Drug Transport Research Articles

Membrane Permeability Dominates over Electrostatic Interactions in Dictating Drug Transport in Osmotically Shocked Escherichia coli.

To combat surging multidrug-resistant Gram-negative bacterial infections, better strategies to improve the efficacy of existing drugs are critical. Because the dual membrane cell envelope is the first line of defense for these bacteria, it is crucial to understand the permeation properties of the drugs through it. Our recent study shows that isosmotic conditions prevent drug permeation inside Gram-negative bacteria, Escherichia coli, while hypoosmotic stress enhances the process. Here, we unravel the reason behind such differential drug penetration. Specifically, we dissect the roles of electrostatic screening and low membrane permeability in the penetration failure of drugs under osmotically balanced conditions. We compare the transport of a quaternary ammonium compound malachite green in the presence of an electrolyte (NaCl) and a wide variety of commonly used organic osmolytes, e.g., sucrose, proline, glycerol, sorbitol, and urea. These osmolytes of different membrane permeability (i.e., nonpermeable sucrose and NaCl, freely permeable urea and glycerol, and partially permeable proline and sorbitol) clarify the role of osmotic stress in cell envelope permeability. The results showcase that under balanced osmotic conditions, drug molecules fail to penetrate inside E. coli cells because of low membrane permeabilities and not because of electrostatic screening imposed by the osmolytes. Contribution of the electrostatic interactions, however, cannot be completely overruled as at osmotically imbalanced conditions, drug transport across the bacterial subcellular compartments is found to be dependent on the osmolytes used.

Structural insights into drug transport by an aquaglyceroporin

Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.

Design and fabrication of 3D-printed gastric floating tablets of captopril: effect of geometry and thermal crosslinking of polymer on floating behavior and drug release

The present study aims to investigate the potential of the 3D printing technique to design gastroretentive floating tablets (GFTs) for modifying the drug release profile of an immediate-release tablet. A 3D-printed floating shell enclosing a captopril tablet was designed having varying number of drug-release windows. The impact of geometrical changes in the design of delivery system and thermal cross-linking of polymers were evaluated to observe the influence on floating ability and drug release. Water uptake, water insolubilization, Differential Scanning Calorimetry (DSC), and Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) were performed to assess the degree of thermal cross-linking of polyvinyl alcohol (PVA) filament. The 3D-printed GFT9 was considered the optimized gastric floating tablet that exhibited >12 h of total floating time with zero floating lag time and successfully accomplished modified-drug release by exhibiting >80% of drug release in 8 h. The zero-order release model, with an r2 value of 0.9923, best fitted the drug release kinetic data of the GFT9, which followed a super case II drug transport mechanism with an n value of 0.95. The optimized gastric floating device (GFT9) also exhibited the highest MDT values (238.55), representing slow drug release from the system due to thermal crosslinking and the presence of a single drug-releasing window in the device.

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

ABCG2 Mediates Resistance to the Dual EGFR and PI3K Inhibitor MTX-211 in Cancer Cells

MTX-211 is a first-in-class dual inhibitor of epidermal growth factor receptor (EGFR) and phosphoinositide-3 kinase (PI3K) signaling pathways with a compelling pharmaceutical profile and could enhance the effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitor therapy in colorectal tumors with KRAS mutations. However, the specific mechanisms contributing to the acquired resistance to MTX-211 in human cancers remain elusive. Here, we discovered that the overexpression of the ATP-binding cassette (ABC) drug transporter ABCG2, a prevalent mechanism associated with multidrug resistance (MDR), could diminish the effectiveness of MTX-211 in human cancer cells. We showed that the drug efflux activity of ABCG2 substantially decreased the intracellular accumulation of MTX-211 in cancer cells. As a result, the cytotoxicity and effectiveness of MTX-211 in suppressing the activation of the EGFR and PI3K pathways were significantly attenuated in cancer cells overexpressing ABCG2. Moreover, the enhancement of the MTX-211-stimulated ATPase activity of ABCG2 and the computational molecular docking analysis illustrating the binding of MTX-211 to the substrate-binding sites of ABCG2 offered a further indication for the interaction between MTX-211 and ABCG2. In summary, our findings indicate that MTX-211 acts as a substrate for ABCG2, underscoring the involvement of ABCG2 in the emergence of resistance to MTX-211. This finding carries clinical implications and merits further exploration.

Induction effect of antiretroviral bictegravir on the expression of Abcb1, Abcg2 and Abcc1 genes associated with P-gp, Bcrp and Mrp1 transporters present in rat peripheral blood mononuclear cells

ABSTRACT Background Antiretrovirals have the potential to cause drug interactions leading to inefficacyor toxicity via activation of efflux transporters through nuclear receptors,altering drug concentrations at their target sites. ResearchDesign and Methods This study used molecular dynamicsimulations and qRT-PCR to investigate bictegravir’s interactions with nuclearreceptors Pxr and Car, and its effects on efflux transporters (P-gp, Bcrp,Mrp1) in rat PBMCs. PBMC/plasma drug concentrations were measured usingLC-MS/MS to assess the functional impact of transporter expression. Results Bictegravir significantly increased the expression of ABC transporters, withCar identified as a key mediator. This suggests that bictegravir’s influence onnuclear receptors could affect drug transport and efficacy at the cellularlevel. Conclusions Bictegravir activates nuclear receptors enhancing efflux transporterexpression. Understanding these interactions is crucial for preventing drug-druginteractions and reducing toxicity in clinical use. Combining Car antagonistswith bictegravir may prevent drug resistance and toxicity. However, thesefindings are based on preclinical data and necessitate further clinical trialsto confirm their applicability in clinical settings.

Genetic Variants in the ABCB1 and ABCG2 Gene Drug Transporters Involved in Gefitinib-Associated Adverse Reaction: A Systematic Review and Meta-Analysis

This systematic review and meta-analysis aimed to verify the association between the genetic variants of adenosine triphosphate (ATP)-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) genes and the presence and severity of gefitinib-associated adverse reactions. We systematically searched PubMed, Virtual Health Library/Bireme, Scopus, Embase, and Web of Science databases for relevant studies published up to February 2024. In total, five studies were included in the review. Additionally, eight genetic variants related to ABCB1 (rs1045642, rs1128503, rs2032582, and rs1025836) and ABCG2 (rs2231142, rs2231137, rs2622604, and 15622C>T) genes were analyzed. Meta-analysis showed a significant association between the ABCB1 gene rs1045642 TT genotype and presence of diarrhea (OR = 5.41, 95% CI: 1.38–21.14, I2 = 0%), the ABCB1 gene rs1128503 TT genotype and CT + TT group and the presence of skin rash (OR = 4.37, 95% CI: 1.51–12.61, I2 = 0% and OR = 6.99, 95%CI: 1.61–30.30, I2= 0%, respectively), and the ABCG2 gene rs2231142 CC genotype and presence of diarrhea (OR = 3.87, 95% CI: 1.53–9.84, I2 = 39%). No ABCB1 or ABCG2 genes were positively associated with the severity of adverse reactions associated with gefitinib. In conclusion, this study showed that ABCB1 and ABCG2 variants are likely to exhibit clinical implications in predicting the presence of adverse reactions to gefitinib.

Sex and the Kidney Drug-Metabolizing Enzymes and Transporters: Are Preclinical Drug Disposition Data Translatable to Humans?

Cross-species differences in drug transport and metabolism are linked to poor translation of preclinical pharmacokinetic and toxicology data to humans, often resulting in the failure of new chemical entities (NCEs) during clinical drug development. Specifically, inaccurate prediction of renal clearance and renal accumulation of NCEs due to differential abundance of enzymes and transporters in kidneys can lead to differences in pharmacokinetics and toxicity between experimental animals and humans. We carried out liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based protein quantification of 78 membrane drug-metabolizing enzymes and transporters (DMETs) in the kidney membrane fractions of humans, rats, and mice for characterization of cross-species and sex-dependent differences. In general, majority of DMET proteins were higher in rodents than in humans. Significant cross-species differences were observed in 30 out of 33membrane DMET proteins quantified in all three species. Although no significant sex-dependent differences were observed in humans, the abundance of 28 and 46 membrane proteins showed significant sex dependence in rats and mice, respectively. These cross-species and sex-dependent quantitative abundance data are valuable for gaining a mechanistic understanding of drug renal disposition and accumulation. Further, these data can also be integrated into systems pharmacology tools, such as physiologically based pharmacokinetic models, to enhance the interpretation of preclinical pharmacokinetic and toxicological data.

In-depth Mechanism, Challenges, and Opportunities of Delivering Therapeutics in Brain Using Intranasal Route.

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood-brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.

Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BackgroundCurrent treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination.Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. MethodsA retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FindingsSixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. InterpretationIn conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

Productizing Nano-Bioactive Glass-Based Bilayer Scaffolds: A Graft for Reconstruction of Mandibular and Femoral Bone Defects.

This investigation aimed to construct a bilayer scaffold integrating alginate and gelatin with nanobioactive glass (BG), recognized for their efficacy in tissue regeneration and drug delivery. Scaffolds, namely, alginate/gelatin (AG), alginate-/actonel gelatin (AGD), alginate actenol/gelatin-45S5 BG (4AGD), and alginate-actonel/gelatin-59S BG (5AGD), were assembled using a cost-effective freeze-drying method, followed by detailed structural investigation via powder X-ray diffraction as well as morphological characterization using field emission scanning electron microscopy (FESEM). FESEM revealed a honeycomb-like morphology with distinct pore sizes for nutrient, oxygen, and drug transport. The scaffolds evidently exhibited hemocompatibility, high porosity, good swelling capacity, and biodegradability. In vitro studies demonstrated sustained drug release, particularly for scaffolds containing actonel. In vivo tests showed that the bilayer scaffold promoted new bone formation, surpassing the control group in bone area increase. The interaction of the scaffold with collagen and released ions improved the osteoblastic function and bone volume fraction. The findings suggest that this bilayer scaffold could be beneficial for treating critical-sized bone defects, especially in the mandibular and femoral regions.

Lenvatinib in hepatocellular carcinoma: Resistance mechanisms and strategies for improved efficacy.

Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes of cancer-related deaths worldwide, approximately 70% of patients with HCC exhibit advanced disease at diagnosis, limiting the potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib for first-line targeted therapy, has become a key treatment. Unfortunately, despite some progress, the prognosis for advanced HCC remains poor because of drug resistance development. However, the molecular mechanisms underlying lenvatinib resistance and ways to relief drug resistance in HCC are largely unknown and lack of systematic summary; thus, this review not only aims to explore factors contributing to lenvatinib resistance in HCC, but more importantly, summary potential methods to conquer or mitigate the resistance. The results suggest that abnormal activation of pathways, drug transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, and other mechanisms are involved in the development of lenvatinib resistance in HCC and subsequent HCC progression. To improve the therapeutic outcomes of lenvatinib, inhibiting acquired resistance, combined therapies, and nano-delivery carriers may be possible approaches.

Circadian ABCG2 Expression Influences the Brain Uptake of Donepezil across the Blood-Cerebrospinal Fluid Barrier.

Donepezil (DNPZ) is a cholinesterase inhibitor used for the management of Alzheimer's disease (AD) and is dependent on membrane transporters such as ABCG2 to actively cross brain barriers and reach its target site of action in the brain. Located in the brain ventricles, the choroid plexus (CP) forms an interface between the cerebrospinal fluid (CSF) and the bloodstream, known as the blood-CSF barrier (BCSFB). Historically, the BCSFB has received little attention as a potential pathway for drug delivery to the central nervous system (CNS). Nonetheless, this barrier is presently viewed as a dynamic transport interface that limits the traffic of molecules into and out of the CNS through the presence of membrane transporters, with parallel activity with the BBB. The localization and expression of drug transporters in brain barriers represent a huge obstacle for drug delivery to the brain and a major challenge for the development of therapeutic approaches to CNS disorders. The widespread interest in understanding how circadian clocks modulate many processes that define drug delivery in order to predict the variability in drug safety and efficacy is the next bridge to improve effective treatment. In this context, this study aims at characterizing the circadian expression of ABCG2 and DNPZ circadian transport profile using an in vitro model of the BCSFB. We found that ABCG2 displays a circadian pattern and DNPZ is transported in a circadian way across this barrier. This study will strongly impact on the capacity to modulate the BCSFB in order to control the penetration of DNPZ into the brain and improve therapeutic strategies for the treatment of AD according to the time of the day.

Role of vacancy defects and nanopumping on drug transport efficiency in boron nitride nanotubes

AbstractBoron nitride nanotubes (BNNTs) are promising nanomaterials for drug delivery due to their remarkable mechanical and electrical properties. BNNTs use nanopumping technique to transport drug molecules to target sites when subjected to an external force, such as an electric field or mechanical forces. Despite numerous efforts to investigate BNNTs/biomolecules interactions, the impact of atomic‐scale intrinsic characteristics of BNNT on drug delivery efficiency and delivery time is not well understood. To investigate this, we use molecular dynamics simulations (MD) to develop two simulation models: one with defective BNNT and another with a non‐defective (pristine) BNNT. Here, the fullerene molecule (C20) is introduced into BNNT and transported towards target cells. Our results show that vacancy defects can significantly impact the effectiveness of the nanopumping process. In pristine BNNTs, drug molecules move primarily by translation motion. However, the presence of vacancy defects and their concentration in BNNTs can affect the translation motion of drug molecules. We show that the judicious selection of oscillation frequency and amplitude of Cu tips is important to achieve efficient drug transport. This work provides new insights into the role of structural defects and oscillation on the drug transport efficiency of C20 molecules in BNNT using the nanopumping mechanism.

Survey of pharmaceutical industry's best practices around in vitro transporter assessment and Implications for Drug Development: Considerations from the IQ Transporter Working Group.

The IQ Transporter Working Group had a rare opportunity to analyse a cross-pharma collation of in vitro data and assay methods for the evaluation of drug transporter substrate and inhibitor potential. Experiments were generally performed in accordance with regulatory guidelines. Discrepancies, such as not considering the impact of pre-incubation for inhibition and free or measured in vitro drug concentrations, may be due to the retrospective nature of the dataset and analysis. Lipophilicity was a frequent indicator of cross-transport inhibition (P-gp, BCRP, OATP1B and OCT1) with high molecular weight ({greater than or equal to}500 Da) also common for OATP1B and BCRP inhibitors. A high level of overlap in in vitro inhibition across transporters was identified for BCRP, OATP1B1 and MATE1 suggesting that prediction of DDIs for these transporters will be common. In contrast inhibition of OAT1 did not coincide with inhibition of any other transporter. Neutrals, bases, and compounds with intermediate-high lipophilicity tended to be P-gp and/or BCRP substrates whilst compounds with MW <500 Da tended to be OAT3 substrates. Interestingly the majority of in vitro inhibitors were not reported to be followed up with a clinical study by the submitting company, whilst those compounds identified as substrates generally were. Approaches to metabolite testing were generally found to be similar to parent testing with metabolites generally being equally or less potent than parent compounds. However, examples where metabolites inhibited transporters in vitro were identified supporting the regulatory requirement for in vitro testing of metabolites to enable integrated clinical DDI risk assessment. Significance Statement A diverse dataset showed transporter inhibition often correlated with lipophilicity and molecular weight (>500 Da). Overlapping transporter inhibition was identified, particularly that inhibition of BCRP, OATP1B1 and MATE1 was frequent if the compound inhibited other transporters. In contrast inhibition of OAT1 did not correlate with the other drug transporters tested.

Deciphering the functional role of clinical mutations in ABCB1, ABCC1, and ABCG2 ABC transporters in endometrial cancer

ATP-binding cassette transporters represent a superfamily of dynamic membrane-based proteins with diverse yet common functions such as use of ATP hydrolysis to efflux substrates across cellular membranes. Three major transporters—P-glycoprotein (P-gp or ABCB1), multidrug resistance protein 1 (MRP1 or ABCC1), and breast cancer resistance protein (BCRP or ABCG2) are notoriously involved in therapy resistance in cancer patients. Despite exhaustive individual characterizations of each of these transporters, there is a lack of understanding in terms of the functional role of mutations in substrate binding and efflux, leading to drug resistance. We analyzed clinical variations reported in endometrial cancers for these transporters. For ABCB1, the majority of key mutations were present in the membrane-facing region, followed by the drug transport channel and ATP-binding regions. Similarly, for ABCG2, the majority of key mutations were located in the membrane-facing region, followed by the ATP-binding region and drug transport channel, thus highlighting the importance of membrane-mediated drug recruitment and efflux in ABCB1 and ABCG2. On the other hand, for ABCC1, the majority of key mutations were present in the inactive nucleotide-binding domain, followed by the drug transport channel and membrane-facing regions, highlighting the importance of the inactive nucleotide-binding domain in facilitating indirect drug efflux in ABCC1. The identified key mutations in endometrial cancer and mapped common mutations present across different types of cancers in ABCB1, ABCC1, and ABCG2 will facilitate the design and discovery of inhibitors targeting unexplored structural regions of these transporters and re-engineering of these transporters to tackle chemoresistance.

Revolutionizing neurotherapeutics: blood-brain barrier-on-a-chip technologies for precise drug delivery.

The blood-brain barrier (BBB) is a critical neurovascular unit regulating substances' passage from the bloodstream to the brain. Its selective permeability poses significant challenges in drug delivery for neurological disorders. Conventional methods often fail due to the BBB's complex structure. The study aims to shed light on their pivotal role in revolutionizing neurotherapeutics and explores the transformative potential of BBB-on-a-Chip technologies in drug delivery research to comprehensively review BBB-on-a-chip technologies, focusing on their design, and substantiate advantages over traditional models. A detailed analysis of existing literature and experimental data pertaining to BBB-on-a-Chip technologies was conducted. Various models, their physiological relevance, and innovative design considerations were examined through databases like Scopus, EbscoHost, PubMed Central, and Medline. Case studies demonstrating enhanced drug transport through BBB-on-a-Chip models were also reviewed, highlighting their potential impact on neurological disorders. BBB-on-a-Chip models offer a revolutionary approach, accurately replicating BBB properties. These microphysiological systems enable high-throughput screening, real-time monitoring of drug transport, and precise localization of drugs. Case studies demonstrate their efficacy in enhancing drug penetration, offering potential therapies for diseases like Parkinson's and Alzheimer's. BBB-on-a-Chip models represent a transformative milestone in drug delivery research. Their ability to replicate BBB complexities, offer real-time monitoring, and enhance drug transport holds immense promise for neurological disorders. Continuous research and development are imperative to unlock BBB-on-a-Chip models' full potential, ushering in a new era of targeted, efficient, and safer drug therapies for challenging neurological conditions.

The full spectrum of SLC22 OCT1 mutations illuminates the bridge between drug transporter biophysics and pharmacogenomics

Mutations in transporters can impact an individual's response to drugs and cause many diseases. Few variants in transporters have been evaluated for their functional impact. Here, we combine saturation mutagenesis and multi-phenotypic screening to dissect the impact of 11,213 missense single-amino-acid deletions, and synonymous variants across the 554 residues of OCT1, a key liver xenobiotic transporter. By quantifying in parallel expression and substrate uptake, we find that most variants exert their primary effect on protein abundance, a phenotype not commonly measured alongside function. Using our mutagenesis results combined with structure prediction and molecular dynamic simulations, we develop accurate structure-function models of the entire transport cycle, providing biophysical characterization of all known and possible human OCT1 polymorphisms. This work provides a complete functional map of OCT1 variants along with a framework for integrating functional genomics, biophysical modeling, and human genetics to predict variant effects on disease and drug efficacy.

Mechanisms of Sorafenib Resistance in HCC Culture Relate to the Impaired Membrane Expression of Organic Cation Transporter 1 (OCT1).

Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC) treatment, encounters resistance in many patients. Deciphering the mechanisms underlying sorafenib resistance is crucial for devising alternative strategies to overcome it. This study aimed to investigate sorafenib resistance mechanisms using a diverse panel of HCC cell lines. HCC cell lines were subjected to continuous sorafenib treatment, and stable cell lines (Huh 7.5 and Huh 7PX) exhibiting sustained growth in its presence were isolated. The investigation of drug resistance mechanisms involved a comparative analysis of drug-targeted signal transduction pathways (EGFR/RAF/MEK/ERK/Cyclin D), sorafenib uptake, and membrane expression of the drug uptake transporter. HCC cell lines (Huh 7.5 and Huh 7PX) with a higher IC50 (10μM) displayed a more frequent development of sorafenib resistance compared to those with a lower IC50 (2-4.8μM), indicating a potential impact of IC50 variation on initial treatment response. Our findings reveal that activated overexpression of Raf1 kinases and impaired sorafenib uptake, mediated by reduced membrane expression of organic cation transporter-1 (OCT1), contribute to sorafenib resistance in HCC cultures. Stable expression of the drug transporter OCT1 through cDNA transfection or adenoviral delivery of OCT1 mRNA increased sorafenib uptake and successfully overcame sorafenib resistance. Additionally, consistent with sorafenib resistance in HCC cultures, cirrhotic liver-associated human HCC tumors often exhibited impaired membrane expression of OCT1 and OCT3. Intrinsic differences among HCC cell clones, affecting sorafenib sensitivity at the expression level of Raf kinases, drug uptake, and OCT1 transporters, were identified. This study underscores the potential of HCC tumor targeted OCT1 expression to enhance sorafenib treatment response.

Implications of environmental nanoparticles on neurodegeneration.

The ubiquity of nanoparticles, sourced from both natural environments and human activities, presents critical challenges for public health. While offering significant potential for innovative biomedical applications-especially in enhancing drug transport across the blood-brain barrier-these particles also introduce possible hazards due to inadvertent exposure. This concise review explores the paradoxical nature of nanoparticles, emphasizing their promising applications in healthcare juxtaposed with their potential neurotoxic consequences. Through a detailed examination, we delineate the pathways through which nanoparticles can reach the brain and the subsequent health implications. There is growing evidence of a disturbing association between nanoparticle exposure and the onset of neurodegenerative conditions, highlighting the imperative for comprehensive research and strategic interventions. Gaining a deep understanding of these mechanisms and enacting protective policies are crucial steps toward reducing the health threats of nanoparticles, thereby maximizing their therapeutic advantages.