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The macrophage soluble receptor AIM/Api6/CD5L displays a broad pathogen recognition spectrum and is involved in early response to microbial aggression

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Cellular & Molecular Immunology 2014年第4期11卷 343-354页

作者： Vanesa G. Martinez Cristina Escoda-Ferran Ines Tadeu Simees Satoko Arai Marc Orta Mascaro esther carreras Mario Martinez-Florensa Jose Yelamos Toru Miyazaki Francisco Lozano Grup d'Immunoreceptors del Sistema Innat i Adaptatiu Institut d'Investigacions Biomediques August Pii Sunyer (IDIBAPS) Barcelona Spain Center for Disease Biology and Integrative Medicine Faculty of Medicine University of Tokyo Tokyo Cancer Research Program Hospital del Mar Medical Research Institute and Department of Immunology Hospital del Mar Barcelona Spain Servei d'Immunologia Centre de DiagnOstic Biomedic Hospital Clinic Barcelona Barcelona Spain Departament de Biologia Cellular Immunologia i Neurociencies Facultat de Medicina Universitat de Barcelona Barcelona Spain

Apoptosis inhibitor of macrophages （AIMs）, a homologue of human Spa, is a mouse soluble member of the scavenger receptor cysteine-rich superfamily （SRCR-SF）. This family integrates a group of proteins expressed by innate and adaptive immune cells for which no unifying function has yet been described. Pleiotropic functions have been ascribed to AIM, from viability support in lymphocytes during thymic selection to lipid metabolism and anti-inflammatory effects in autoimmune pathologies. In the present report, the pathogen binding properties of AIM have been explored. By using a recombinant form of AIM （rAIM） expressed in mammalian cells, it is shown that this protein is able to bind and aggregate Gram-positive and Gram-negative bacteria, as well as pathogenic and saprophytic fungal species. Importantly, endogenous AIM from mouse serum also binds to microorganisms and secretion of AIM was rapidly induced in mouse spleen macrophages following exposure to conserved microbial cell wall components. Cytokine release induced by well-known bacterial and fungal Toll-like receptor （TLR） ligands on mouse splenocytes was also inhibited in the presence of rAIM. Furthermore, mouse models of pathogen-associated molecular patterns （PAMPs）-induced septic shock of bacterial and fungal origin showed that serum AIM levels changed in a time-dependent manner. Altogether, these data suggest that AIM plays a general homeostatic role by supporting innate humoral defense during pathogen aggression.

关键词： innate immunity pattern recognition receptor scavenger receptor

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering

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Science China Materials 2020年第1期63卷 147-156页

作者： Eric Volta-Duran Olivia Cano-Garrido Naroa Serna Hector Lopez-Laguna Laura Sanchez-Garcia Mireia Pesarrodona Alejandro Sanchez-Chardi Ramon Mangues Antonio Villaverde esther Vazquez Ugutz Unzueta Institut de Biotecnologia i de Biomedicina Universitat Autònoma de BarcelonaBellaterra08193 BarcelonaSpain Departament de Genetica i de Microbiologia Universitat Autònoma de BarcelonaBellaterra08193 BarcelonaSpain CIBER de Bioingeniería Biomateriales y Nanomedicina(CIBER-BBN)C/Monforte de Lemos 3-528029 MadridSpain Nanoligent SL Edifici EUREKAUniversitat Autonoma de BarcelonaBellaterra08193 BarcelonaSpain Institut dInvestigacions Biomèdiques Sant Pau and Josep carreras Research Institute Hospital de la Santa Creu i Sant Pau08041 BarcelonaSpain Departament de Biologia Evolutiva Ecologia i Ciencies AmbientalsFacultat de BiologiaUniversitat de BarcelonaAv.Diagonal 64308028 BarcelonaSpain Institute for Research in Biomedicine(IRB Barcelona) The Barcelona Institute of Science and Technology08028 BarcelonaSpain

Modular protein engineering is suited to recruit complex and multiple functionalities in single-chain polypeptides. Although still unexplored in a systematic way, it is anticipated that the positioning of functional domains would impact and refine these activities, including the ability to organize as supramolecular entities and to generate multifunctional protein materials. To explore this concept, we have repositioned functional segments in the modular protein T22-GFP-H6 and characterized the resulting alternative fusions. In T22-GFP-H6, the combination of T22 and H6 promotes selfassembling as regular nanoparticles and selective binding and internalization of this material in CXCR4-overexpressing tumor cells, making them appealing as vehicles for selective drug delivery. The results show that the pleiotropic activities are dramatically affected in module-swapped constructs, proving the need of a carboxy terminal positioning of H6 for protein self-assembling, and the accommodation of T22 at the amino terminus as a requisite for CXCR4^+ cell binding and internalization. Furthermore, the failure of self-assembling as regular oligomers reduces cellular penetrability of the fusions while keeping the specificity of the T22-CXCR4 *** these data instruct how multifunctional nanoscale protein carriers can be designed for smart, protein-driven drug delivery, not only for the treatment of CXCR4^+ human neoplasias, but also for the development of anti-HIV drugs and other pathologies in which CXCR4 is a relevant homing marker.

关键词： nanoparticles protein materials recombinant proteins drug delivery self-assembling cancer cell targeting

Site-directed cysteine coupling of disulfide-containing non-antibody carrier proteins(THIOCAPs)

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Science China Materials 2023年第10期66卷 4109-4120页

作者： Ariana Rueda Julian I.Mendoza Lorena Alba-Castellon Eloi Parladé Eric Voltà-Durán David Paez Anna Avino Ramon Eritja esther Vázquez Antonio Villaverde Ramón Mangues Ugutz Unzueta Institut d'Investigació Biomèdica Sant Pau(IIB Sant Pau) Sant Quintí 77-7908041 BarcelonaSpain Josep carreras Leukaemia Research Institute(IJC Campus Sant Pau) 08041 BarcelonaSpain CIBER de Bioingeniería Biomateriales y NanomedicinaInstituto de Salud Carlos Ⅲ28029 MadridSpain Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona08193 BellaterraSpain Departament de Genètica i de Microbiologia Universitat Autònoma de Barcelona08193 BellaterraSpain Department of Medical Oncology Hospital de la Santa Creu i Sant Pau.Barcelona08025 BarcelonaSpain CIBER de Enfermedades Raras(CIBERER) Instituto de Salud Carlos Ⅲ28029 MadridSpain Institute for Advanced Chemistry of Catalonia(IQAC) CSIC08034 BarcelonaSpain

The development of a new generation of nonantibody protein drug delivery systems requires site-directed conjugation strategies to produce homogeneous,reproducible and scalable *** that,the genetic addition of cysteine residues into solvent-exposed positions allows the thiol-mediated cysteine coupling of therapeutic drugs into protein-based ***,the high reactivity of unpaired cysteine residues usually reduces protein stability,consequently imposing the use of more methodologically demanding purification *** is especially relevant for disulfide-containing nanocarriers,as previously observed in ***,although many protein scaffolds and targeting ligands are also rich in disulfide bridges,the use of these methodologies over emerging non-antibody carrier proteins has been completely ***,we report the development of a simple and straightforward procedure for a onestep production and site-directed cysteine conjugation of disulfide-containing non-antibody thiolated carrier proteins(THIOCAPs).This method is validated in a fluorescent C-X-C chemokine receptor 4(CXCR4)-targeted multivalent nanocarrier containing two intramolecular disulfide bridges and one reactive cysteine residue strategically placed into a solvent-exposed position(THIO-T22-GFP-H6)for drug conjugation and in a humanized alternative intended for clinical applications(T22-HSNBT-H6).Thus,we produce very stable,homogeneous and fully functional antitumoral nanoconjugates(THIO-T22-GFP-H6-MMAE and T22-HSNBT-H6-MMAE)that selectively eliminate target cancer cells via ***,the developed methodology appears as a powerful tool for the rational engineering of emerging non-antibody,cell-targeted protein nanocarriers that contain disulfide bridges together with a solvent-exposed reactive cysteine(THIOCAP).This should pave the way for the development of a new generation of stable,homogeneous and efficient nanomedicines.

关键词： disulfide directed bridges

Self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4^(+) head and neck squamous cell carcinoma tumors

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2578-2591页

作者： Elisa Rioja-Blanco Irene Arroyo-Solera Patriciaálamo Isolda Casanova Alberto Gallardo Ugutz Unzueta Naroa Serna Laura Sánchez-García Miquel Quer Antonio Villaverde esther Vázquez Ramon Mangues Lorena Alba-Castellón Xavier León Institut d'InvestigacióBiomèdica Sant Pau(IIB-Sant Pau) Barcelona 08041Spain Institut de Recerca contra la Leucèmia Josep carreras Barcelona 08025Spain CIBER de Bioingeniería Biomateriales y Nanomedicina(CIBER-BBN)Madrid 28029Spain Department of Pathology Hospital de la Santa Creu i Sant PauBarcelona 08041Spain Institut de Biotecnologia i de Biomedicina Universitat Autònoma de BarcelonaBellaterra 08193Spain Departament de Genètica i de Microbiologia Universitat Autònoma de BarcelonaBellaterra 08193Spain Department of Otorhinolaryngology Hospital de la Santa Creu i Sant PauBarcelona 08041Spain

Loco-regional recurrences and distant metastases represent the main cause of head and neck squamous cell carcinoma(HNSCC) mortality. The overexpression of chemokine receptor 4(CXCR4) in HNSCC primary tumors associates with higher risk of developing loco-regional recurrences and distant metastases, thus making CXCR4 an ideal entry pathway for targeted drug delivery. In this context, our group has generated the self-assembling protein nanocarrier T22-GFP-H6, displaying multiple T22 peptidic ligands that specifically target CXCR4. This study aimed to validate T22-GFP-H6 as a suitable nanocarrier to selectively deliver cytotoxic agents to CXCR4^(+)tumors in a HNSCC model. Here we demonstrate that T22-GFP-H6 selectively internalizes in CXCR4^(+)HNSCC cells, achieving a high accumulation in CXCR4^(+)tumors in vivo, while showing negligible nanocarrier distribution in non-tumor bearing organs. Moreover, this T22-empowered nanocarrier can incorporate bacterial toxin domains to generate therapeutic nanotoxins that induce cell death in CXCR4-overexpressing tumors in the absence of histological alterations in normal organs. Altogether, these results show the potential use of this T22-empowered nanocarrier platform to incorporate polypeptidic domains of choice to selectively eliminate CXCR4^(+)cells in HNSCC. Remarkably, to our knowledge, this is the first study testing targeted proteinonly nanoparticles in this cancer type, which may represent a novel treatment approach for HNSCC patients.

关键词： Targeted drug delivery Protein nanoparticles CXCR4 receptor HNSCC Cell targeting Recombinant proteins Nanotoxins Cancer therapy

Engineering a recombinant chlorotoxin as celltargeted cytotoxic nanoparticles

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Science China Materials 2019年第6期62卷 892-898页

作者： Raquel Díaz Laura Sánchez-García Naroa Serna Alejandro Sánchez-Chardi Olivia Cano-Garrido Julieta M.Sánchez Ugutz Unzueta esther Vazquez Antonio Villaverde Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona Departament de Genètica i de Microbiologia Universitat Autònoma de Barcelona CIBER de Bioingeniería Biomateriales y Nanomedicina(CIBER-BBN) Servei de Microscòpia Universitat Autònoma de Barcelona Biomedical Research Institute Sant Pau(IIB-Sant Pau)and Josep carreras Research Institute Hospital de la Santa Creu i Sant Pau Universidad Nacional de Córdoba Facultad de Ciencias ExactasFísicas y Naturales.ICTA and Departamento de QuímicaCátedra de Química Biológica.Córdoba.Argentina.CONICETInstituto de Investigaciones Biológicas y Tecnológicas(IIBYT)

Cytotoxic proteins have a wide applicability in human therapies, especially in those conditions that require efficient and selective cell killing, such as cancer. Chlorotoxin (CTX) is a small (4 kDa) basic peptide from the venom of the yellow scorpion Leiurus quinquestriatus , which blocks small-conductance chloride channels thus paralyzing the scorpion prey. Being not extremely potent as a cytotoxin (for instance when compared with ribosome-inactivating proteins), it has gained interest as a targeting agent.

关键词：重组DNA技术细胞毒活性纳米颗粒蝎毒素癌细胞可生物降解氯药物载体