Molecular Pharmaceutics最新文献

{"title":"Templated Nucleation of Clotrimazole and Ketoprofen on Polymer Substrates.","authors":"Michael A Bellucci, Lina Yuan, Grahame R Woollam, Bing Wang, Liwen Fang, Yunfei Zhou, Chandler Greenwell, Sivakumar Sekharan, Xiaolan Ling, GuangXu Sun","doi":"10.1021/acs.molpharmaceut.4c00491","DOIUrl":"10.1021/acs.molpharmaceut.4c00491","url":null,"abstract":"<p><p>The use of different template surfaces in crystallization experiments can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). Consequently, templated nucleation is an attractive approach to enhance crystal nucleation kinetics and preferentially nucleate desired crystal polymorphs for solid-form drug molecules, particularly large and flexible molecules that are difficult to crystallize. Herein, we investigate the effect of polymer templates on the crystal nucleation of clotrimazole and ketoprofen with both experiments and computational methods. Crystallization was carried out in toluene solvent for both APIs with a template library consisting of 12 different polymers. In complement to the experimental studies, we developed a computational workflow based on molecular dynamics (MD) and derived descriptors from the simulations to score and rank API-polymer interactions. The descriptors were used to measure the energy of interaction (EOI), hydrogen bonding, and rugosity (surface roughness) similarity between the APIs and polymer templates. We used a variety of machine learning models (14 in total) along with these descriptors to predict the crystallization outcome of the polymer templates. We found that simply rank-ordering the polymers by their API-polymer interaction energy descriptors yielded 92% accuracy in predicting the experimental outcome for clotrimazole and ketoprofen. The most accurate machine learning model for both APIs was found to be a random forest model. Using these models, we were able to predict the crystallization outcomes for all polymers. Additionally, we have performed a feature importance analysis using the trained models and found that the most predictive features are the energy descriptors. These results demonstrate that API-polymer interaction energies are correlated with heterogeneous crystallization outcomes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease-Inspired Design of Biomimetic Tannic Acid-Based Hybrid Nanocarriers for Enhancing the Treatment of Bacterial-Induced Sepsis.","authors":"Eman Elhassan, Calvin A Omolo, Mohammed Ali Gafar, Lucy W Kiruri, Usri H Ibrahim, Eman A Ismail, Nikita Devnarain, Thirumala Govender","doi":"10.1021/acs.molpharmaceut.4c00048","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00048","url":null,"abstract":"<p><p>This study explored the development of novel biomimetic tannic acid-based hybrid nanocarriers (HNs) for targeted delivery of ciprofloxacin (CIP-loaded TAH-NPs) against bacterial-induced sepsis. The prepared CIP-loaded TAH-NPs exhibited appropriate physicochemical characteristics and demonstrated biocompatibility and nonhemolytic properties. Computational simulations and microscale thermophoresis studies validated the strong binding affinity of tannic acid (TA) and its nanoformulation to human Toll-like receptor 4, surpassing that of the natural substrate lipopolysaccharide (LPS), suggesting a potential competitive inhibition against LPS-induced inflammatory responses. CIP released from TAH-NPs displayed a sustained release profile over 72 h. The <i>in vitro</i> antibacterial activity studies revealed that CIP-loaded TAH-NPs exhibited enhanced antibacterial efficacy and efflux pump inhibitory activity. Specifically, they showed a 3-fold increase in biofilm eradication activity against MRSA and a 2-fold increase against <i>P. aeruginosa</i> compared to bare CIP. Time-killing assays demonstrated complete bacterial clearance within 8 h of treatment with CIP-loaded TAH-NPs. <i>In vitro</i> DPPH scavenging and anti-inflammatory investigations confirmed the ability of the prepared hybrid nanosystem to neutralize reactive oxygen species (ROS) and modulate LPS-induced inflammatory responses. Collectively, these results suggest that CIP-loaded TAH-NPs may serve as an innovative nanocarrier for the effective and targeted delivery of antibiotics against bacterial-induced sepsis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-Inducible Factor-1α-Activated Protein Switch Based on Allosteric Self-Splicing Reduces Nonspecific Cytotoxicity of Pharmaceutical Drugs.","authors":"Min Wei, Wenxin Chen, Yuguo Dong, Yiyang Gu, Dongzhi Wei, Jian Zhang, Yuhong Ren","doi":"10.1021/acs.molpharmaceut.4c00921","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00921","url":null,"abstract":"<p><p>Protein-based therapeutic agents currently used for targeted tumor therapy exhibit limited penetrability, nonspecific toxicity, and a short circulation half-life. Although targeting cell surface receptors improves cancer selectivity, the receptors are also slightly expressed in normal cells; consequently, the nonspecific toxicity of recombinant protein-based therapeutic agents has not been eliminated. In this study, an allosteric-regulated protein switch was designed that achieved cytoplasmic reorganization of engineered immunotoxins in tumor cells via interactions between allosteric self-splicing elements and cancer markers. It can target the accumulated HIF-1α in hypoxic cancer cells and undergo allosteric activation, and the splicing products were present in hypoxic cancer cells but were absent in normoxic cells, selectively killing tumor cells and reducing nonspecific toxicity to normal cells. The engineered pro-protein provides a platform for targeted therapy of tumors while offering a novel universal strategy for combining the activation of therapeutic functions with specific cancer markers. The allosteric self-splicing element is a powerful tool that significantly reduces the nonspecific cytotoxicity of therapeutic proteins.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coarse-Grained Molecular Dynamics Simulation of Heterogeneous Polysorbate 80 Surfactants and their Interactions with Small Molecules and Proteins.","authors":"Hao Lou, Yaqi Wu, Krzysztof Kuczera, Christian Schöneich","doi":"10.1021/acs.molpharmaceut.4c00461","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00461","url":null,"abstract":"<p><p>Polysorbate 80 (PS80) is widely used in pharmaceutical formulations, and its commercial grades exhibit certain levels of structural heterogeneity. The objective of this study was to apply coarse-grained molecular dynamics simulations to better understand the effect of PS80 heterogeneity on micelle self-assembly, the loading of hydrophobic small molecules into the micelle core, and the interactions between PS80 and a protein, bovine serum albumin (BSA). Four representative PS80 variants with different head and tail structures were studied. Our simulations found that PS80 structural heterogeneity could affect blank micelle properties such as solvent-accessible surface area, aggregation number, and micelle aspect ratio. It was also found that hydrophobic small molecules such as ethinyl estradiol preferentially partitioned into the PS80 micelle core and PS80 dioleates formed a more hydrophobic core compared to PS80 monooleates. Furthermore, multiple PS80 molecules could bind to BSA, and PS80 heterogeneity profoundly changed the binding ratio as well as the surfactant-protein contact area.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling Microarray Patch Performance: The Role of <i>In Vitro</i> Release Medium and Biorelevant Testing.","authors":"Maja Railic, Abina M Crean, Sonja Vucen","doi":"10.1021/acs.molpharmaceut.4c00459","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00459","url":null,"abstract":"<p><p>The absence of established protocols for studying the <i>in vitro</i> performance of dissolvable microarray patches (MAPs) poses a significant challenge within the field. To overcome this challenge, it is essential to optimize testing methods in a way that closely mimics the skin's environment, ensuring biorelevance and enhancing the precision of assessing MAP performance. This study focuses on optimizing <i>in vitro</i> release testing (IVRT) and <i>in vitro</i> permeation testing (IVPT) methods for MAPs containing the antihistamine drugs loratadine (LOR) and chlorpheniramine maleate (CPM). Our primary objective is to investigate the impact of the composition of <i>in vitro</i> release media on the drug release rate, penetration through the skin, and permeation into the release medium. Artificial interstitial fluid is introduced as a biorelevant release medium and compared with commonly used media in IVRT and IVPT studies. Prior to these studies, we evaluated drug solubility in different release media and developed a method for LOR and CPM extraction from the skin using a design of experiment approach. Our findings highlight the effect of the <i>in vitro</i> release medium composition on both LOR and CPM release rate and their penetration through the skin. Furthermore, we identified the importance of considering the interplay between the physicochemical attributes of the drug molecules, the design of the MAP formulation, and the structural properties of the skin when designing IVRT and IVPT protocols.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Characterization of a Peptide-Bisphosphonate Nanoparticle for the Treatment of Breast Cancer.","authors":"Kimberley Glass, Cory Fines, Paula Coulter, Lynn Jena, Helen O McCarthy, Niamh Buckley","doi":"10.1021/acs.molpharmaceut.4c00299","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00299","url":null,"abstract":"<p><p>In women, breast cancer (BC) is the most common cancer, and despite advancements in diagnosis and treatment, 20-30% of early stage BC patients develop metastatic disease. Metastatic BC is deemed an incurable disease, which accounts for 90% of BC related deaths, with only 26% of metastatic patients reaching a 5 year survival rate. Therefore, there is an unmet need for the prevention or treatment of metastasis in early stage breast cancer patients. Bisphosphonates (BPs) are potent inhibitors of bone resorption and are extensively used for the prevention of osteoporosis and other skeletal disorders, as well as for the treatment of secondary bone cancer in BC patients. Furthermore, the direct anticancer activity of BPs has been established in primary tumor models. However, these studies were limited by the need for dosages far above the clinical range to overcome BPs' high affinity for bones and poor accumulation in the tumor itself, which leads to toxicity, including osteonecrosis of the jaw. To decrease BP dosage, increase bioavailability, and direct anticancer activity, we used the RALA (R-) peptide delivery system to form highly stable NPs with the nitrogen containing BP, risedronate (R-RIS). In vitro studies showed that, in comparison to RIS, R-RIS nanoparticles increased cytotoxicity and reduced metastatic features such as proliferation, migration, invasion, and adhesion of metastatic BC cells to bones. Furthermore, in an in vivo model, R-RIS had increased tumor accumulation while still maintaining similar bone accumulation to RIS alone. This increase in tumor accumulation corresponded with decreased tumor volume and lungs metastasis. R-RIS has great potential to be used in combination with standard of care chemotherapy for the treatment of primary BC and its metastasis while still having its bone resorption inhibiting properties.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Additive Manufacturing of SmartEx QD 100 Designed Oral Three-Dimensional Printlets Containing Isoniazid for Immediate Gastric Release by Selective Laser Sintering.","authors":"Tukaram Karanwad, Sachin B Jorvekar, Santa Mandal, Roshan M Borkar, Subham Banerjee","doi":"10.1021/acs.molpharmaceut.4c00693","DOIUrl":"10.1021/acs.molpharmaceut.4c00693","url":null,"abstract":"<p><p>The selection of appropriate materials and compatibility of selected materials with drugs and formulations are limiting steps in three-dimensional printing technology. In this study, SmartEx QD 100 (SM QD 100) was introduced as a novel, coprocessed, unexplored excipient that can be used in SLS-mediated 3D printing. The current study aimed to evaluate the feasibility of fabricating SM QD 100 containing INH-embedded SLS-mediated immediate gastric release tablets. The prepared physical mixtures were subjected to the fabrication of 3D printlets by using SLS-mediated 3D printing. The fabricated 3D printlets were subjected to physicochemical characterization by using various analytical techniques. After oral administration of sintered 3D printlets to rabbits, samples were collected and pharmacokinetic parameters were analyzed using the developed LC-APCI-MS/MS method. The optimized batch was able to release 100% INH within 15 min, which confirmed the immediate gastric release. Similarly, sintered 3D printlets were stable under accelerated stability conditions for three months. Finally, the pharmacokinetic parameters revealed the rate and extent of absorption of INH from sintered 3D printlets. As evidenced by <i>in vitro</i> and <i>in vivo</i> analyses, SM QD 100 was able to sinter SLS-mediated INH-embedded stable immediate gastric release tablets. SM QD 100 is a novel material for SLS-mediated 3D printing in pharmaceutical applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Octa-Arginine-Conjugated Liposomal Nimodipine Incorporated in a Temperature-Responsive Gel for Nasoencephalic Delivery.","authors":"Shuai Hong, Changxiu Lin, Junsheng Hu, Jingshu Piao, Ming Guan Piao","doi":"10.1021/acs.molpharmaceut.4c00634","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00634","url":null,"abstract":"<p><p>Nimodipine is the primary clinical drug used to treat cerebral vasospasm following subarachnoid hemorrhage. Currently, tablets have low bioavailability when taken orally, and injections contain ethanol. Therefore, we investigated a new method of nimodipine administration, namely, nasoencephalic administration. Nasal administration of nimodipine was carried out by attaching the cell-penetrating peptide octa-arginine (R8) to liposomes of nimodipine and incorporating it into a temperature-sensitive in situ gel. The prepared liposomes and gels underwent separate evaluations for in vitro characterization. In vitro release exhibited a significant slow-release effect. In vitro toad maxillary cilia model, RPMI 2650 cytotoxicity, and in vivo SD rat pathological histotoxicity experiments showed that all the dosage from the groups had no significant toxicity to toad maxillary cilia, RPMI 2650 cells, and SD rat tissues and organs, and the cilia continued to oscillate up to 694 ± 10.15 min, with the survival rate of the cells being above 85%. A transwell nasal mucosa cell model and an isolated porcine nasal mucosa model were established, and the results showed that the osmolality of the R8-modified nimodipine liposomal gel to nasal mucosal cells and isolated porcine nasal mucosa was 30.41 ± 2.14 and 65.9 ± 7.34 μg/mL, respectively, which was significantly higher than that of the NM-Solution and PEGylated nimodipine liposome gel groups. Animal fluorescence imaging studies revealed that the R8-modified nimodipine liposomal gel displayed increased brain fluorescence intensity compared to the normal liposomal gel. Pharmacokinetic results showed that after transnasal administration, the AUC_(0-∞) of the R8-modified nimodipine liposomal gel was 11.662 ± 1.97 μg·mL^-1, which was significantly higher than that of the plain nimodipine liposomal gel (5.499 ± 2.89 μg·mL^-1). Brain-targeting experiments showed that the brain-targeting efficiencies of the PEGylated nimodipine liposome gel and R8-modified PEGylated nimodipine liposome gels were 20.44 and 33.45, respectively, suggesting that R8/PEG/Lip-NM-TSG significantly increased the brain-targeting of the drug.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging Pulmonary Fibrosis and Treatment Efficacy In Vivo with Autotaxin-Specific PET Ligand [¹⁸F]ATX-1905.","authors":"Xiaoyun Deng, Junyi Liu, Jianyuan Zhou, Yifan Shi, Shuang Song, Jiahui Chen, Yinlong Li, Bo Yu, Steven H Liang, Xiaohua Zhu","doi":"10.1021/acs.molpharmaceut.4c00571","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00571","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of ¹⁸F-labeled ATX-targeted tracer [¹⁸F]ATX-1905, in comparison with [¹⁸F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [¹⁸F]FDG and [¹⁸F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [¹⁸F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [¹⁸F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [¹⁸F]ATX-1905. [¹⁸F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [¹⁸F]ATX-1905 (SUV_max = 2.2) was significantly higher than that of [¹⁸F]FDG (SUV_max = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [¹⁸F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [¹⁸F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute Neuroinflammation Alters the Transport of a Model Therapeutic Protein from the Brain into Lymph and Blood.","authors":"Thu A Hoang, Liang Jin, Joseph A Nicolazzo, Natalie L Trevaskis","doi":"10.1021/acs.molpharmaceut.4c00516","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00516","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The drainage of fluid and solutes along lymphatic pathways from the brain has been found to be impaired in mouse models of multiple sclerosis, Alzheimer's disease, and Parkinson's disease where neuroinflammation is present. We recently demonstrated that &lt;sup&gt;3&lt;/sup&gt;H-albumin, a model therapeutic protein (∼65 kDa), undergoes preferential lymphatic transport from the brain using a cervical lymph cannulation model in healthy rats. We thus hypothesized that neuroinflammation would impede the lymphatic transport of &lt;sup&gt;3&lt;/sup&gt;H-albumin from the brain. Our aim was to quantify the impact of acute neuroinflammation on drainage of the model therapeutic protein (&lt;sup&gt;3&lt;/sup&gt;H-albumin) from the rat brain into blood and deep cervical lymph. To establish the required neuroinflammation model, male Sprague-Dawley rats were administered an intraperitoneal (IP) dose of 0.5-2 mg/kg lipopolysaccharide (LPS, &lt;i&gt;Escherichia coli&lt;/i&gt;) or a saline control. After 12 or 24 h, brain samples were collected and analyzed for concentrations of interferon gamma (IFN-γ) using a commercial enzyme-linked immunosorbent assay (ELISA) kit. The impact of neuroinflammation on the drainage of &lt;sup&gt;3&lt;/sup&gt;H-albumin from the brain was determined via IP administration of 2 mg/kg LPS or saline followed by cannulation of the carotid artery for blood collection 24 h later with/without cannulation or ligation at the efferent deep cervical lymph trunk. Rats were then administered &lt;sup&gt;3&lt;/sup&gt;H-albumin via direct injection into the brain striatum or via intravenous (IV) injection (lymph-intact group only). Blood ± lymph samples were collected for up to 8 h following dosing. At the end of the study, brain and lymph node samples were harvested for biodistribution analysis, with samples analyzed for radioactivity levels via scintillation counting. Brain concentrations of the pro-inflammatory cytokine IFN-γ were only significantly elevated 24 h after IP administration of 2 mg/kg LPS compared to saline control. Therefore, this induction regimen was utilized for subsequent studies. The plasma concentrations of &lt;sup&gt;3&lt;/sup&gt;H-albumin over time were elevated in LPS-induced rats compared to saline-injected rats in the lymph-intact and lymph-ligated groups but not in the lymph-cannulated group. In the deep cervical lymph-cannulated animals, the lymph transport of &lt;sup&gt;3&lt;/sup&gt;H-albumin was not increased and appeared to be slower in the LPS-administered rats. Acute LPS-induced neuroinflammation therefore led to an enhanced overall transport of &lt;sup&gt;3&lt;/sup&gt;H-albumin from the brain into the systemic circulation. This appeared to be primarily due to increased transport of &lt;sup&gt;3&lt;/sup&gt;H-albumin from the brain directly into the blood circulation as &lt;sup&gt;3&lt;/sup&gt;H-albumin transport from the brain via the lymphatics was not increased in the LPS-induced neuroinflammation model. Such changes in the clearance of therapeutic proteins from the brain in the setting of neuroinflammation may impact the therapeutic e","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}