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At least 37 records · Page 2Linked to original sources
PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) ≥50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗
PubMedDate not supplied

A double-blind comparison of 1% hydrocortisone plus 10% urea ('Alphaderm') and 0.1% betamethasone 17-valerate in the treatment of non-infective inflammatory dermatoses.

A double-blind controlled trial was carried out over a period of 3 weeks to assess the effectiveness of 1% hydrocortisone, in a specialized carbamide drug delivery system, compared with 0.1% betamethasone 17-valerate cream in the treatment of 21 patients with bilateral, symmetrical, non-infective inflammatory dermatoses. The trial preparations were applied topically twice daily, each to one side only during the trial. Although overall patient preference tended to favour betamethasone 17-valerate, the physician's assessment of clinical improvement, based on severity rating scores, indicated that both preparations were equally effective and there were no significant differences between the calculated mean percentage clinical improvements at the end of each week.

Administration, Topical↗
PubMed1979

The implantable infusion pump: a new concept in drug delivery.

Several of our most useful drugs cannot be administered orally. This paper is a summary of our work with a new drug delivery system: a totally implantable, continuous infusion pump, with a self-contained inexhaustible power source. Currently, after bench tests and animal experimentation, we have initiated clinical series utilizing this device to treat individuals with refractory thromboembolic conditions by intravenous heparin, and patients with localized solid tumors by intra-arterial chemotherapy. The use of this device for the infusion of insulin in the management of diabetes mellitus is yet in the laboratory stage of development. In addition to improving dy-today diabetic control and obviating the need for daily insulin injections, this pump offers an ideal opportunity to test whether optimal blood glucose control can significantly prevent or delay the onset of the crippling vascular complications of diabetes. The potential uses of this device, in many fields, are myriad.

Adult↗
PubMed1979

Preparation and evaluation of microencapsulated ion-exchange resin beads.

Ion-exchange resin beads in the benzoate form were coated by several microencapsulation techniques to alter and improve characteristics, especially the control of drug release, of this type of drug delivery system. The most successful techniques included polymer-polymer interaction, temperature change, and nonsolvent addition. The microencapsulated beads then were studied with respect to the release rate of the organic anion to determine the effects of microencapsulation. The release rate of the organic anion could be controlled over a wide range, depending on the encapsulating material characteristics. Factors affecting the extent and rate of release as result of microencapsulation are discussed.

Benzoates↗
PubMed2026

Multidimensional Protein Corona Analysis Toward Predictive Nano-Bio Interface Design.

Nanoparticles entering biological fluids are rapidly coated by proteins and other biomolecules, converting their synthetic surfaces into biologically active nano-bio interfaces. These coronas regulate colloidal stability, immune recognition, cellular uptake, biodistribution, pharmacokinetics, cargo delivery, and toxicity. Yet a protein list obtained by mass spectrometry captures only part of this interface. Corona identity and function are also shaped by protein organization, binding stability, exchange dynamics, conformational changes, and molecular accessibility. Here, we discuss recent progress in protein corona isolation and analysis from a question-oriented analytical perspective, with emphasis on how centrifugation, magnetic recovery, affinity- or chemistry-enabled capture, chromatography, filtration, and field-flow fractionation (FFF) influence the fidelity, integrity, and comparability of recovered coronas. We then examine how proteomic profiling can be integrated with binding measurements, interfacial structural analysis and functional validation to distinguish descriptive corona signatures from biologically meaningful mechanisms. We further consider how biofluid composition, disease state, tissue interfaces and cellular environments remodel corona identity, presentation, and bioactivity. Finally, we argue that standardized reporting, computational modeling, and AI-enabled approaches are essential for converting protein corona datasets into reproducible and predictive knowledge that can guide the design of drug delivery systems and precision nanomedicines.

Protein Corona↗
PubMed2017

Drug target ontology to classify and integrate drug discovery data.

BACKGROUND: One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. RESULTS: As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL-DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. CONCLUSIONS: DTO was built based on the need for a formal semantic model for druggable targets including various related information such as protein, gene, protein domain, protein structure, binding site, small molecule drug, mechanism of action, protein tissue localization, disease association, and many other types of information. DTO will further facilitate the otherwise challenging integration and formal linking to biological assays, phenotypes, disease models, drug poly-pharmacology, binding kinetics and many other processes, functions and qualities that are at the core of drug discovery. The first version of DTO is publically available via the website http://drugtargetontology.org/ , Github ( http://github.com/DrugTargetOntology/DTO ), and the NCBO Bioportal ( http://bioportal.bioontology.org/ontologies/DTO ). The long-term goal of DTO is to provide such an integrative framework and to populate the ontology with this information as a community resource.

Biological Ontologies↗
PubMed2026

HIV-Associated Lymphomas: Updates from Pathogenesis to Treatment Strategies.

HIV-associated lymphoma (HAL) is an aggressive malignancy directly linked to HIV infection and accounts for more than 30% of cancer-related deaths in people living with HIV (PLWH). HAL subtypes, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), primary effusion lymphoma (PEL), and plasmablastic lymphoma (PBL), exhibit five to ten times higher incidence rates and distinct molecular profiles compared to HIV-negative lymphomas. Pathogenesis involves HIV-driven CD4+ T-cell depletion, chronic B-cell activation, and oncogenic viral coinfection. First-line therapy combines antiretroviral therapy (ART) with chemotherapy, achieving complete remission rates of 60-70% for DLBCL using R-EPOCH and 50-60% for BL with CODOX-M/IVAC. Relapsed/refractory cases show durable responses to CD19- CAR-T therapy; however, only 10% of HAL patients are enrolled in pivotal immunotherapy trials. Severe immunosuppression necessitates PET-CT-guided de-escalation and nanoparticlebased drug delivery systems to minimize toxicity. Emerging strategies include PD-1 inhibitors and broad-spectrum antivirals targeting HIV reservoirs, underscoring the need for precision medicine that integrates tumor genomics and viral dynamics.

Humans↗
PubMed2026

Engineering strategies and translational progress in targeted nanoparticle drug delivery.

INTRODUCTION: Nanoparticle-based drug delivery has emerged as a transformative approach in modern therapeutics, offering improved targeting efficiency, enhanced pharmacokinetics, and reduced systemic toxicity compared to conventional drug delivery systems. AREAS COVERED: This review comprehensively examines major nanocarrier platforms, including lipid-based, polymeric, inorganic, and hybrid systems, with emphasis on their structural design and functional properties. It further explores current advancements in targeting strategies, including passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand-receptor interactions involving antibodies, peptides, aptamers, and small molecules. Key biological and technological barriers to clinical translation are also discussed, such as tumor heterogeneity, abnormal vasculature, dense extracellular matrix, immune clearance, and limited cellular uptake. Additionally, emerging stimuli-responsive systems, including pH-, redox-, and enzyme-sensitive nanocarriers, are highlighted for their role in controlled and site-specific drug release. EXPERT OPINION/COMMENTARY: Despite significant progress, the clinical translation of nanomedicine remains constrained by biological complexities and scalability challenges. Future advancements integrating biomimetic strategies, multifunctional design, and artificial intelligence-driven modeling are expected to enhance targeting precision, biocompatibility, and translational success.

Humans↗
PubMed2021

GCN2 kinase activation by ATP-competitive kinase inhibitors.

Small-molecule kinase inhibitors represent a major group of cancer therapeutics, but tumor responses are often incomplete. To identify pathways that modulate kinase inhibitor response, we conducted a genome-wide knockout (KO) screen in glioblastoma cells treated with the pan-ErbB inhibitor neratinib. Loss of general control nonderepressible 2 (GCN2) kinase rendered cells resistant to neratinib, whereas depletion of the GADD34 phosphatase increased neratinib sensitivity. Loss of GCN2 conferred neratinib resistance by preventing binding and activation of GCN2 by neratinib. Several other Food and Drug Administration (FDA)-approved inhibitors, such erlotinib and sunitinib, also bound and activated GCN2. Our results highlight the utility of genome-wide functional screens to uncover novel mechanisms of drug action and document the role of the integrated stress response (ISR) in modulating the response to inhibitors of oncogenic kinases.

Adenosine Triphosphate↗
PubMed1975

Elementary osmotic pump.

The elementary osmotic pump is a new delivery system for drugs or other active agents; it delivers the agent by an osmotic process at a controlled rate. Control resides in the: (a) water permeation characteristics of a semipermeable membrane surrounding the formulated agent, and (b) osmotic properties of the formulation. In its simplest embodiment, the system is constructed by coating an osmotically activie solid agent with the rate-controlling, semipermeable membrane. This membrane contains an orifice of critical size through which solubilized agent is dispensed. The system can contain the agent in solid form at loading higher than 90% of the total volume, and the agent can be delivered at rates several orders of magnitude higher than can be achieved by solution diffusion through polymeric membranes. The delivery rate, the fraction of total content delivered at zero order, and the system's delivery portal size have been calculated for delivery of a single compound. Experimental work verified the theory. The release rate from the system was found to be independent of outside agitation when the system is not deformed by shaking action, the pH of the environment, and delivery portal size for sizes within a specified range. The delivery rate from this system in vitro and in the GI tract of dogs was found to be equal.

Animals↗
PubMed1977

Systems approach to vaginal delivery of drugs IV: methodology for determination of membrane surface pH.

A physical model including a diffusional layer in series with the membrane was developed for studying the possible differences between the pH at the membrane surface and that in the bulk solution. Both the membrane-secreted substances (acids and bases) and buffer constituents in the bulk solutions are assumed to contribute to the surface pH. Equations derived for this situation, together with experimental determinations of the acidic dissociation constant of the secreted material, the total secretion flux, the flux of total secreted acidic species, and the diffusion layer thickness, allow estimates to be made of the pH at the membrane surface. With the rabbit vagina, the membrane surface pH was close to that of the bulk solution in most cases. These results were supported by the fact that the absorption of 1-alkanoic acids in pH 2.2 phosphate buffers was relatively constant over the buffer concentration range of 0.003-0.1 M phosphate.

Absorption↗
PubMed1977

Systems approach to vaginal delivery of drugs V: in situ vaginal absorption of 1-alkanoic acids.

The vaginal absorption of a homologous series of ionizable compounds, the 1-alkanoic acids, was studied using a perfusion method with a rib-cage cell surgically implanted in the rabbit vagina. The absorption rates of these compounds followed first-order kinetics. The physical model previously used for the 1-alkanols, but accounting for the pKa and pH effects in the present case was employed in the analysis of the carboxylic acid data. The aqueous diffusion layer thickness was 0.031 cm. The permeability coefficient for the lipoidal pathway increased 3.5-fold per methylene group. Both values agree reasonably well with those obtained in the alcohol study.

Absorption↗
PubMed2026

Food-derived extracellular vesicles as delivery platforms for medicine-food homology components in metabolic syndrome.

Diet-induced obesity and associated metabolic syndromes have become major global public health challenge, highlighting the urgent need for safe and effective strategies. Recently, food-derived extracellular vesicles (FDEVs) have garnered increasing attention as natural nanocarriers due to their excellent biocompatibility and specific targeted delivery capabilities. FDEVs can efficiently deliver medicine-food homology components (MFHCs) to precisely regulate lipid metabolism, inflammatory responses, and insulin sensitivity, thereby improving obesity and its metabolic abnormalities. This systematic review summarizes recent advances in the use of FDEVs as delivery vehicles for MFHCs to suppress diet-induced obesity and metabolic syndrome, with a particular focus on the underlying molecular mechanisms, including signaling pathway regulation and cellular metabolic remodeling. In addition, the clinical translational potential and industrial application prospects of FDEVs are evaluated, and key challenges related to preparation techniques, safety assessment, and large-scale production are discussed. By integrating current evidence, this review aims to provide theoretical framework and future perspectives for the development of FDEVs as a novel targeted delivery platform and treatment of metabolic diseases.

Extracellular Vesicles↗
PubMed2024

Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Brain Neoplasms↗
PubMed1979

Therapeutic problems arising from the use of the intravenous route for drug administration.

The kinetics of drug delivery were studied under conditions of varying iv flow rates and varying sites of drug administration into an iv system. The iv sites and rates were selected on the basis of questionnaire data obtained from nursing personnel. The rate of drug delivery from the iv system was dependent upon the iv flow rate and site of injection of the drug into the iv system. Under conditions of slow iv flow rates (3 ml/hour) there was the expected time delay required for the drug to begin to be infused but an unanticipated protracted time required for actual completion of the drug infusion. Calculation of theoretical drug blood levels based on the results of these iv studies revealed very different blood levels of drug at respective times, including different peak concentrations, depending on the iv flow rate and site at which the drug was injected into the system. Failure to appreciate the effects of slow iv rates and distal iv injection sites on actual rates of drug administration can adversely affect pharmacokinetic decisions and conceivably influence therapeutic success or failure.

Aminophylline↗
PubMed1979

Controlled release of tetracycline I: In vitro studies with a trilaminate 2-hydroxyethyl methacrylate-methyl methacrylate system.

A membrane-controlled drug delivery device was developed to release tetracycline at zero-order rates. The tetracycline delivery vehicle is a trilaminate disk consisting of core and coating membranes fabricated from a series of 2-hydroxyethyl methacrylate and methyl methacrylate copolymers. Appropriate adjustment of the monomer composition ratio imparts a hydrophobic nature to the copolymer outer coating membrane (relative to the core material), which serves as the rate-limiting membrane in drug diffusion. The trilaminate disks demonstrated a zero-order tetracycline release over 4 months in vitro. The zero-order release rate was a function of the general device geometry, coating membrane thickness, disk surface, area, level of core reservoir drug loading, and membrane coating copolymer composition. Permeability parameters of tetracycline diffusion through a series of 2-hydroxyethyl methacrylate-methyl methacrylate copolymer membranes were determined by a flux-lag time method. Equilibrium hydration values of these membranes also were determined. The ability of trilaminate 2-hydroxyethyl methacrylate-methyl methacrylate devices to release tetracycline at constant rates over a prolonged period offers unique therapeutic and investigational possibilities.

Acrylates↗
PubMed2014

Combinatorial approaches for the identification of brain drug delivery targets.

The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral vasculature and the inherent low levels of transcytosis mediated by such systems. In this review, approaches designed to increase the repertoire of transcytosing receptors which can be targeted for the purpose of drug delivery are discussed. In particular, combinatorial protein libraries can be screened on BBB cells in vitro or in vivo to isolate targeting peptides or antibodies that can trigger transcytosis. Once these targeting reagents are discovered, the cognate BBB transcytosis system can be identified using techniques such as expression cloning or immunoprecipitation coupled with mass spectrometry. Continued technological advances in BBB genomics and proteomics, membrane protein manipulation, and in vitro BBB technology promise to further advance the capability to identify and optimize peptides and antibodies capable of mediating drug transport across the BBB.

Animals↗