Molecular Pharmaceutics最新文献

{"title":"Correction to \"Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles\".","authors":"Savvas Dimiou, James McCabe, Rebecca Booth, Jonathan Booth, Kalyan Nidadavole, Olof Svensson, Anders Sparén, Lennart Lindfors, Vasiliki Paraskevopoulou, Heather Mead, Lydia Coates, David Workman, Dave Martin, Kevin Treacher, Sanyogitta Puri, Lynne S Taylor, Bin Yang","doi":"10.1021/acs.molpharmaceut.5c00307","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00307","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707768","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":"Utilizing PET Imaging To Visualize Immune Activation and Tumor Apoptosis.","authors":"Yuan Feng, Zhaoguo Lin, Wenzhu Hu, Xingyi Wang, Zihan Zhang, Xiaoli Lan, Xiao Zhang","doi":"10.1021/acs.molpharmaceut.4c01314","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01314","url":null,"abstract":"<p><p>Immunotherapy-induced tumor apoptosis is one of the crucial pathways in tumor cell death. This study aimed to explore the potential of PET imaging for noninvasively visualizing pivotal processes in immunotherapy, specifically immune activation and tumor apoptosis, by targeting granzyme-B and caspase-3. Bioinformatic analyses validated granzyme-B and caspase-3 expression in cancer tissues and their associations with immune infiltration and patient prognosis using the GEPIA and TIMER databases. Two radiolabeled probes, [⁶⁸Ga]Ga-GZP and [⁶⁸Ga]Ga-AC3, were used to specifically target granzyme-B and caspase-3 for PET imaging, respectively. CT26 xenograft tumor models were assigned to PD-1 inhibitor or PBS control groups to receive treatment every 3 days, with imaging conducted at baseline and after each treatment. Imaging results showed significantly increased tumor uptake of both [⁶⁸Ga]Ga-GZP and [⁶⁸Ga]Ga-AC3 in the ICB-treated group compared to controls, indicating early molecular changes in immune activation and tumor apoptosis. Immunofluorescence analysis further supported these findings, revealing upregulated granzyme-B and caspase-3 expression in treated tumor tissues. Immunohistochemistry also confirmed increased T-cell infiltration and elevated levels of effector molecules, such as IFN-γ and TNF-α, in the ICB group. This study demonstrates that granzyme-B and caspase-3 PET/CT can noninvasively visualize early molecular changes in immunotherapy-induced CD8⁺ T cell activation and tumor apoptosis. These noninvasive diagnostic techniques hold significant promise for future clinical applications, particularly for a more accurate evaluation of immunotherapy efficacy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707779","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":"Non-Viral RNA Therapies for Non-Small Cell Lung Cancer and Their Corresponding Clinical Trials.","authors":"Palas Balakdas Tiwade, Vincent Fung, Rachel VanKeulen-Miller, Eshan Amruth Narasipura, Yutian Ma, Owen S Fenton","doi":"10.1021/acs.molpharmaceut.4c00871","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00871","url":null,"abstract":"<p><p>Ribonucleic acid (RNA)-based therapies represent a promising class of drugs for the treatment of non-small cell lung cancer (NSCLC) due to their ability to modulate gene expression. Therapies leveraging small interfering RNA (siRNA), messenger RNA (mRNA), microRNA (miRNA), and antisense oligonucleotides (ASOs) offer various advantages over conventional treatments, including the ability to target specific genetic mutations and the potential for personalized medicine approaches. However, the clinical translation of these therapeutics for the treatment of NSCLC faces challenges in delivery due to their immunogenicity, negative charge, and large size, which can be mitigated with delivery platforms. In this review, we provide a description of the pathophysiology of NSCLC and an overview of RNA-based therapeutics, specifically highlighting their potential application in the treatment of NSCLC. We discuss relevant classes of RNA and their therapeutic potential for NSCLC. We then discuss challenges in delivery and non-viral delivery strategies such as lipid- and polymer-based nanoparticles that have been developed to address these issues in preclinical models. Furthermore, we provide a summary table of clinical trials that leverage RNA therapies for NSCLC [which includes their National Clinical Trial (NCT) numbers] to highlight the current progress in NSCLC. We also discuss how these NSCLC therapies can be integrated with existing treatment modalities to enhance their efficacy and improve patient outcomes. Overall, we aim to highlight non-viral strategies that tackle RNA delivery challenges while showcasing RNA's potential as a next-generation therapy for NSCLC treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699109","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":"Lipopolysaccharide Induces Resistance to CAR-T Cell Therapy of Colorectal Cancer Cells through TGF-β-Mediated Stemness Enhancement.","authors":"Min Tao, Mengmeng Xue, Daoyu Zhou, Luyao Zhang, Xiaojuan Hou, Xinyu Zhu, Shiyao Feng, Haixin Yan, Xiaofeng Qian, Lixin Wei, Chen Zong, Xue Yang, Li Zhang","doi":"10.1021/acs.molpharmaceut.4c00264","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00264","url":null,"abstract":"<p><p>Chimeric antigen receptor-T (CAR-T) cell therapy is a cellular immunotherapy that has emerged in recent years, and increasing studies showed that therapeutic resistance to CAR-T cell therapy presents in colorectal cancer patients. Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is known to preserve a high concentration in the colon. Whether LPS is a contributing factor to the development of resistance in colorectal cancer cells against CAR-T cell therapy remains unclear. For <i>in vivo</i> experiments, colorectal cancer cells COLO205 were pretreated with LPS for 24 h and then were injected into nude mice through the tail vein, followed by CAR-T cells transplantation one day later. Later, the number of tumors in the lung tissues of the mice was observed. The <i>in vitro</i> experiments were performed on COLO205 cells, which were treated with LPS for 24 h. The effect of LPS on the stemness of COLO205 and SW620 cells was observed by using the colony formation assay and spheroidization experiments. The effect of LPS on the expression of stemness-related genes, including CD44, SOX2, and NANOG, was observed by qRT-PCR assay, Western blotting assay, and immunofluorescence staining. Inhibitors of TGF-β and the MYD88 inhibitor were used to study the mechanisms by which LPS induces the stemness enhancement and resistance to CAR-T cell therapy of COLO205 cells. The correlation between <i>MYD88</i> and <i>TGFB1</i>, as well as the correlation between <i>TGFB1</i> and stemness-related genes was analyzed using the TCGA database. Both the <i>in vivo</i> assay of nude mice and the <i>in vitro</i> assay showed that LPS pretreatment could induce resistance to CAR-T cell therapy of colorectal cancer cells. LPS could enhance COLO205 and SW620 cells stemness presented by upregulation of CD44, SOX2, and NANOG. The reverse interfering assay using the TGF-β inhibitor indicated that the autosecretion of TGF-β induced by LPS played a critical role in the stemness enhancement of colorectal cancer cells. The TCGA database analysis revealed a strong positive correlation between <i>MYD88</i> and <i>TGFB1</i>. Additionally, <i>TGFB1</i> has been found to upregulate the expression of genes associated with stemness. Further mechanism studies showed that the TLR4/MYD88 pathway medicates LPS-induced TGF-β expression. Our results suggested that LPS-induced resistance to CAR-T cell therapy of colorectal cancer cells through stemness enhancement. TLR4/MYD88 signal pathway-dependent TGF-β expression was involved in stemness enhancement and CAR-T cell therapy resistance. In conclusion, our findings help us to understand the underlying mechanisms of CAR-T cell therapy resistance and indicate that inhibitors of TGF-β and MYD88 are promising targeting candidates to promote a therapeutic effect of CAR-T cell therapy in colorectal cancer in the clinic.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672935","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":"Impact of Composition of Lipid-Based Formulations on First-Pass Drug Metabolism after Oral Administration.","authors":"Yusuke Tanaka, Rikuto Fukaishi, Daiki Okamoto, Takanori Kurakazu, Tokio Nakai, Haruya Yagi, Shinji Sakuma","doi":"10.1021/acs.molpharmaceut.4c01299","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01299","url":null,"abstract":"<p><p>This study aimed to elucidate the drug absorption mechanisms after oral administration of lipid-based formulations (LBFs), emphasizing the impact of their composition on first-pass drug metabolism. Ketoconazole (KTZ), a CYP3A substrate, was loaded into two types of LBFs: a long-chain LBF (type II-LC) and a lipid-free formulation (type IV). Following oral administration of type II-LC, the systemic exposure of KTZ was lower compared to that for the type IV and a control suspension. However, pretreatment with 1-aminobenzotriazole, a nonspecific CYP inhibitor, revealed equivalent in vivo exposure among the formulations tested. The absorption of KTZ from type II-LC in the early period was slower than that from the suspension and type IV. Experiments on in vitro digestion in sequence with in vitro permeation across a dialysis membrane showed that the drug permeation rate for type II-LC was extremely low. This was probably due to the reduction in free drug molecules in the donor compartment via the incorporation of KTZ into mixed micelles comprising digestion products derived from type II-LC and bile components. Furthermore, luminal concentration measurements revealed that gastric emptying was delayed when a type II-LC was administered. The reduced free drug concentration and transient delay in gastric emptying of KTZ resulted in the slower absorption of KTZ for type II-LC. The product of the fraction of drug absorbed and fraction of the drug not metabolized in the gut wall (Fa × Fg) calculated from the systemic and portal plasma concentration-time courses of KTZ was 0.185 for type II-LC and 0.327 for suspension. Since the luminal concentration measurement demonstrated complete absorption of KTZ from the gastrointestinal tract (Fa ≅ 1), the Fa × Fg values can be regarded as Fg. In conclusion, the lower in vivo exposure following oral administration of type II-LC was attributed to reduced Fg, that is, slower drug absorption from the jejunum resulted in low KTZ concentration in enterocytes, leading to enhanced metabolic efficiency. Our findings can be valuable when selecting excipients for designing LBFs with the preferred in vivo performance for highly metabolized drugs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672931","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":"Computational Approaches for Predicting Drug Interactions with Human Organic Anion Transporter 4 (OAT4).","authors":"Lucy Martinez-Guerrero, Patricia A Vignaux, Joshua S Harris, Thomas R Lane, Fabio Urbina, Stephen H Wright, Sean Ekins, Nathan J Cherrington","doi":"10.1021/acs.molpharmaceut.4c00984","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00984","url":null,"abstract":"<p><p>Human Organic Anion Transporter 4 (OAT4) is predominantly expressed in the kidneys, particularly in the apical membrane of the proximal tubule cells. This transporter is involved in the renal handling of endogenous and exogenous organic anions (OAs), making it an important transporter for drug-drug interactions (DDIs). To better understand OAT4-compound interactions, we generated single concentration (25 μM) <i>in vitro</i> inhibition data for over 1400 small molecules against the uptake of the fluorescent OA 6-carboxyfluorescein (6-CF) in Chinese hamster ovary (CHO) cells. Several drugs exhibiting higher than 50% inhibition in this initial screen were selected to determine IC₅₀ values against three structurally distinct OAT4 substrates: estrone sulfate (ES), ochratoxin A (OTA), and 6-CF. These IC₅₀ values were then compared to the drug plasma concentration as per the 2020 FDA drug-drug interaction (DDI) guidance. Several screened compounds, including some not previously reported, emerged as novel inhibitors of OAT4. These data were also used to build machine learning classification models to predict the activity of potential OAT4 inhibitors. We compared multiple machine learning algorithms and data cleaning techniques to model these screening data and investigated the utility of conformal predictors to predict OAT4 inhibition of a leave-out set. These experimental and computational approaches allowed us to model diverse and unbalanced data to enable predictions for DDIs mediated by this transporter.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668488","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":"Lyophilization Strategy Enhances the Thermostability and Field-Based Stability of Conjugated and Comixed Subunit Liposomal Adjuvant-containing Tuberculosis Vaccine Formulation (ID93 + GLA-LSQ).","authors":"Babatunde Ayodeji Adeagbo, Morayo Alao, Ochuko Orherhe, Abdulafeez Akinloye, Gerhardt Boukes, Elize Willenburg, Caryn Fenner, Oluseye Oladotun Bolaji, Christopher B Fox","doi":"10.1021/acs.molpharmaceut.5c00150","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00150","url":null,"abstract":"<p><p>ID93 + GLA-LSQ is an adjuvanted recombinant protein vaccine candidate that has demonstrated robust T-cell immunity and reduced bacterial burden in preclinical studies. Here, we explored the strategy of lyophilization by introducing 10% Trehalose as a bulking agent and cryoprotectant to develop a thermostable single-vial formulation of ID93 + GLA-LSQ. We further examined the stability of lyophilized formulations stored at 4 and 37 °C in the research laboratory and field stability across five study sites. Co-mixed (CoVL) and conjugated (ConjVL) formulations were prepared and assessed for various stability parameters including cake quality, melting point, liposome reformation, particle size, GLA/QS-21 concentration, presence of ID93, and biological activity for three months in the research laboratory and nine months at ambient temperature in five health centers. Stability assessment for both formulations stored in the research laboratory for three months showed that they were physically stable and biologically active. The field-based ambient stability assessment showed that the formulations maintained physical integrity, liposomal structure, and antigen integrity, with limited chemical degradation of GLA and QS-21 adjuvants observed. ConjVL retains GLA slightly better than the CoVL formulation, and a moderate increase in particle size was observed after nine months. These findings showed that the formulations demonstrate a promising stability profile after extended storage at ambient temperature, suggesting the potential for real-world application without strict refrigeration requirements.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655523","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":"Mechanistic Insights into the Antibiofilm Activity of Simvastatin and Lovastatin against <i>Bacillus subtilis</i>.","authors":"Nidhi Verma, Mamta Bajiya, Ragini Dolhey, Surabhi, Abhishek Singh Yadav, Chhavi Chaudhary, Dhankesh Meena, Hemant Arya, Tarun K Bhatt, Jay Kant Yadav, Jayendra Nath Shukla, Shiv Swaroop, Janmejay Pandey","doi":"10.1021/acs.molpharmaceut.5c00191","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00191","url":null,"abstract":"<p><p>Statins have been reported for diverse pleiotropic activities, including antimicrobial and antibiofilm. However, due to the limited understanding of their mode of action, none of the statins have gained approval for antimicrobial or antibiofilm applications. In a recent drug repurposing study, we observed that two statins (<i>i.e</i>., Simvastatin and Lovastatin) interact stably with TasA_(28-261), the principal extracellular matrix protein of <i>Bacillus subtilis</i>, and also induce inhibition of biofilm formation. Nevertheless, the underlying mechanism remained elusive. In the present study, we examined the impact of these statins on the physiological activity of TasA_(28-261), specifically its interaction with TapA_(33-253) and aggregation into the amyloid-like structure using purified recombinant TasA_(28-261) and TapA_(33-253) in amyloid detection-specific <i>in vitro</i> assays (<i>i.e</i>., CR binding and ThT staining assays). Results revealed that both statins interfered with amyloid formation by the TasA_(28-261)-TapA_(33-253) complex, while neither statin inhibited amyloid formation by lysozyme, a model amyloid-forming protein. Moreover, neither statin significantly altered the expressions of terminal regulatory genes (<i>viz</i>, <i>sinR</i>, <i>sinI</i>) and terminal effector genes (<i>viz</i>, <i>tasA</i>, <i>tapA</i>, and <i>bslA</i>) involved in biofilm formation by <i>B. subtilis</i>. While the intricate interplay between Simvastatin and Lovastatin with the diverse molecular constituents of <i>B. subtilis</i> biofilm remains to be elucidated conclusively, the findings obtained during the present study suggest that the underlying mechanism for Simvastatin- and Lovastatin-mediated inhibition of <i>B. subtilis</i> biofilm formation is manifested by interfering with the aggregation and amyloid formation by TasA_(28-261)-TapA_(33-253). These results represent one of the first experimental evidence for the underlying mechanism of antibiofilm activity of statins and offer valuable directions for future research to harness statins as antibiofilm therapeutics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655524","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":"Enhanced Retention of NTSR1-Targeted Radionuclide Therapeutics via Covalent Inhibitors in Pancreatic, Colorectal, and Prostate Cancer Models.","authors":"Wenting Zhang, Wei Fan, Katie Brake, Alireza Basiri, Megan A Hyun, Lynette M Smith, Subodh M Lele, Abhijit Aithal, Maneesh Jain, Jered C Garrison","doi":"10.1021/acs.molpharmaceut.4c01324","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01324","url":null,"abstract":"<p><p>Neurotensin receptor subtype 1 (NTSR1) is overexpressed in numerous cancers. Our laboratory is exploring the utilization of covalent cysteine protease inhibitors (e.g., E-64) to increase tumor retention of targeted radionuclide therapeutics (TRTs) through protein adduct formation. Using this approach, we reported [¹⁷⁷Lu]Lu-NA-ET1, an NTSR1-targeted construct. In this work, we continue the exploration of [¹⁷⁷Lu]Lu-NA-ET1 in three different NTSR1-positive cancer models. [¹⁷⁷Lu]Lu-3BP-227, a clinically investigated NTSR1-targeted construct, was utilized as a comparative benchmark. Both [¹⁷⁷Lu]Lu-NA-ET1 and [¹⁷⁷Lu]Lu-3BP-227 underwent in vitro investigation, including internalization and autoradiographic sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies, in NTSR1-positive AsPC-1, HT-29, and PC-3 cell lines. Biodistribution, human radiation dosimetry, and in vivo autoradiographic SDS-PAGE studies were performed by using the same models. A dose escalation study using 585 MBq (15.8 mCi) of [¹⁷⁷Lu]Lu-NA-ET1 was implemented in immunocompetent CF-1 mice. In all three cell lines, [¹⁷⁷Lu]Lu-NA-ET1 demonstrated similar cellular uptake profiles relative to those of [¹⁷⁷Lu]Lu-3BP-227. Biodistribution studies of [¹⁷⁷Lu]Lu-NA-ET1 revealed increased (1.9-4.4-fold) tumor retention and radiation dose delivery relative to the control. Analysis of the in vitro and in vivo cellular and tissue lysates showed protein adducts that ranged from approximately 25-35 kDa, consistent with cysteine cathepsins, the speculative protein binding partner. A total of 585 MBq (15.8 mCi) of [¹⁷⁷Lu]Lu-NA-ET1 was administered and found to be well-tolerated. Incorporating the covalent inhibitor in [¹⁷⁷Lu]Lu-NA-ET1 resulted in an improved retention and radiation dose delivery profile compared to [¹⁷⁷Lu]Lu-3BP-227. Examination of the therapeutic potential of [¹⁷⁷Lu]Lu-NA-ET1 and further exploration of the chemical biology of this approach is underway.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655519","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":"Topical Administration of Mucoadhesive Liposomes-Epoetin-β for Targeting the Ocular Posterior Segment.","authors":"Sarvenaz Pakian, Mohammad Reza Nabid, Leila Satarian, Hamid Sadeghi Abandansari, Ahmad Mirkani","doi":"10.1021/acs.molpharmaceut.5c00079","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00079","url":null,"abstract":"<p><p>Delivering drugs to the posterior eye segment is a complex task, particularly for treating retinal diseases. Neuroprotective approaches to maintain neuronal integrity have garnered significant attention in recent research. Here, we developed a mucoadhesive nanoparticulate system based on thiolated hyaluronic acid-modified cationic liposomes (HA-SH@liposomes) for topical administration. To fabricate these liposomes, we utilized microfluidic technology with a toroidal mixer to ensure consistent size and stability. Cationic liposomes were prepared by using the microfluidic method, and Epoetin-β (EPOβ), a neuroprotective agent, was loaded into the liposomes. Following this, HA-SH was conjugated to the EPOβ/HA-SH@liposomes using a postmicrofluidics conjugation method, wherein HA-SH was added dropwise to facilitate electrostatic interactions between the cationic liposomes and the anionic polymer. The resulting liposomes exhibited a mean size of 144 ± 1.3 nm and a polydispersity index (PDI) of 0.09 ± 0.01, indicating their uniformity. We evaluated the biocompatibility of the EPOβ/HA-SH@liposomes in vitro using live/dead and MTS assays on the RGC-5 cell line, demonstrating no notable cytotoxicity compared to the controls. To assess the in vivo performance, we conducted extensive ophthalmological examinations in C57/BL6 mice, including immunofluorescence staining to track the distribution of EPOβ and EPOβ/HA-SH@liposomes within the eyeball. Additionally, we quantified EPOβ levels in the retina using an enzyme-linked immunosorbent assay (ELISA) kit after the topical application of free EPOβ and the EPOβ/HA-SH@liposome formulation. The immunofluorescence staining revealed efficient delivery of EPOβ into the retina and choroid via the transcorneal route when administered as EPOβ/HA-SH@liposomes. ELISA results showed that the liposomal formulation achieved approximately 1.9× greater penetration efficiency than free EPOβ. Furthermore, optokinetic response (OKR) assays indicated that animals treated with EPOβ/HA-SH@liposomes exhibited slightly improved visual acuity compared with those treated with free EPOβ, though the difference was not statistically significant. In conclusion, the topical ocular administration of EPOβ/HA-SH@liposomes facilitated the efficient delivery of EPOβ to the retina, promoting retinal recovery and confirming its neuroprotective properties. This preclinical study provides a foundation for innovative strategies in the topical delivery of neuroprotective agents in ocular therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655525","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}