Molecular Pharmaceutics最新文献

{"title":"Cu²⁺/Zn²⁺ \"Antimicrobial Chamber\" with Self-Enhanced Photothermal Activity Supports Infected Wound Healing.","authors":"Hanzhu Shi, Xue Zhou, Jue Wang, Xiuhong Zhou, Chenwei Dai, Lu Li, Xuechao Dong","doi":"10.1021/acs.molpharmaceut.5c00089","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00089","url":null,"abstract":"<p><p>Wound healing of drug-resistant bacterial infection is a major challenge in clinical practice, and existing treatments suffer from the drawbacks of high dosage, low efficiency, and insufficient biosafety. Herein, we coated ultrasmall copper sulfide nanoparticles (CuS NPs) into zeolitic imidazolate framework-8 (ZIF-8) and modified them with polydopamine (PDA) to obtain CuS@ZIF-8@PDA NPs for bacterial infection wound treatment. Due to the presence of CuS and the degradability of ZIF-8, CuS@ZIF-8@PDA NPs can continuously release Cu²⁺ and Zn²⁺ in a slightly acidic environment under near-infrared (NIR) irradiation. Furthermore, the introduction of PDA endows it with an excellent photothermal property. The synergistic effect of dual ions/photothermal enables it to effectively eradicate <i>Staphylococcus aureus</i> (<i>S. aureus</i>) and <i>Escherichia coli</i> (<i>E. coli</i>). Moreover, <i>in vivo</i> experimental results confirm that released Cu²⁺ and Zn²⁺ can promote epithelial regeneration, thereby accelerating wound healing. In the bacterially infected mouse model, CuS@ZIF-8@PDA NPs exhibit excellent synergistic antimicrobial and wound healing effects, while having no toxic side effects on major organs. The study of the dual-ion/photothermal synergistic antibacterial strategy based on CuS@ZIF-8@PDA NPs provides a new insight into bacterial infection wound repair.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148673","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":"Additivity of Transfer Free Energies Enables the Description of Complex Protein Formulations in Implicit Solvent Molecular Dynamics Simulations.","authors":"Dominik Brandstetter, Max Unger, Tim Menzen, Hristo L Svilenov, Andrea Arsiccio","doi":"10.1021/acs.molpharmaceut.5c00169","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00169","url":null,"abstract":"<p><p>A complex 3D structure and the surrounding environment determine the function and stability of a protein. Various osmolytes can be added to a protein drug formulation to stabilize the native protein structure by preventing unfolding and aggregation. In this context, the concept of transfer free energy, which represents the change in chemical potential of a protein being transferred from water to an osmolyte solution, has emerged as a powerful tool to elucidate the energetics involved in the protein-osmolyte interaction. In the present work, we experimentally determine the transfer free energies for the excipients sodium chloride, arginine hydrochloride, and polysorbate 20, which are frequently used in pharmaceutical protein formulations. We show that these excipients display distinct patterns of exclusion or interaction toward different moieties on the protein surface. Furthermore, we report that the free energy cost for transferring a protein to a formulation composed of multiple components can be calculated by summing up the contributions of the individual components. This finding suggests that additivity applies to the transfer free energies. We demonstrate that this additive behavior can be leveraged to accurately and efficiently model complex protein formulations. Additionally, we discuss how transfer free energies can be incorporated within implicit solvent molecular dynamics calculations, providing a direct link between experiments and simulations. Our molecular dynamics results show good agreement with experimental data for lysozyme, interferon α-2a, and granulocyte colony-stimulating factor, for both single- and multicomponent matrices, demonstrating the validity of our approach.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148670","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":"Breaking Biofilm Barriers: Using CATH-ICG-Loaded Bilayer Dissolving Microneedle-Assisted Photodynamic Therapy for Deep Skin Candidiasis.","authors":"Yaseen Hussain, Amos Dormocara, Huifang Li, Chengguo Li, Muhammad Kamran Khan, Yonghao Ma, Gang Leng, Yipeng Wang, Ben-Gang You, Jing-Hao Cui","doi":"10.1021/acs.molpharmaceut.5c00367","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00367","url":null,"abstract":"<p><p>Deep skin fungal infections, particularly biofilm-associated <i>Candida albicans</i> (<i>C. albicans</i>), pose significant clinical challenges due to their resistance to conventional antifungal therapies. The stratum corneum acts as a barrier to high molecular weight drugs, limiting the penetration of systemic and topical antifungal agents. In this study, we explored a transdermal delivery system utilizing novel Cathelicidin─HcCATH-KL30 (CATH)-loaded dissolving microneedles (DMNs) for the treatment of deep dermal <i>C. albicans</i> biofilm infections. Preliminary evaluations demonstrated that CATH exhibited potent antifungal activity against nonfilamentous and filamentous <i>C. albicans</i> but was ineffective against biofilm-embedded Candida, suggesting biofilm penetration limitations. To enhance its efficacy, we integrated indocyanine green into DMNs and applied photodynamic therapy (PDT) using near-infrared (NIR) irradiation. The generated reactive oxygen species disrupted the biofilm matrix, allowing a deeper penetration of CATH for enhanced antifungal activity. Results from in vitro, ex vivo, and in vivo models demonstrated a significant reduction (∼94%) in fungal burden with CATH-ICG-DMNs following NIR irradiation, highlighting a synergistic effect. Findings of the study were mechanistically validated through qRT-PCR and propodeum iodide staining, which were in accordance with the proposed hypothesis. The current research work for the first time explored the novel antimicrobial peptide from a drug delivery platform in order to investigate its potential. This study establishes a promising microneedle-based PDT strategy for combating deep skin fungal infections, overcoming biofilm-mediated resistance and enhancing antifungal therapy efficacy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148671","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":"Comprehensive Head-to-Head Study between Meta-[²¹¹At]astato-benzylguanidine and with Meta-[¹³¹I]iodo-benzylguanidine in Pheochromocytoma.","authors":"Hwisoo Lim, Sang Gyu Hwang, Yong Jin Lee, Sangchul Mun, Seyoung Oh, Choong Mo Kang, Jae Yong Choi","doi":"10.1021/acs.molpharmaceut.5c00404","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00404","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Pheochromocytoma (PCC) is a rare neuroendocrine tumor that is often nonfunctional in its early stages, making detection difficult during the prodromal phase. Targeted radionuclide therapy using radiopharmaceuticals has been explored for treating PCC. We aimed to evaluate and compare the therapeutic efficacy of &lt;i&gt;meta&lt;/i&gt;-[&lt;sup&gt;131&lt;/sup&gt;I]iodobenzylguanidine ([&lt;sup&gt;131&lt;/sup&gt;I]MIBG) and &lt;i&gt;meta&lt;/i&gt;-[&lt;sup&gt;211&lt;/sup&gt;At]astatobenzylguanidine ([&lt;sup&gt;211&lt;/sup&gt;At]MABG) &lt;i&gt;in vitro&lt;/i&gt; and in a PCC animal model. Astatine-211 was radiolabeled with a benzylguanidine precursor, and the crude product was purified using high-performance liquid chromatography, followed by formulation to prepare an injectable [&lt;sup&gt;211&lt;/sup&gt;At]MABG. [&lt;sup&gt;131&lt;/sup&gt;I]MIBG was obtained from the Korea Atomic Energy Research Institute. The stability of [&lt;sup&gt;211&lt;/sup&gt;At]MABG was assessed in saline and human serum with or without sodium ascorbate. &lt;i&gt;In vitro&lt;/i&gt; experiments included evaluating cellular uptake in PC-12 cells, colony formation inhibition (clonogenic assay), and DNA damage (Comet assay). &lt;i&gt;In vivo&lt;/i&gt; studies were conducted using PC-12 tumor-bearing mice to assess biodistribution, tumor volume reduction, survival rates, and body weight changes. Immunohistochemical analyses of tumor proliferation and apoptosis were performed using &lt;i&gt;K&lt;/i&gt;&lt;sub&gt;i&lt;/sub&gt;-67, proliferating cell nuclear antigen (PCNA), and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. [&lt;sup&gt;211&lt;/sup&gt;At]MABG was successfully synthesized with a radiochemical yield of 48.4% (decay-corrected). The radiochemical purity (RCP) was 99.3%, and the specific activity was 1.27-8.13 MBq·nmol&lt;sup&gt;-1&lt;/sup&gt; at the end of synthesis (&lt;i&gt;n&lt;/i&gt; = 3). In chemical stability tests of [&lt;sup&gt;211&lt;/sup&gt;At]MABG, when sodium ascorbate was not added, the RCP was 76% at 24 h after production; however, when sodium ascorbate was added, its purity was 92% at the same time. &lt;i&gt;In vitro&lt;/i&gt; uptake assays revealed that [&lt;sup&gt;211&lt;/sup&gt;At]MABG exhibited higher cellular uptake in PC-12 cells compared with [&lt;sup&gt;211&lt;/sup&gt;At]NaAt and [&lt;sup&gt;131&lt;/sup&gt;I]MIBG, initially accumulating in the cytosol and progressively increasing over 24 h. DNA double-strand breaks were confirmed using the Comet assay. Biodistribution studies demonstrated that administration of [&lt;sup&gt;211&lt;/sup&gt;At]MABG containing sodium ascorbate reduced thyroid uptake and enhanced tumor accumulation of [&lt;sup&gt;211&lt;/sup&gt;At]MABG. Treatment with 0.93 MBq [&lt;sup&gt;211&lt;/sup&gt;At]MABG resulted in superior tumor suppression compared with 19.25 MBq [&lt;sup&gt;131&lt;/sup&gt;I]MIBG and improved survival rates. Immunohistochemical analyses confirmed decreased tumor proliferation and increased apoptosis following [&lt;sup&gt;211&lt;/sup&gt;At]MABG treatment. The stability of [&lt;sup&gt;211&lt;/sup&gt;At]MABG in human serum was significantly enhanced by sodium ascorbate. Even at doses 20 times lower than [&lt;sup&gt;131&lt;/sup&gt;I]MIBG, [&lt;sup&gt;211&lt;/sup&gt;At]MABG demonstrated superior antitumor efficacy without induc","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148672","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":"Antitumor Efficacy, Pharmacokinetics, and Toxicity Studies of Novel Estrogen Receptors Targeted PEGylated Liposomes Encapsulating Paclitaxel and Cisplatin in SKOV-3 Tumor-Bearing Nude Mice, ICR Mice, and SD Rats.","authors":"Ming Zhu, Juan Jia, Huan Tang, Yizhuo Xie, Zhe Lv, Han Bao, Yan Zhang, Dongfanghui Miao, Xin Guo, Kejia Chen, Shanshan Wang, Liangping Yu, Jin Pei","doi":"10.1021/acs.molpharmaceut.4c01457","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01457","url":null,"abstract":"<p><p>Ovarian malignancies overexpress estrogen receptors (ERs), offering a therapeutic avenue for targeted drug delivery. Here, we developed a novel ER-targeted PEGylated liposome (ES-SSL-PTX/CDDP) coencapsulating paclitaxel (PTX) and cisplatin (CDDP) to enhance therapeutic efficacy and mitigate systemic toxicity. ES-SSL-PTX/CDDP exhibited a spherical shape with a hydrodynamic diameter of around 150 nm, a negative zeta potential of about -20 mV, and high encapsulation efficiencies of 83.7% for PTX and 41.1% for CDDP. ES-SSL-PTX/CDDP showed a sustained release pattern, with release rates of <60% for both drugs within 12 h. Meanwhile, ES-SSL-PTX/CDDP demonstrated excellent storage and serum stability, with the leakage rates less than 30% when stored at either 4 or 25 °C. ES-SSL-PTX/CDDP exhibited a strong antitumor effect in athymic mice with the tumor volume 8.50 times smaller than that in the control group on the 27th day, and the tumor inhibition rate reached 87.3%. Pharmacokinetic studies revealed prolonged circulation of ES-SSL-PTX/CDDP, with elimination half-lives (<i>t</i>_1/2β) of 13.84 h (PTX) and 7.18 h (CDDP), which were 8.82- and 1.83-fold higher than those of PTX/CDDP, and clearance rates reduced to 0.01 L/h/kg (PTX) and 0.02 L/h/kg (CDDP), being 18.0- and 4.0-fold lower than those of PTX/CDDP. Acute toxicity results demonstrated a 2.12-fold increase in the LD₅₀ of ES-SSL-PTX/CDDP (27.82 mg/kg for PTX; 19.87 mg/kg for CDDP) versus PTX/CDDP. Long-term toxicity studies demonstrated that ES-SSL-PTX/CDDP attenuated myelosuppression and nephrotoxicity, with no histopathological abnormalities observed across 32 tissues after 16 weeks of administration. This study highlights the potential of ES-SSL-PTX/CDDP to improve the efficacy and reduce the toxicity of platinum-taxane regimens in the treatment of ovarian cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140883","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":"Advancing Photodynamic Therapy: The Role of PET and SPECT in Imaging-Guided Theranostics.","authors":"Emman Saeed, Khudaima Bibi, Sajid Mushtaq, Iqra Bibi, Ji-Ae Park","doi":"10.1021/acs.molpharmaceut.5c00551","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00551","url":null,"abstract":"<p><p>Early cancer diagnosis is crucial for better treatment outcomes. Selecting the most effective therapy relies on accurate and specific diagnostic tools. Imaging plays a key role in evaluating new treatments, assessing disease progression, and monitoring tumor changes during therapy. It also aids in refining treatment strategies after completion. PDT shows significant promise in cancer treatment, using light-activated compounds to target cancer cells. Nuclear medicine techniques like PET and SPECT are particularly valuable for planning and monitoring PDT. Radiolabeled photosensitizers and clinically approved radiopharmaceuticals enable tracking of drug distribution and treatment effects, such as cell death, metabolism, and vascular damage. This review highlights the role of nuclear imaging in supporting PDT for cancer treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140880","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":"Revolutionizing Neurological Therapies: The Multifaceted Potential of Zein-Based Nanoparticles for Brain-Targeted Drug Delivery.","authors":"Somesh Narayan, Piyush Kumar Gupta, Kalpana Nagpal","doi":"10.1021/acs.molpharmaceut.5c00062","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00062","url":null,"abstract":"<p><p>Zein nanoparticles (ZNPs) have gained significant attention as biocompatible and biodegradable nanocarrier systems for brain-targeted drug delivery. Their ability to encapsulate hydrophobic drugs and undergo surface modifications enables effective blood-brain barrier (BBB) penetration through receptor-mediated transcytosis. Functionalization approaches, such as PEGylation and ligand conjugation, have been explored to enhance BBB transport and improve drug bioavailability. Additionally, ZNPs hold the potential for theranostic applications, integrating drug delivery with real-time diagnostics to facilitate personalized treatment strategies. This review provides a comprehensive evaluation of ZNPs, discussing their fabrication techniques, surface modifications, and transport mechanisms across the BBB. A comparative analysis with other nanocarrier systems (liposomes, polymeric NPs, dendrimers, lipid-based NPs, and carbon nanotubes) highlights their superior biodegradability, lower toxicity, and potential for clinical translation. Furthermore, we explore the latest advancements in ZNP-based drug delivery for neurological disorders, including glioblastoma, Parkinson's, and Alzheimer's. Despite their advantages, the clinical translation of ZNPs remains challenging due to scalability issues, batch-to-batch variability, and regulatory constraints. Future research should optimize functionalization strategies, enhance drug release kinetics, and conduct long-term safety evaluations. With continued advancements in nanotechnology and pharmaceutical engineering, ZNPs represent a promising, sustainable platform for improving brain-targeted therapeutic interventions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140991","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":"Preparation of a Kit Formulation of [^99mTc]Tc-CN7DM, a Mannose Derivative for Tumor Imaging, and an Exploratory Human Study.","authors":"Guangxing Yin, Qing Ruan, Dajie Ding, Yuhao Jiang, Peiwen Han, Qingna Xiao, Xiaoliang Chen, Junbo Zhang","doi":"10.1021/acs.molpharmaceut.5c00437","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00437","url":null,"abstract":"<p><p>Lung cancer is the most prevalent malignancy worldwide in terms of both incidence and mortality. Therefore, diagnosing lung cancer early is important. Nuclear medicine imaging is an integral modality for cancer diagnosis, in which radiopharmaceuticals are essential elements. Thus, we explored the potential of the novel, previously reported ^99mTc-labeled mannose derivative ([^99mTc]Tc-CN7DM) as a radiopharmaceutical with excellent performance that can be easily clinically translated for tumor imaging. However, when we used a kit formulation which was directly prepared from the ligand CN7DM for preparing [^99mTc]Tc-CN7DM, some unknown radioactive compounds were found. In order to solve this problem, in this study, we synthesized the cuprous complex [Cu(CN7DM)₄]BF₄ for kit formulation to prepare [^99mTc]Tc-CN7DM and evaluated its biological properties and safety profile. Moreover, a preliminary imaging study was conducted with lung cancer patients, and the results demonstrated that [^99mTc]Tc-CN7DM allowed clear visualization of tumor lesions, giving it promising prospects for clinical application.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140940","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":"Macropinocytosis and Fast Endophilin-Mediated Endocytosis Mediate Absorption of Garlic Chive-Derived Vesicle-like Nanoparticles in Human Intestinal Epithelial Cells.","authors":"Phuong Linh Nguyen, Baolong Liu, Shuying Zhang, Jingjie Hao, Jiujiu Yu","doi":"10.1021/acs.molpharmaceut.5c00190","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00190","url":null,"abstract":"<p><p>Dietary extracellular vesicles (EVs) or vesicle-like nanoparticles (VLNs) have been shown to exert beneficial functions in a wide range of diseases such as cancer, colitis, and metabolic diseases. They have also been used as natural carriers for medications. Despite the promising translational potential of dietary EVs or VLNs, the molecular mechanisms of their absorption in the gastrointestinal tract are not well understood. In this study, we investigated the absorption mechanisms of garlic chive-derived VLNs (GC-VLNs) using C57BL/6J mice and a human intestinal epithelial cell line, Caco-2 cells. We found that orally administered GC-VLNs crossed the epithelial layer of the small intestine and entered the underlying lamina propria. GC-VLNs were taken up and transported across the fully differentiated Caco-2 epithelial monolayer. Proteins and lipids, but not RNAs, in GC-VLNs mediated their uptake by Caco-2 cells. Chemical inhibitor treatments demonstrated that macropinocytosis and fast endophilin-mediated endocytosis (FEME) played key roles in the internalization of GC-VLNs. On the other hand, clathrin-coated pit-mediated endocytosis and clathrin-independent carrier/glycosylphosphatidylinositol-anchored protein-enriched early endocytic compartment endocytosis did not contribute to GC-VLN uptake. Activation of macropinocytosis and FEME using their specific activators promoted the internalization of GC-VLNs. In addition, genetic manipulation of key molecules in macropinocytosis and FEME confirmed the important engagement of these two specific endocytic pathways in GC-VLN absorption by human intestinal epithelial cells. Our study has provided proof-of-principle evidence to advance our understanding of the absorption mechanism of GC-VLNs, which would be the key to further manipulation and engineering of these nanoparticles to improve their delivery efficiency as therapeutic modalities or drug carriers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131835","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":"¹⁷⁷Lu-Anti-CD25 Antibody for Interleukin-2 Receptor-α-Targeted Radioimmunotherapy of SUDHL1 Lymphomas in Mice.","authors":"Choong Mo Kang, Jung Lim Kim, Hye Jin Jung, Kyung-Ho Jung, Mina Kim, Giro Kim, Hyunjong Lee, Kyung-Han Lee","doi":"10.1021/acs.molpharmaceut.4c01410","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01410","url":null,"abstract":"<p><p>Antibodies (Abs) conjugated with particle-emitting radioisotopes are used for cancer therapy, and the CD25 receptor (IL-2Rα) is a promising target for lymphomas. We functionalized an anti-CD25 Ab with TCO-PEG₃-maleimide, specifically on sulfhydryl moieties, at 1.89 molecules per Ab. Radiosynthesis was achieved by efficiently prelabeling DOTA-PEG₄-tetrazine with ¹⁷⁷Lu at a high temperature and then linking it to the TCO-conjugated Abs via facile click chemistry under mild conditions. The [¹⁷⁷Lu]Lu-DOTA-PEG₄-Tz-TCO-PEG₃-anti-CD25 Ab (¹⁷⁷Lu-CD25 Ab) had a radiochemical purity of >99%, a specific activity of 707.9 ± 271.5 MBq/mg, an immunoreactive fraction of 77.6%, and high radiolabel stability in serum for up to 7 days. CD25-positive SUDHL1 human T lymphoma cells showed ¹⁷⁷Lu-CD25 Ab uptake that was completely blocked by pretreatment with unlabeled Ab. The ¹⁷⁷Lu-CD25 Ab dose-dependently suppressed SUDHL1 cell survival <i>in vitro</i>. In mice, ¹⁷⁷Lu-CD25 Ab uptake at 5 days was high in the SUDHL1 tumors (7.1 ± 1.6%ID/g), modest in the liver, kidneys, and spleen, and low in the blood, lungs, and bones. CD25-specific targeting was confirmed by 66.7% suppression of tumor uptake by pretreatment with unlabeled CD25 Ab. Treatment with 18.5 MBq of ¹⁷⁷Lu-CD25 Ab shrank the xenograft tumors, and they remained undetectable until study termination on day 61. In contrast, the tumors in all control and CD25 Ab-treated mice grew to exceed the end point criterion of 2,000 mm³. The standardized tumor growth rate and 19-day tumor volume were completely suppressed in the ¹⁷⁷Lu-CD25 Ab group (109.9 ± 73.5 and 132.6 ± 111.5 mm³), compared with the control (1053.9 ± 151.1 and 1804.5 ± 283.1 mm³) and CD25 Ab groups (1049.7 ± 212.2 and 1443.8 ± 839.4 mm³; all <i>p</i> < 0.001). A Kaplan-Meier survival analysis showed that ¹⁷⁷Lu-CD25 Ab-treated mice survived significantly longer than mice in the control and CD25 Ab groups. Tumors in a separate set of mice that were treated with ¹⁷⁷Lu-CD25 Ab displayed increased PARP1 cleavage fragments, a signature of apoptosis. Toxicity studies showed that white blood cell, red blood cell, and platelet counts in the ¹⁷⁷Lu-CD25 Ab group decreased from days 3-14, reaching a nadir on days 17-21 and returning to the normal range by days 24-31. Liver and renal function tests on day 28 did not differ from those of untreated mice. Thus, the ¹⁷⁷Lu-CD25 Ab prepared as described here could be useful for radioimmunotherapy of CD25-positive lymphomas.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131815","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}