Molecular Pharmaceutics最新文献

{"title":"Polyinosinic/Polycytidylic Lipid Nanoparticles Enhance Immune Cell Infiltration and Improve Survival in the Glioblastoma Mouse Model.","authors":"Melanie M T Brüßeler, Alaa Zam, Víctor M Moreno-Zafra, Nadia Rouatbi, Osama W M Hassuneh, Alessia Marrocu, Revadee Liam-Or, Hend Mohamed Abdel-Bar, Adam Alexander Walters, Khuloud T Al-Jamal","doi":"10.1021/acs.molpharmaceut.4c00875","DOIUrl":"10.1021/acs.molpharmaceut.4c00875","url":null,"abstract":"<p><p>Glioblastoma (GBM) immunotherapy is particularly challenging due to the pro-tumorigenic microenvironment, marked by low levels and inactive immune cells. Toll-like receptor (TLR) agonists have emerged as potent immune adjuvants but failed to show improved outcomes in clinical trials when administered as a monotherapy. We hypothesize that a combined nanoparticulate formulation of TLR agonist and immunogenic cell death-inducing drug (doxorubicin) will synergize to induce improved GBM immunotherapy. Lipid nanoparticle (LNP) formulations of the TLR agonists CpG and polyinosinic/polycytidylic (pIpC), with and without Dox, were first prepared, achieving an encapsulation efficiency >75% and a size <140 nm. In vitro studies identified that LNP pIpC was superior to CpG at activating bone marrow-derived immune cell populations (dendritic cells and macrophages) with minimal toxicity. It was also observed that the pIpC formulation can skew macrophage polarization toward the antitumorigenic M1 phenotype and increase macrophage phagocytosis of cancer cells. Upon intratumoral administration, pIpC Dox LNPs led to significant immune cell infiltration and activation. In survival models, the inclusion of Dox into pIpC LNP improved mice survival compared to control. However, addition of Dox did not show significant improvement in mice's survival compared to singly formulated pIpC LNP. This study has illustrated the potential of pIpC LNP formulations in prospective GBM immunotherapeutic regimes. Future studies will focus on optimizing dosage regimen and/or combination with other modalities, including the standard of care (temozolomide), immune checkpoint blockade, or cancer vaccines.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6339-6352"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Protein Therapeutics in Frozen Conditions Using DNP MAS NMR: A Study on Pembrolizumab.","authors":"Daniel Banks, James G Kempf, Yong Du, Paul Reichert, Chakravarthy Narasimhan, Rui Fang, Soonbum Kwon, Jing Ling, Ashley Lay-Fortenbery, Yongqian Zhang, Qing Zhe Ni, Aaron Cote, Yongchao Su","doi":"10.1021/acs.molpharmaceut.4c00929","DOIUrl":"10.1021/acs.molpharmaceut.4c00929","url":null,"abstract":"<p><p>The success of modern biopharmaceutical products depends on enhancing the stability of protein therapeutics. Freezing and thawing, which are common thermal stresses encountered throughout the lifecycle of drug substances, spanning protein production, formulation design, manufacturing, storage, and shipping, can impact this stability. Understanding the physicochemical and molecular behaviors of components in biological drug products at temperatures relevant to manufacturing and shipping is essential for assessing stability risks and determining appropriate storage conditions. This study focuses on the stability of high-concentration monoclonal antibody (mAb) pembrolizumab, the drug substance of Keytruda (Merck & Co., Inc., Rahway, NJ, United States), and its excipients in a frozen solution. By leveraging dynamic nuclear polarization (DNP), we achieve more than 100-fold signal enhancements in solid-state NMR (ssNMR), enabling efficient low-temperature (LT) analysis of pembrolizumab without isotopic enrichment. Through both ex situ and in situ ssNMR experiments conducted across a temperature range of 297 to 77 K, we provide insights into the stability of crystalline pembrolizumab under frozen conditions. Importantly, utilizing LT magic-angle spinning (MAS) probes allows us to study molecular dynamics in pembrolizumab from room temperature down to liquid nitrogen temperatures (<100 K). Our results demonstrate that valuable insights into protein conformation and dynamics, crystallinity, and the phase transformations of excipients during the freezing of the formulation matrix can be readily obtained for biological drug products. This study underscores the potential of LT-MAS ssNMR and DNP techniques for analyzing protein therapeutics and vaccines in frozen solutions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6363-6375"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646479","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":"Innovative Long-Acting Bisoprolol Patch: Synergistic Ion-Pair Skin Adsorption for Drug Delivery Control Coupled with Dynamic Modulation of Penetration Enhancers.","authors":"Yu Pang, Wenxuan Jia, Liuyang Wang, Yang Zhang, Kaihua Gong, Liang Fang","doi":"10.1021/acs.molpharmaceut.4c00738","DOIUrl":"10.1021/acs.molpharmaceut.4c00738","url":null,"abstract":"<p><p>This study aims to develop a sustained release patch for bisoprolol (BSP) to address the issue of blood pressure fluctuations caused by traditional dosing methods, ensuring continuous drug release and efficient utilization. Long-chain saturated fatty acids (C₆-C₁₂) were chosen as counterions to precisely control BSP's permeation rate in the patch formulation, and the ion-pairing strategy's mechanism in drug delivery was thoroughly investigated. Molecular docking results revealed significant differences in the adsorption capacities of different ion pairs in the stratum corneum (SC) and epidermis, directly influencing their residence times and thereby regulating BSP's passive diffusion rate. Particularly, the BSP-C₁₀ ion pair successfully reduced BSP's permeation rate to one-third of its baseline. To enhance drug delivery efficiency and reduce costs, chemical permeation enhancers (CPEs) are typically added to sustained release patches. In contrast to traditional static analyses based on cumulative permeation, this study utilized ATR-FTIR dynamic detection of isopropyl myristate (IPM) as a preferred enhancer, studying its disruptive effects on the skin barrier during drug delivery. The study observed that during drug delivery, the interaction between IPM and skin lipids follows a U-shaped trend: initially increasing, then decreasing, with the peak occurring at 10 h. Similarly, the drug delivery rate displays a comparable pattern. The addition of IPM as CPE increased the patch utilization rate from 39.8 ± 4.31 to 79.8 ± 7.27%. This strategy aims to rapidly reduce blood pressure in the initial phase with subsequent weakening of IPM disruption, allowing the ion-pairing strategy to dominate drug delivery control and maintain stable long-term therapeutic effects. Pharmacokinetic studies demonstrated that the newly developed BSP sustained release patch maintains stable blood drug concentrations, reduces burst release effects, increases bioavailability to 84.679%, doubles MRT_0-<i>t</i>, halves <i>C</i>_max, and significantly reduces the occurrence of blood pressure fluctuations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6290-6301"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520354","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":"A Study on the Stability of High Drug Solubility Characteristics of Hydroxyphenyl Adhesives under the Interference of CPEs.","authors":"Shuai Zhang, Jiaxu Wu, Peng Sun, Liang Fang","doi":"10.1021/acs.molpharmaceut.4c00362","DOIUrl":"10.1021/acs.molpharmaceut.4c00362","url":null,"abstract":"<p><p>Novel hydroxyphenyl adhesives (HP-PSAs) could significantly increase drug solubility and control drug release through a doubly ionic hydrogen bond (DIH bond) in the patch. However, chemical penetration enhancers (CPEs) always destroy the performance of most adhesives. As a result, this work investigated the stability of both the HP-PSA features and the DIH bond under the interference of the CPEs. Donepezil (DON) was chosen as the model drug, and CPEs with hydroxyl, carboxyl, amido, and ester groups were selected as model CPEs. Unlike the commonly used neutral H-bond, the DIH bond between DON and the HP-PSA was still stable under the interference of the CPEs, resulting in the 2-3-fold drug solubility in the HP-PSA, which was higher than that in the nonfunctional PSA, which reduced the drug crystallization risk and the difficulty of formulation design. FT-IR, ¹H NMR, XPS, dynamic simulation, and molecular docking revealed the mechanism of the stability feature of both the DIH bond and the high drug solubility of the HP-PSA, which was that the formed neutral H-bond interaction caused by CPEs is weaker than that of the DIH bond between DON and the HP-PSA. Furthermore, the drug release, skin permeation, and CPE release study showed that the newly formed weak H-bond and strong ionic H-bond interaction promoted or controlled both DON and CPE release, respectively, thereby influencing drug skin permeation, which provided a theoretical basis for drug release regulation. To summarize, besides the reversible, strong features of the DIH bond in our previous study, the stability of the interaction made the HP-PSA's high drug solubility potential to be applied in the TDDS.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6166-6176"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575267","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":"Plant Virus Intratumoral Immunotherapy with CPMV and PVX Elicits Durable Antitumor Immunity in a Mouse Model of Diffuse Large B-Cell Lymphoma.","authors":"Jessica Fernanda Affonso de Oliveira, Miguel A Moreno-Gonzalez, Yifeng Ma, Xinyi Deng, Juliane Schuphan, Nicole F Steinmetz","doi":"10.1021/acs.molpharmaceut.4c00507","DOIUrl":"10.1021/acs.molpharmaceut.4c00507","url":null,"abstract":"<p><p>Plant viruses are naturally occurring nanoparticles and adjuvants that interact with the mammalian immune system. This property can be harnessed in vaccines and immunotherapy. We have previously demonstrated that intratumoral immunotherapy with cowpea mosaic virus (CPMV) stimulates systemic and durable antitumor immunity in mouse tumor models and canine cancer patients. Here we compared the antitumor efficacy of CPMV with potato virus X (PVX) using a mouse model B-cell lymphoma (A20 and BALB/c mice). Despite their diverse morphologies and physiochemical properties, both plant viruses elicited systemic and long-lasting antitumor immune memory, preventing the recurrence of A20 lymphoma in rechallenge experiments. Data indicate differences in the underlying mechanism: CPMV persists longer in the tumor microenvironment (TME) compared to PVX; CPMV is a potent and multivalent toll-like receptor (TLR) agonist (activating TLRs 2, 4 and 7) while PVX may only weakly engage with TLR7. While CPMV and PVX recruit myeloid cells (neutrophils)─CPMV also recruits macrophages. Data further indicate that antiviral T cells may play a role in antitumor efficacy in the case of CPMV immunotherapy, however this may not be the case for PVX. Regardless of the mechanism of action, both CPMV and PVX elicited a durable antitumor response against a B-cell lymphoma tumor model and thus are intratumoral immunotherapy candidates for clinical development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6206-6219"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612768","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":"Prediction of Successful Amorphous Solid Dispersion Pairs through Liquid State Nuclear Magnetic Resonance.","authors":"Ana L Coutinho, Kellie Hom, James E Polli","doi":"10.1021/acs.molpharmaceut.4c00359","DOIUrl":"10.1021/acs.molpharmaceut.4c00359","url":null,"abstract":"<p><p>Amorphous solid dispersions (ASDs) function in part via a \"parachute effect\", i.e., polymer-enabled prolonged drug supersaturation, presumably through drug-polymer interactions in the liquid state. We aim to expand the utility of liquid state nuclear magnetic resonance (¹HNMR) to streamline polymer selection for ASDs. Our hypothesis is that strong molecular interactions between polymer and drug in ¹HNMR anticipate reduced precipitation kinetics in supersaturation studies. For three drug-polymer pairs (i.e., etravirine with each HPMC, HPMCAS-M, and PVP-VA), ¹HNMR findings were compared to more common supersaturation studies. Drug-polymer interactions were assessed by saturation transfer difference NMR (STD-NMR) and <i>T</i>₁ relaxation time. 2D-¹H NOESY experiments were also performed. Supersaturation studies involved precipitation inhibition using the solvent-shift methodology. The results from STD-NMR and <i>T</i>₁ relaxation time indicate etravirine bound preferably to HPMCAS-M > HPMC ≫ PVP-VA. STD-NMR and <i>T</i>₁ relaxation time yielded insight into which fragments of etravirine structure bind with HPMCAS-M and HPMC. The strong interactions from STD-NMR and <i>T</i>₁ relaxation time changes indicated that HPMCAS-M and HPMC, but not PVP-VA, are suitable polymers to maintain etravirine supersaturation and inhibit drug precipitation. 2D-¹H NOESY results corroborate the findings of STD-NMR and <i>T</i>₁ relaxation time, showing that etravirine interacts preferably to HPMCAS-M than to PVP-VA. Supersaturation studies using solvent-shift technique corroborated our hypothesis as predissolved HPMCAS-M and HPMC, but to a less extent PVP-VA, markedly promoted etravirine supersaturation and inhibited drug precipitation. Supersaturation studies agreed with STD-NMR and <i>T</i>₁ relaxation time predictions, as HPMC and HPMCAS-M maintained etravirine in solution for longer time than PVP-VA. The results show promise of ¹HNMR to streamline polymer selection in a nondestructive and resource sparing fashion for subsequent ASD development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6153-6165"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving Targeted Delivery and Antitumor Efficacy of TRAIL through Fusion with a B7H3-Antagonistic Affibody.","authors":"Xiaomeng Lu, Xinyu Zhan, Guozi Xia, Feifei Wang, Mingjia Lv, Renwei Liu, Yuxue Liu, Chen Zi, Guangyong Li, Rui Wang, Jun Li, Fengjiao Yuan, Dianlong Jia","doi":"10.1021/acs.molpharmaceut.4c00891","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00891","url":null,"abstract":"<p><p>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive candidate for anticancer therapeutics due to its efficient pro-apoptotic activity against tumor cells and its well-tolerated safety profile. However, the in vivo antitumor efficacy of TRAIL is often limited by its poor tumor targeting capacity. Nowadays, the B7 homologue 3 (B7-H3) immune checkpoint has emerged as a promising target for tumor immunotherapy and drug delivery. Here, we report the achievement of tumor-targeted delivery of TRAIL by genetically fusing it with a B7H3-antagonistic affibody. The affibody-TRAIL fusion protein, named ACT, was easily expressed in <i>Escherichia coli</i> with a high yield and could form the active trimeric state. In vitro ACT showed significantly increased cellular binding to multiple B7H3-positive tumor cells and improved cytotoxicity by 2-3 times compared to the parent TRAIL. In vivo ACT demonstrated a 2.4-fold higher tumor uptake than TRAIL in mice bearing B7H3-positive A431 tumor grafts. More importantly, ACT exhibited significantly improved antitumor efficacy against tumors in vivo. In addition, ACT treatment did not cause body weight loss or histopathological changes in the major organs of mice, indicating its good safety profile. Overall, our findings demonstrate that targeting B7H3 to enhance TRAIL delivery is a viable approach to improve its therapeutic efficacy, and ACT may be a potential agent for targeted therapy of B7H3-positive tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764843","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":"Molecular Imaging Reveals Antineuroinflammatory Effects of HDAC6 Inhibition in Stroke Models.","authors":"Yanting Zhou, Chen Li, Rui Wu, Honghai Yin, Gang Liu, Hui Meng, Weiyao Xie, Vishal C Birar, Changning Wang, Xiaoai Wu, Ping Bai","doi":"10.1021/acs.molpharmaceut.4c01006","DOIUrl":"10.1021/acs.molpharmaceut.4c01006","url":null,"abstract":"<p><p>Ischemic stroke is a devastating disease that causes neuronal death, neuroinflammation, and other cerebral damage. However, effective therapeutic strategies for ischemic stroke are still lacking. Histone deacetylase 6 (HDAC6) has been implicated in the pathogenesis of ischemic stroke, and the pharmacological inhibition of HDAC6 has shown promising neuroprotective effects. In this study, we utilized positron emission tomography (PET) imaging with the HDAC6-specific radioligand [¹⁸F]PB118 to investigate the dynamic changes of HDAC6 expression in the brain after ischemic injury. The results revealed a significant decline in [¹⁸F]PB118 uptake in the ipsilateral hemisphere on the first day after ischemia, followed by a gradual increase on days 4 and 7. To evaluate the therapeutic potential of HDAC6 inhibitors, we developed a novel brain-permeable and potent HDAC6 inhibitor, PB131, and assessed its neuroprotective effects in an ischemic stroke mouse model. PET imaging studies demonstrated that PB131 treatment alleviated the decline in [¹⁸F]PB118 uptake and reduced the infarct size in middle cerebral artery occlusion mice. Furthermore, PET imaging with the TSPO-specific radioligand [¹⁸F]FEPPA revealed that PB131 significantly suppressed neuroinflammation in the ischemic brain. These findings provide insights into the dynamic changes of HDAC6 in ischemic stroke and the potential of HDAC6 inhibitors as novel therapeutic agents for this condition.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6433-6443"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589546","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":"Methyl-β-cyclodextrin Enhances Tumor Cellular Uptake and Accumulation of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles.","authors":"Meiqi Xu, Junwei Liu, Jianming Yu, Jingwen Wang, Hui Li, Ting Zhong, Yanli Hao, Zhuoyue Li, Jingru Wang, Xu Huang, Hui Wang, Yubo Tian, Heng Zhao, Qingchao Wei, Xuan Zhang","doi":"10.1021/acs.molpharmaceut.4c00190","DOIUrl":"10.1021/acs.molpharmaceut.4c00190","url":null,"abstract":"<p><p>Improving nanomedicine uptake by tumor cells is key to achieving intracellular drug delivery. In this study, we found that methyl-β-cyclodextrin (MβCD) can significantly promote the intracellular accumulation of nanoparticulated α-linolenic acid-paclitaxel conjugates (ALA-PTX NPs) via enhanced clathrin-mediated endocytosis and limited degradation in lysosomes. Our in vitro results indicated that MβCD not only reduced the plasma membrane cholesterol content and increased plasma membrane fluidity, leading to ALA-PTX NPs being more easily incorporated into the plasma membrane, further enhancing membrane fluidity and making the plasma membrane more susceptible to tensile deformation, forming intracellular vesicles to enhance ALA-PTX NP cellular uptake, but also destroyed lysosomes and then limited ALA-PTX NPs' degradation in lysosomes. In HepG2 tumor-bearing mice, MβCD was also able to enhance the antitumor activity of ALA-PTX NPs in vivo. Moreover, we found that MβCD specifically promoted PUFA-paclitaxel conjugate NP cellular uptake. The cellular uptake of PTX liposome which shares an endocytosis pathway with ALA-PTX NPs could be enhanced by MβCD combined with ALA or ALA-PTX NPs. Therefore, we suggested that MβCD combined with polyunsaturated fatty acid-conjugation would be an effective strategy for improving intracellular delivery of nanoparticulated chemotherapeutic drugs used for combination administration to enhance antitumor efficiency.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6109-6122"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566411","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":"Evaluation of a Novel MET-Targeting Camelid-Derived Antibody in Head and Neck Cancer.","authors":"Rachel L Minne, Natalie Y Luo, Caroline M Mork, Madalynn R Wopat, Karla Esbona, Saahil Javeri, Kwangok P Nickel, Reinier Hernandez, Aaron M LeBeau, Randall J Kimple, Andrew M Baschnagel","doi":"10.1021/acs.molpharmaceut.4c00938","DOIUrl":"10.1021/acs.molpharmaceut.4c00938","url":null,"abstract":"<p><p>In head and neck squamous cell carcinoma (HNSCC), the mesenchymal epithelial transition (MET) receptor drives cancer growth, proliferation, and metastasis. MET is known to be overexpressed in HNSCC and, therefore, is an appealing therapeutic target. In this study, we evaluated MET expression in patients with HNSCC and investigated the potential imaging application of a novel MET-binding single-domain camelid antibody using positron emission tomography/computed tomography (PET/CT) in a preclinical MET-expressing HNSCC model. Multiplex immunostaining for MET protein performed on a tissue microarray from 203 patients with HNSCC found 86% of patients to have MET expression, with 14% having high expression and 53% having low MET expression. Using The Cancer Genome Atlas (TCGA) database, high MET RNA expression was associated with worse progression-free survival and overall survival in patients with HPV-negative HSNCC. Utilizing flow cytometry and immunofluorescence, our novel camelid antibody fused to a human IgG Fc chain (1E7-Fc) showed high binding affinity and specificity to high MET-expressing Detroit 562 cells but not to low MET-expressing HNSCC cells. The efficacy and biodistribution of [⁸⁹Zr]Zr-1E7-Fc as a PET imaging agent was then investigated in a MET-expressing head and neck xenograft model. [⁸⁹Zr]Zr-1E7-Fc rapidly localized and showed high tumor uptake in Detroit 562 xenografts (8.4% ID/g at 72 h postinjection), with rapid clearance from the circulatory system (2.7 tumor-to-blood radioactivity ratio at 72 h postinjection). Our preclinical data suggest that the camelid antibody 1E7-Fc could be a potential theranostic agent for HNSCC. Further investigations are warranted to confirm these findings in patients and to evaluate 1E7-Fc as an imaging agent and platform to deliver radionuclide or drug therapy to MET-driven cancers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6376-6384"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602057","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}