with excellent linearity, accuracy, precision, and specificity. Additionally, this method was applied for the evaluation of raw material supplied from 10 commercial sources, none of which report a specification for free cyanide within their certificate of analysis. The measured free cyanide from these vendors ranged from 8 to 80 mM concentration, thereby confirming the value of screening these raw materials. Finally, we demonstrate the impact of free cyanide on a model bioconjugation reaction between ornithine and glyceraldehyde.

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引用次数: 0
Development of Transiently Strainable Benzocycloheptenes for Catalyst-Free, Visible-Light-Mediated [3 + 2]-Cycloadditions.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-02-04 DOI: 10.1021/acs.bioconjchem.4c00595
Shivangi Kharbanda, Osaid Alkhamayseh, Georgia Eastham, Jimmie D Weaver

Dynamic photogeneration of ephemeral and reactive species is enabling for chemical reactions, providing spatial and temporal control. A previous study from our group established the ability of 6,7-dihydro-5H-benzo[7]annulene, benzocycloheptene (BC7), to convert photochemical energy into ring strain, enabling the rapid cycloaddition of alkyl azides with the reversibly formed and transient trans-isomer, affording versatile nonaromatic triazolines. Despite the conceptual advances of the previous study, some challenges remained: the fragility of the triazoline products, the low regioselectivity for the cycloaddition, a need for an iridium-based photosensitizer and organic-based solvents, and a lack of convenient linchpin functional group handles. Herein, we communicate the development of a second generation of BC7 molecules that overcome the issues of the first generation. A method to convert fragile triazoline products to stable triazoles was developed. The alkene component was polarized with a carbonyl group, dramatically improving the regioselectivity while simultaneously red-shifting the absorbance of the cycloalkene into the visible region, which was expected to facilitate direct excitation and eliminate the need for photocatalysts. However, experiments indicated that the cycloaddition involved passage through a triplet manifold, complicating the direct excitation strategy. This was successfully overcome by attaching a bromine atom directly to the alkene moiety, which accelerated singlet-to-triplet intersystem crossing by the heavy atom effect. Further exploration identified sites of substitution that can increase the water solubility and provide a handle for the loading of chemical tools and probes.

短暂和反应性物种的动态光生成有利于化学反应,提供空间和时间控制。我们研究小组之前的一项研究证实,6,7-二氢-5H-苯并[7]萘,即苯并环庚烯(BC7),能够将光化学能量转化为环应变,从而使烷基叠氮化物与可逆形成的瞬时反式异构体快速发生环加成反应,生成多功能的非芳香族三唑类化合物。尽管之前的研究在概念上取得了进展,但仍存在一些挑战:三唑啉产物易碎、环化反应的区域选择性低、需要铱基光敏剂和有机溶剂,以及缺乏方便的关键官能团处理。在此,我们介绍了第二代 BC7 分子的开发情况,它克服了第一代 BC7 分子存在的问题。我们开发了一种将脆弱的三唑啉产物转化为稳定的三唑的方法。烯烃成分被羰基极化,极大地提高了区域选择性,同时将环烯烃的吸光度红移到可见光区域,这有望促进直接激发并消除对光催化剂的需求。然而,实验表明,环化反应需要通过三重歧管,这使得直接激发策略变得复杂。通过在烯分子上直接连接一个溴原子,在重原子效应的作用下加速了单三重体系间的交叉,从而成功地克服了这一问题。进一步的探索确定了可提高水溶性的取代位点,并为化学工具和探针的装载提供了一个把手。
{"title":"Development of Transiently Strainable Benzocycloheptenes for Catalyst-Free, Visible-Light-Mediated [3 + 2]-Cycloadditions.","authors":"Shivangi Kharbanda, Osaid Alkhamayseh, Georgia Eastham, Jimmie D Weaver","doi":"10.1021/acs.bioconjchem.4c00595","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00595","url":null,"abstract":"<p><p>Dynamic photogeneration of ephemeral and reactive species is enabling for chemical reactions, providing spatial and temporal control. A previous study from our group established the ability of 6,7-dihydro-5H-benzo[7]annulene, benzocycloheptene (<b>BC7</b>), to convert photochemical energy into ring strain, enabling the rapid cycloaddition of alkyl azides with the reversibly formed and transient <i>trans</i>-isomer, affording versatile nonaromatic triazolines. Despite the conceptual advances of the previous study, some challenges remained: the fragility of the triazoline products, the low regioselectivity for the cycloaddition, a need for an iridium-based photosensitizer and organic-based solvents, and a lack of convenient linchpin functional group handles. Herein, we communicate the development of a second generation of <b>BC7</b> molecules that overcome the issues of the first generation. A method to convert fragile triazoline products to stable triazoles was developed. The alkene component was polarized with a carbonyl group, dramatically improving the regioselectivity while simultaneously red-shifting the absorbance of the cycloalkene into the visible region, which was expected to facilitate direct excitation and eliminate the need for photocatalysts. However, experiments indicated that the cycloaddition involved passage through a triplet manifold, complicating the direct excitation strategy. This was successfully overcome by attaching a bromine atom directly to the alkene moiety, which accelerated singlet-to-triplet intersystem crossing by the heavy atom effect. Further exploration identified sites of substitution that can increase the water solubility and provide a handle for the loading of chemical tools and probes.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Unique Prodrug Targeting the Prostate-Specific Membrane Antigen for the Delivery of Monomethyl Auristatin E.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-29 DOI: 10.1021/acs.bioconjchem.4c00297
Hunter N Bomba, Melody D Fulton, Emily A Savoy, Beatrice Langton-Webster, Clifford E Berkman

Monomethyl auristatin E (MMAE) is a promising treatment option for patients diagnosed with prostate cancer (PCa); however, toxicities prevent MMAE from being administered as free drug. No MMAE-based treatment is currently marketed for PCa. Herein, we describe a small-molecule-drug conjugate, CTT2274, for the selective delivery of MMAE. CTT2274 is composed of a prostate-specific membrane antigen (PSMA)-binding scaffold, a biphenyl motif, a pH-sensitive phosphoramidate linker, and MMAE payload. We demonstrate that CTT2274 shows selective binding to PSMA, which is overexpressed on PCa cells, and induces tumor cell death in vitro. In a patient-derived xenograft tumor model of PCa in mice, we show that weekly intravenous dosing of CTT2274 at 3.6 mg/kg for six weeks is superior to treatment with free MMAE at equivalent doses. Mice treated with CTT2274 experienced prolonged tumor suppression and significantly greater overall survival than mice treated with PBS. Additionally, the safety of CTT2274 compared to an equivalent dose of MMAE was assessed in healthy, non-tumor-bearing mice. Our results demonstrate that CTT2274 therapy is as efficacious as MMAE, results in superior overall survival, and has a more favorable safety profile. Together, these data indicate that CTT2274 is a candidate for clinical translation for the treatment of PCa.

{"title":"A Unique Prodrug Targeting the Prostate-Specific Membrane Antigen for the Delivery of Monomethyl Auristatin E.","authors":"Hunter N Bomba, Melody D Fulton, Emily A Savoy, Beatrice Langton-Webster, Clifford E Berkman","doi":"10.1021/acs.bioconjchem.4c00297","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00297","url":null,"abstract":"<p><p>Monomethyl auristatin E (MMAE) is a promising treatment option for patients diagnosed with prostate cancer (PCa); however, toxicities prevent MMAE from being administered as free drug. No MMAE-based treatment is currently marketed for PCa. Herein, we describe a small-molecule-drug conjugate, CTT2274, for the selective delivery of MMAE. CTT2274 is composed of a prostate-specific membrane antigen (PSMA)-binding scaffold, a biphenyl motif, a pH-sensitive phosphoramidate linker, and MMAE payload. We demonstrate that CTT2274 shows selective binding to PSMA, which is overexpressed on PCa cells, and induces tumor cell death <i>in vitro</i>. In a patient-derived xenograft tumor model of PCa in mice, we show that weekly intravenous dosing of CTT2274 at 3.6 mg/kg for six weeks is superior to treatment with free MMAE at equivalent doses. Mice treated with CTT2274 experienced prolonged tumor suppression and significantly greater overall survival than mice treated with PBS. Additionally, the safety of CTT2274 compared to an equivalent dose of MMAE was assessed in healthy, non-tumor-bearing mice. Our results demonstrate that CTT2274 therapy is as efficacious as MMAE, results in superior overall survival, and has a more favorable safety profile. Together, these data indicate that CTT2274 is a candidate for clinical translation for the treatment of PCa.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nanoscale Effects in the Room-Temperature UV-Visible Photoluminescence from Silica Particles and Its Cancer Cell Imaging.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-29 DOI: 10.1021/acs.bioconjchem.4c00420
Divya Rani, Deepika Singh, Anil Kumar, Monika Dhiman, Anjali Saini, Partho Biswas, Rachana Rachana, Partha Roy, Mrinal Dutta, Arup Samanta

Silica nano/microparticles have generated significant interest for the past decades, emerging as a versatile material with a wide range of applications in photonic crystals, bioimaging, chemical sensors, and catalysis. This study focused on synthesizing silica nano/microparticles ranging from 20 nm to 1.2 μm using the Stöber and modified Stöber methods. The particles exhibited photoluminescence emission across a UV-visible range, specifically in the UV (∼290, ∼327, ∼339, and ∼377 nm), blue (∼450 nm), green (∼500 nm), yellow (∼576 nm), and red (∼634 nm) range of the electromagnetic spectrum. These emissions are due to radiative relaxation processes involving oxygen-deficient centers arising due to unrelaxed oxygen vacancies, strong interacting surface silanols, 2-fold coordinated silicon, self-trapped excitons, hydrogen-related species, strain-induced defects, and nonbridging oxygen hole centers excited via two-photon and single photon absorption. The increased PL intensity with a decreasing particle size was attributed to higher concentrations of defect sites in the case of smaller-sized particles. The MTT assay, AO/EB staining, and the DCFDA assay confirmed the biocompatible nature of silica particles in the HepG2 cell line. In addition, the cell viability assay in a normal cell line (HEK293) also showed no substantial cell death. Successful bioimaging of HepG2 cells was performed with silica nano/microparticles, which exhibited blue and green fluorescence, along with Hoechst33258 dye. Even though 20 nm-sized silica particles showed higher PL emission, particles sized above 20 nm showed better fluorescence in HepG2 cells, citing their potential in in vitro bioimaging applications.

{"title":"Nanoscale Effects in the Room-Temperature UV-Visible Photoluminescence from Silica Particles and Its Cancer Cell Imaging.","authors":"Divya Rani, Deepika Singh, Anil Kumar, Monika Dhiman, Anjali Saini, Partho Biswas, Rachana Rachana, Partha Roy, Mrinal Dutta, Arup Samanta","doi":"10.1021/acs.bioconjchem.4c00420","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00420","url":null,"abstract":"<p><p>Silica nano/microparticles have generated significant interest for the past decades, emerging as a versatile material with a wide range of applications in photonic crystals, bioimaging, chemical sensors, and catalysis. This study focused on synthesizing silica nano/microparticles ranging from 20 nm to 1.2 μm using the Stöber and modified Stöber methods. The particles exhibited photoluminescence emission across a UV-visible range, specifically in the UV (∼290, ∼327, ∼339, and ∼377 nm), blue (∼450 nm), green (∼500 nm), yellow (∼576 nm), and red (∼634 nm) range of the electromagnetic spectrum. These emissions are due to radiative relaxation processes involving oxygen-deficient centers arising due to unrelaxed oxygen vacancies, strong interacting surface silanols, 2-fold coordinated silicon, self-trapped excitons, hydrogen-related species, strain-induced defects, and nonbridging oxygen hole centers excited via two-photon and single photon absorption. The increased PL intensity with a decreasing particle size was attributed to higher concentrations of defect sites in the case of smaller-sized particles. The MTT assay, AO/EB staining, and the DCFDA assay confirmed the biocompatible nature of silica particles in the HepG2 cell line. In addition, the cell viability assay in a normal cell line (HEK293) also showed no substantial cell death. Successful bioimaging of HepG2 cells was performed with silica nano/microparticles, which exhibited blue and green fluorescence, along with Hoechst33258 dye. Even though 20 nm-sized silica particles showed higher PL emission, particles sized above 20 nm showed better fluorescence in HepG2 cells, citing their potential in <i>in vitro</i> bioimaging applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Biomechanical and Functional Features of the Carrier Erythrocytes Prolonging Circulation Time of Biotherapeutic Targeted to Glycophorin A.
IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-27 DOI: 10.1021/acs.bioconjchem.4c00522
Alina D Peshkova, Taylor V Brysgel, Parth Mody, Jia Nong, Zhicheng Wang, Jacob W Myerson, Rustem I Litvinov, John W Weisel, Jacob S Brenner, Patrick M Glassman, Oscar A Marcos-Contreras, Vladimir R Muzykantov

Red blood cells (RBCs) serve as natural transporters and can be modified to enhance the pharmacokinetics and pharmacodynamics of a protein cargo. Affinity targeting of Factor IX (FIX) to the RBC membrane is a promising approach to improve the (pro)enzyme's pharmacokinetics. For RBC targeting, purified human FIX was conjugated to the anti-mouse glycophorin A monoclonal antibody Ter119. The goal of this study was to characterize the activity of the FIX-Ter119 conjugate and efficacy of its loading on RBCs, as well as to investigate the biodistribution, pharmacokinetics, and various biological properties of the loaded RBCs. Mouse RBCs were incubated with the Ter119-FIX conjugate, where adding 10,000 molecules per RBC resulted in 37% binding (4K/RBC), and 50,000 molecules per RBC resulted in 34% binding (17K/RBC). The pharmacokinetics (PK) profile showed that more than 90% of the Ter119-FIX conjugate was associated with RBCs and circulated stably bound to the RBCs for 24 h, increasing the area under the PK curve 7.6 times vs free FIX. Ter119-FIX loaded RBCs have specific procoagulant FIXa activity, including promotion of thrombin generation and acceleration of clotting in FIX-deficient plasma. Morphological characterization shows that Ter119-FIX-loaded RBCs undergo a shape change, with an increased fraction of echinocytes and spheroidal RBCs. Ektacytometry and electron microscopy assessment of RBC compressibility reveal a dose-dependent reduction in the deformability of RBCs loaded with Ter119-FIX. In conclusion, RBCs loaded with Ter119-FIX have the potential to serve as prohemostatic agents, but their reduced deformability warrants further engineering of Ter119-FIX to improve the safety profile.

{"title":"Biomechanical and Functional Features of the Carrier Erythrocytes Prolonging Circulation Time of Biotherapeutic Targeted to Glycophorin A.","authors":"Alina D Peshkova, Taylor V Brysgel, Parth Mody, Jia Nong, Zhicheng Wang, Jacob W Myerson, Rustem I Litvinov, John W Weisel, Jacob S Brenner, Patrick M Glassman, Oscar A Marcos-Contreras, Vladimir R Muzykantov","doi":"10.1021/acs.bioconjchem.4c00522","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00522","url":null,"abstract":"<p><p>Red blood cells (RBCs) serve as natural transporters and can be modified to enhance the pharmacokinetics and pharmacodynamics of a protein cargo. Affinity targeting of Factor IX (FIX) to the RBC membrane is a promising approach to improve the (pro)enzyme's pharmacokinetics. For RBC targeting, purified human FIX was conjugated to the anti-mouse glycophorin A monoclonal antibody Ter119. The goal of this study was to characterize the activity of the FIX-Ter119 conjugate and efficacy of its loading on RBCs, as well as to investigate the biodistribution, pharmacokinetics, and various biological properties of the loaded RBCs. Mouse RBCs were incubated with the Ter119-FIX conjugate, where adding 10,000 molecules per RBC resulted in 37% binding (4K/RBC), and 50,000 molecules per RBC resulted in 34% binding (17K/RBC). The pharmacokinetics (PK) profile showed that more than 90% of the Ter119-FIX conjugate was associated with RBCs and circulated stably bound to the RBCs for 24 h, increasing the area under the PK curve 7.6 times vs free FIX. Ter119-FIX loaded RBCs have specific procoagulant FIXa activity, including promotion of thrombin generation and acceleration of clotting in FIX-deficient plasma. Morphological characterization shows that Ter119-FIX-loaded RBCs undergo a shape change, with an increased fraction of echinocytes and spheroidal RBCs. Ektacytometry and electron microscopy assessment of RBC compressibility reveal a dose-dependent reduction in the deformability of RBCs loaded with Ter119-FIX. In conclusion, RBCs loaded with Ter119-FIX have the potential to serve as prohemostatic agents, but their reduced deformability warrants further engineering of Ter119-FIX to improve the safety profile.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Bioconjugate Chemistry
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