Advances in pharmacology最新文献

Toward non-invasive CNS delivery: The emergence of brain shuttle peptides. 迈向无创中枢神经传递：脑穿梭肽的出现。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-04-28 DOI: 10.1016/bs.apha.2026.03.001

Macarena Sánchez-Navarro, Benjamí Oller-Salvia

{"title":"Toward non-invasive CNS delivery: The emergence of brain shuttle peptides.","authors":"Macarena Sánchez-Navarro, Benjamí Oller-Salvia","doi":"10.1016/bs.apha.2026.03.001","DOIUrl":"10.1016/bs.apha.2026.03.001","url":null,"abstract":"The blood-brain barrier (BBB) is a highly specialized interface that preserves neural homeostasis but severely limits the entry of therapeutic agents, posing a major challenge for central nervous system (CNS) drug development. While invasive approaches such as intracerebral injection and focused ultrasound can transiently bypass the barrier, their complexity and safety concerns restrict clinical applicability, particularly in chronic conditions. Non-invasive strategies that exploit endogenous transport mechanisms-carrier-mediated uptake, adsorptive-mediated transcytosis (AMT), and receptor-mediated transcytosis (RMT)-may offer a safer solution. Within this framework, brain shuttles have emerged as molecular vectors designed to cooperate with endothelial biology rather than disrupt it. These include antibodies, proteins, small molecules, and peptides, each with distinct advantages and limitations. Among them, peptides stand out for their versatility, manufacturability, and chemical tunability. Advances in solid-phase synthesis, non-natural modifications, and rational design have enabled peptides to achieve a balance between uptake efficiency and release beyond the endothelium. Their modular nature supports conjugation to diverse payloads, including small molecules, proteins, nucleic acids, and nanoparticles, while maintaining functional integrity. Peptide shuttles also offer broader receptor targeting and compatibility with multiple administration routes, positioning them as a cornerstone of future CNS delivery platforms. This chapter provides a mechanistic overview of the BBB, reviews invasive and non-invasive delivery strategies, and introduces the concept and evolution of brain shuttle peptides. It sets the stage for subsequent discussions on discovery methodologies, chemical optimization, validation models, and translational pathways, highlighting the promise of peptide-enabled systems to transform therapeutic access to the brain.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"105 ","pages":"1-39"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Brain shuttle peptides derived from natural proteins. 脑穿梭肽来源于天然蛋白质。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-02-20 DOI: 10.1016/bs.apha.2026.01.002

Andrej Nikolić, Toni Todorovski

{"title":"Brain shuttle peptides derived from natural proteins.","authors":"Andrej Nikolić, Toni Todorovski","doi":"10.1016/bs.apha.2026.01.002","DOIUrl":"10.1016/bs.apha.2026.01.002","url":null,"abstract":"Blood-brain barrier (BBB) is the primary physiological barrier that regulates the movement of substances between the systemic circulation and the brain. Its unique structure, based on specialized endothelial cells, allows tight regulation of central nervous system (CNS) homeostasis and at the same time is the main hurdle in the modern medicine to treat neurological conditions. Many promising in vitro drugs become ineffective in vivo due to BBB restrictive permeability. However, in the last two decades, a variety of molecules, mainly peptide-based and named brain shuttle peptides, were able to ferry various payloads (small molecules, proteins, antibodies etc.) into the brain. Therefore, these shuttles could become key future therapeutics to fight various CNS conditions. Brain shuttle peptides are part of a larger family of cell-penetrating peptides (CPPs) that utilize different modes of membrane transport with predominance of adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). The discovery and development process of new brain shuttle peptides is mainly guided by using rational design and bioinformatics approaches focusing mostly on proteins from natural sources (viruses, amphibians, reptiles and mammals). In the last years, the virus- and mammal-derived brain shuttle peptides have been gaining increased attention due to their superb translocation capacity, low immunogenicity and toxicity, good stability and ease of preparation. Here, we will focus on the most prominent brain shuttle peptides of viral and animal origin with documented BBB crossing capabilities, discussing their mechanisms of translocation and therapeutic applications. Notably, the two brain shuttle peptides that have successfully progressed to clinical trials thus far originate from a viral source (TAT) and a mammalian source (Angiopep-2).","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"105 ","pages":"41-82"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro blood-brain barrier models for the study of brain shuttle peptide transport. 体外血脑屏障模型研究脑穿梭肽运输。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-02-25 DOI: 10.1016/bs.apha.2026.01.003

Ana Martins, Ana Raquel Santa-Maria, Nóra Kucsápszky, Luíza Santa Brígida de Barros Góes, Kinga Molnár, Sheila Sousa Gomes Fortes, Emanuel Carrilho, Maria A Deli, Fruzsina R Walter

{"title":"In vitro blood-brain barrier models for the study of brain shuttle peptide transport.","authors":"Ana Martins, Ana Raquel Santa-Maria, Nóra Kucsápszky, Luíza Santa Brígida de Barros Góes, Kinga Molnár, Sheila Sousa Gomes Fortes, Emanuel Carrilho, Maria A Deli, Fruzsina R Walter","doi":"10.1016/bs.apha.2026.01.003","DOIUrl":"10.1016/bs.apha.2026.01.003","url":null,"abstract":"Brain shuttles, such as antibody fragments, bispecific antibodies, peptides, or nanocarriers, are engineered to exploit the blood-brain barrier (BBB) transport mechanisms to deliver therapeutics to the brain. This strategy has emerged as a potential game-changer to overcome the therapeutic challenge of many brain diseases: the hindered passage of molecules across the BBB. Due to special tight junctions, low intracellular vesicles, negatively charged glycocalyx, and highly regulated transport, brain endothelial cells limit central nervous system drug delivery. To facilitate drug passage to the brain, brain shuttles utilize endogenous transport pathways, such as receptor-mediated and adsorptive-mediated transcytosis. In vitro BBB models provide a controlled environment to evaluate the passage of brain shuttles across the BBB. Here, we present the cellular and methodological basis for selecting an appropriate model type for any shuttle study, with relevant barrier tightness and cellular composition. We explain how to apply rigorous experimental controls to assess transport efficiency, receptor specificity, cytotoxicity, and barrier integrity, which helps to identify specific transport phenomena, and exclude artefacts.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"105 ","pages":"365-413"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Manufacturing as biology: How T-cell processing shapes therapeutic outcomes. 作为生物学的制造：t细胞加工如何影响治疗结果。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-05-25 DOI: 10.1016/bs.apha.2026.05.005

Nikolai Przybylski, Qinghe Zeng, Xiao Huang

{"title":"Manufacturing as biology: How T-cell processing shapes therapeutic outcomes.","authors":"Nikolai Przybylski, Qinghe Zeng, Xiao Huang","doi":"10.1016/bs.apha.2026.05.005","DOIUrl":"10.1016/bs.apha.2026.05.005","url":null,"abstract":"T-cell therapies have transformed the treatment landscape for hematologic malignancies and show growing promise for solid tumors and non-oncologic diseases. Unlike conventional drugs, these living therapeutics are shaped not only by genetic engineering but also by the ex vivo manufacturing process itself, which functions as a powerful biological determinant of cell fate and function. Here, we present a framework that conceptualizes manufacturing as a form of biological programming that governs therapeutic outcomes through its effects on T-cell phenotype, fitness, and functional durability. We review how each major processing step, including isolation, selection, activation, transduction, expansion, and formulation, influences the balance between cell quantity and quality, the two principal determinants of clinical efficacy. Particular emphasis is placed on how extracellular cues encountered during manufacturing, such as physical properties of activation materials, stimulatory ligand presentation, cytokine and nutrient composition, and gene delivery method, shape transcriptional, epigenetic, and metabolic programs that define cell phenotypes directly linked to cell quantity and quality. Emerging strategies to deliberately steer T-cell differentiation toward persistence-associated phenotypes, enhance metabolic fitness, and reduce vein-to-vein time are highlighted as critical avenues for next-generation manufacturing. Additionally, reducing inconsistency and cost remain areas of strategic importance to expand availability. Collectively, this review underscores that optimizing T-cell therapy requires treating manufacturing not as a logistical necessity but as a controllable biological intervention. A mechanistic understanding of how processing decisions program cellular behavior will enable the rational design of more potent, durable, and scalable T-cell products for diverse clinical applications.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"106 ","pages":"141-177"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering T cell metabolism to enhance therapeutic efficacy. 改造T细胞代谢，提高治疗效果。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-05-26 DOI: 10.1016/bs.apha.2026.05.001

Laura Anderson, Nicola J Mason, Roddy S O'Connor

{"title":"Engineering T cell metabolism to enhance therapeutic efficacy.","authors":"Laura Anderson, Nicola J Mason, Roddy S O'Connor","doi":"10.1016/bs.apha.2026.05.001","DOIUrl":"https://doi.org/10.1016/bs.apha.2026.05.001","url":null,"abstract":"Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T cells, function as \"living drugs\" whose efficacy depends not only on target recognition but also on the metabolic state of the infused product. T cell metabolism governs energy production, redox homeostasis, biomass generation, and adaptation to persistent antigen exposure and nutrient stress, thereby shaping expansion, effector function, persistence, and susceptibility to exhaustion. Core metabolic programs relevant to these outcomes include glycolysis and mitochondrial respiration, anaplerosis and amino acid metabolism, lipid metabolism, and NAD- and redox-linked pathways. These programs help determine adoptive cell therapy-relevant phenotypes, including the balance between immediate cytotoxicity and long-term durability. Increasing evidence further suggests that metabolism can be therapeutically manipulated across the lifecycle of adoptive cell therapy through ex vivo manufacturing, receptor and signaling design, direct gene engineering, and post-infusion support. Collectively, these findings support a pharmacologic framework in which metabolic state is not merely a descriptive correlate of product quality, but a controllable determinant of therapeutic performance. A deeper mechanistic understanding of these pathways may enable more precise strategies to improve persistence, function, and long-term antitumor efficacy.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"106 ","pages":"117-139"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiological strategies for brain delivery. 脑输送的生理策略。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-03-19 DOI: 10.1016/bs.apha.2026.02.007

Daniel Gonzalez-Carter

{"title":"Physiological strategies for brain delivery.","authors":"Daniel Gonzalez-Carter","doi":"10.1016/bs.apha.2026.02.007","DOIUrl":"10.1016/bs.apha.2026.02.007","url":null,"abstract":"The blood-brain barrier (BBB) remains an obstacle to treat neurological diseases, prompting the development of delivery strategies to target therapies to the brain. Receptor-mediated transport has become a major focus of research efforts aiming to exploit innate transport mechanisms. The last decade has seen important innovations ranging from ligand-modified nanocarriers to engineered biologics that harness trafficking pathways. However, such developments have demonstrated brain delivery requires a nuanced engagement of target proteins to ensure efficient internalization and intracellular trafficking. Therefore, much remains to be understood of BBB transport mechanisms to ensure maximal brain delivery of therapeutics. Furthermore, accumulating evidence indicates cell-membrane targets do not necessarily require an innate biological transport function to promote transport across the BBB. These observations open the possibility of expanding our target repertoire beyond transport-related proteins. Novel targets may therefore include structural or signalling proteins which have a more favourable brain-to-periphery expression ratio. In addition, they may include non-protein components of the cell membrane, for instance the glycocalyx covering endothelial surfaces. Such novel targets would therefore allow us to harness more fully the phenotypic specialization of brain endothelial cells. In addition, recent years have witnessed the development of targeting strategies harnessing not only structural differences of brain endothelial cells, but in addition take advantage of the dynamic control of BBB specialization. As such, advances have been made to exploit cell-membrane dynamics; haemodynamic response; vascular segmentation; or pathological modulation. The field of brain delivery is therefore advancing towards exploiting the highly unique physiology of the BBB to achieve a more dynamic approach to BBB targeting and maximize transport into the brain.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"105 ","pages":"415-456"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Brain delivery of proteins with shuttle peptides. 用穿梭肽传递大脑中的蛋白质。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-02-24 DOI: 10.1016/bs.apha.2026.02.006

Alejandro Benítez-Troncoso, Macarena Sánchez-Navarro, Marina Plaza-Garrido

引用次数: 0

In vivo transduction of CAR T cells: Pharmacological principles, delivery platforms, and the road to clinical translation. CAR - T细胞的体内转导：药理学原理、传递平台和临床转导之路。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-06-08 DOI: 10.1016/bs.apha.2026.05.003

Saar I Gill

引用次数: 0

Tracking therapeutic T cells in vivo. 在体内追踪治疗性T细胞。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-05-27 DOI: 10.1016/bs.apha.2026.05.004

Angela Z Gong, Mark A Sellmyer

引用次数: 0

Transient T cell therapies. 瞬时T细胞疗法。

Advances in pharmacology Pub Date : 2026-01-01 Epub Date: 2026-05-25 DOI: 10.1016/bs.apha.2026.05.007

Yudian Xiao, Mingliang Bai, Melgious Jin Yan Ang, Michael J Mitchell, Xuexiang Han

{"title":"Transient T cell therapies.","authors":"Yudian Xiao, Mingliang Bai, Melgious Jin Yan Ang, Michael J Mitchell, Xuexiang Han","doi":"10.1016/bs.apha.2026.05.007","DOIUrl":"https://doi.org/10.1016/bs.apha.2026.05.007","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has achieved clinical success in hematological malignancies, but its reliance on viral vectors and complex ex vivo manufacturing poses challenges related to safety, cost, and scalability. Next-generation strategies, including universal (\"off-the-shelf\") and in vivo CAR-T cell therapies, have emerged to address these limitations. The latter strategy employs targeted delivery systems to directly program patients' T cells in situ, bypassing ex vivo manipulation and offering a more streamlined, scalable, and safer therapeutic paradigm. The success of in vivo CAR-T cell therapy relies on targeted delivery systems. While engineered lentiviruses enable stable integration, non-viral vectors for transient CAR expression offer superior pharmacological control. This approach, exemplified by lipid nanoparticles in combination with mRNA, avoids risks of insertional mutagenesis and enables titratable, short-lived CAR expression, thereby enhancing safety management and suitability for applications beyond oncology. In this chapter, we first delineate the pharmacological imperative for transient CAR expression. Next, various delivery strategies are systematically reviewed, including ex vivo electroporation, in vivo non-viral systems, and engineered virus-like particles. Afterwards, we summarize the ongoing clinical trials of transient CAR-T cell therapy for oncology and non-oncology indications. Finally, we provide perspectives on the development of next-generation transient CAR-T cell therapies.","PeriodicalId":7366,"journal":{"name":"Advances in pharmacology","volume":"106 ","pages":"179-212"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0