Molecular Pharmaceutics最新文献

{"title":"From Sequence to System: Enhancing IVT mRNA Vaccine Effectiveness through Cutting-Edge Technologies.","authors":"Lifeng Xu, Chao Li, Rui Liao, Qin Xiao, Xiaoran Wang, Zhuo Zhao, Weijun Zhang, Xiaoyan Ding, Yuxue Cao, Larry Cai, Joseph Rosenecker, Shan Guan, Jie Tang","doi":"10.1021/acs.molpharmaceut.4c00863","DOIUrl":"10.1021/acs.molpharmaceut.4c00863","url":null,"abstract":"<p><p>The COVID-19 pandemic has spotlighted the potential of in vitro transcribed (IVT) mRNA vaccines with their demonstrated efficacy, safety, cost-effectiveness, and rapid manufacturing. Numerous IVT mRNA vaccines are now under clinical trials for a range of targets, including infectious diseases, cancers, and genetic disorders. Despite their promise, IVT mRNA vaccines face hurdles such as limited expression levels, nonspecific targeting beyond the liver, rapid degradation, and unintended immune activation. Overcoming these challenges is crucial to harnessing the full therapeutic potential of IVT mRNA vaccines for global health advancement. This review provides a comprehensive overview of the latest research progress and optimization strategies for IVT mRNA molecules and delivery systems, including the application of artificial intelligence (AI) models and deep learning techniques for IVT mRNA structure optimization and mRNA delivery formulation design. We also discuss recent development of the delivery platforms, such as lipid nanoparticles (LNPs), polymers, and exosomes, which aim to address challenges related to IVT mRNA protection, cellular uptake, and targeted delivery. Lastly, we offer insights into future directions for improving IVT mRNA vaccines, with the hope to spur further progress in IVT mRNA vaccine research and development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"81-102"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724275","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":"Novel Radiotheranostic Ligands Targeting Prostate-Specific Membrane Antigen Based on Dual Linker Approach.","authors":"Nobuki Kazuta, Kazuma Nakashima, Yuta Tarumizu, Takumi Sato, Yoshifumi Maya, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1021/acs.molpharmaceut.4c00974","DOIUrl":"10.1021/acs.molpharmaceut.4c00974","url":null,"abstract":"<p><p>Radiotheranostics using prostate-specific membrane antigen (PSMA)-targeting radioligands offers precision medicine by performing radionuclide therapy based on results of diagnosis. Albumin binder (ALB) binds to albumin reversibly and contributes to effective radiotheranostics by enhancing tumor accumulation of PSMA-targeting radioligands. We newly developed two ALB-containing PSMA-targeting radioligands including dual functional linkers, a hydrophilic linker, d-glutamic acid, and a hydrophobic linker, 4-(aminomethyl)benzoic acid, with the opposite arrangement (PNT-DA6 and PNT-DA7). A biodistribution study of [¹¹¹In]In-PNT-DA6 indicated that the introduction and arrangement of dual functional linkers contributed to improved pharmacokinetics. A single photon emission computed tomography study of [¹¹¹In]In-PNT-DA6 produced a clear PSMA-expressing tumor image. Moreover, [²²⁵Ac]Ac-PNT-DA6 showed the inhibition of tumor growth in targeted radionuclide therapy in PSMA-expressing tumor-bearing mice. These results indicated that [¹¹¹In]In-PNT-DA6 and [²²⁵Ac]Ac-PNT-DA6 exhibited useful characteristics as PSMA-targeting radiotheranostic ligands.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"377-386"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764845","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":"Synthesis and Preclinical Evaluation of Dual-Specific Probe Targeting Glypican-3 and Prostate-Specific Membrane Antigen for Hepatocellular Carcinoma PET Imaging.","authors":"Lixing Chen, Siyuan Cheng, Dongling Zhu, Guangfa Bao, Ziqiang Wang, Xiaoyun Deng, Xiaoguang Liu, Xiang Ma, Jun Zhao, Lei Zhu, Xiaohua Zhu","doi":"10.1021/acs.molpharmaceut.4c00838","DOIUrl":"10.1021/acs.molpharmaceut.4c00838","url":null,"abstract":"<p><p>Positron emission tomography (PET) is a promising modality for early diagnosis, accurate detection, and staging of hepatocellular carcinoma (HCC). Hereby, a dual-specific probe targeting Glypican-3 (GPC3) and prostate-specific membrane antigen (PSMA) was evaluated for HCC PET imaging. The probe was prepared by conjugating TJ12P2, a GPC3-targeting peptide previously reported by our group, to a highly potent PSMA inhibitor via a polyethylene glycol linker and further tethered to the 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator. The resultant probe, NOTA-TJ12P2-PSMA, abbreviated as T2P, was labeled with gallium-68 and fluorine-18, respectively, and evaluated in murine HCC models of various levels of GPC3 and PSMA expression. Targeting specificity was confirmed by blocking studies. The synthesized [⁶⁸Ga]Ga-T2P and [¹⁸F]AlF-T2P were stable in saline and fetal bovine serum for over 2 h, and bound to their respective targets with high affinity and specificity in cell assays. PET imaging at 60 min postinjection (p.i.) showed that [⁶⁸Ga]Ga-T2P exhibited higher uptake (1.75 ± 0.16%ID/g) in Huh7 models with high expression of GPC3 and PSMA than gallium-68 labeled TJ12P2 (1.25 ± 0.07%ID/g, <i>p</i> < 0.01) or gallium-68 labeled PSMA-617 (1.07 ± 0.06%ID/g, <i>p < 0.001</i>). The uptake of [⁶⁸Ga]Ga-T2P in Huh7 tumors was higher than that in PC-3 tumors with low expression of GPC3 or PSMA (0.55 ± 0.24%ID/g, <i>p</i> < 0.01). The uptake of [¹⁸F]AlF-T2P or [⁶⁸Ga]Ga-T2P in the Huh7 tumor was substantially blocked by TJ12P2, TJ12P2 + PSMA, or T2P, but only partially blocked by PSMA. And the PSMA and TJ12P2 monomer blocking effect was less than that of TJ12P2 + PSMA and T2P. [¹⁸F]AlF-T2P had higher tumor-to-muscle ratios than [⁶⁸Ga]Ga-T2P at 90 min postinjection (4.31 ± 0.10 vs 3.80 ± 0.17, <i>p < 0.05</i>) in Huh7 tumor models. To conclude, radiolabeled T2P exhibited a higher uptake and longer retention in Huh7 tumors than its monomeric counterparts. PET imaging via gallium-68 and fluorine-18 labeled T2P showed a similar imaging quality with comparable signal-to-background ratios. Our results demonstrate that T2P is a promising tool for future clinical diagnosis of HCC.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"209-220"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798737","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":"Enhancing Buccal Drug Delivery: The Impact of Glycerol in Slot-Die-Coated Pectin Films.","authors":"Eleftheria Pantazoglou, Matteo Tollemeto, Nazanin Zanjanizadeh Ezazi, Tien-Jen Chang, Leticia Hosta Rigau, Jette Jacobsen, Line Hagner Nielsen","doi":"10.1021/acs.molpharmaceut.4c01051","DOIUrl":"10.1021/acs.molpharmaceut.4c01051","url":null,"abstract":"<p><p>Buccal delivery offers a promising alternative to e.g., oral or parenteral drug administrations by leveraging the mucosal membranes of the mouth to enhance drug absorption and enhance patient compliance. Buccal films offer a promising approach for enhancing drug delivery by utilizing the mucoadhesive properties of the biopolymer pectin and glycerol's plasticizing effects. Designed to provide fast drug release, these films address the challenges of patient compliance, particularly among the elderly, children, and individuals with dysphagia. This study characterized the physicochemical properties of slot-die-coated films with pectin containing varying amounts of glycerol, including swelling behavior, disintegration rate, mechanical properties, mucoadhesion, and drug release profiles, using paracetamol as a model drug. Different methods such as quartz crystal microbalance with dissipation and open-source force analyzer were employed for the characterization. The results demonstrated that a high glycerol content in the films led to slower drug release with 95% paracetamol released for film without glycerol (GLY0) compared to only 74% released for film with 20% w/v glycerol (GLY20) after 60 min Additionally, higher glycerol levels resulted in enhanced mucoadhesive properties. Films containing 20% glycerol also showed superior permeability of paracetamol through ex vivo porcine buccal mucosa, with double the amount of paracetamol permeating in the first 120 min from GLY20 films compared to GLY0 films. These findings suggest that the pectin-glycerol buccal films, fabricated with slot-die coating as a novel technique, are user-friendly, exhibit interaction with the mucosa, and can be adjusted for specific disintegration and drug release rates, presenting a promising option for efficient, targeted drug delivery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"433-445"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845313","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":"Aqueous Solubility of Sodium and Chloride Salts of Glycine─\"Uncommon\" Common-Ion Effects of Self-Titrating Solids.","authors":"Alex Avdeef, Abu T M Serajuddin, Hari P Kandagatla","doi":"10.1021/acs.molpharmaceut.4c01066","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01066","url":null,"abstract":"<p><p>Although glycine is the simplest of the amino acids, its solution and solid-state properties are far from straightforward. The aqueous solubility of glycine plays an important role in various applications, including nutrition, food products, biodegradable plastics, and drug development. There is evidence that glycine in subsaturated pH 3-8 solutions forms a dimer, as suggested by several techniques. However, what takes place below pH 3 and above pH 8 in saturated solutions has been sparsely explored and is thought to exhibit complex properties. Although the solubility measurements in the pH 0-13 range have been reported by several groups, the interlaboratory variance between the data below pH 3 and above pH 8 has been high. In a couple of cases, there appears to be no pH dependence on solubility across the wide pH range, even though the reported glycine p<i>K</i>_a values are 2.34 and 9.61. The solubility of the salt forms of glycine is largely uncharacterized. The solubility products of the simplest salts, glycine hydrochloride and sodium glycinate, appear not to have been published. In this study, five series of precision solubility measurements of glycine and its salts were performed at 25 °C, covering the range of pH -0.4 to 12.4, where in each case, just enough glycine was added to reach saturation. We have developed an equilibrium model to rationalize the complicated salt regions. Elemental analysis of isolated solids from saturated solutions supports the speciation model. At least three different salt forms have been indicated in acidic solutions and one salt form in alkaline solutions. Solubility products are reported here. The presence of a water-soluble cationic dimer is also proposed. Data analysis was performed with the aid of the <i>p</i>DISOL-X computer program. Activity corrections based on the Stokes-Robinson hydration theory have been implemented in saturated solutions with ionic strength in some cases exceeding 5 M. Although salt solubility is not a constant, since it depends on two independently controlled reactant concentrations, the salt solubility product is commonly expected to be a constant. However, in the glycine salt region below pH 3, our solubility measurements demonstrate that the solubility products depend on the total amount of added glycine in a saturated solution. We view this as an \"uncommon\" common-ion effect.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925828","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":"Novel Ru(II) Complexes as Type-I/-II Photosensitizers for Multimodal Hypoxia-Tolerant Chemo-Photodynamic/Immune Therapy.","authors":"Xiao Liu, Hongwei Zheng, Yiqian Peng, Dongliang Ji, Chen Wang, Dezhi Wang, Zihan Jia, Yingxue Chang, Xiangming Cai, Lei Wang, Yong Ling","doi":"10.1021/acs.molpharmaceut.4c01046","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01046","url":null,"abstract":"<p><p>Photodynamic therapy (PDT) is increasingly regarded as an attractive approach for cancer treatment due to its advantages of low invasiveness, minimal side effects, and high efficiency. Here, two novel Ru(II) complexes <b>8a</b>,<b>b</b> were designed and synthesized by coordinating phenanthroline and biquinoline ligands with Ru(II) center, and their chemo-photodynamic therapy and immunotherapy were explored. Both <b>8a</b> and <b>8b</b> exhibited significant phototoxicity against A549 and 4T1 tumor cells <i>via</i> type-I/-II PDT. Among them, <b>8b</b> exhibited superior oxygen-independent antitumor effects (IC₅₀s = 1.50-1.76 μM) upon laser irradiation, and displayed micromolar-level chemotherapeutic activities, indicating its potential for chemo/photodynamic dual effects. Furthermore, <b>8b</b> also initiated an ICD cascade, enhancing recruitment and maturation of antigen-presenting cells, thus triggering a CD8⁺ T cell antitumor immune response. Finally, <i>in vivo</i> antitumor experiments demonstrated that <b>8b</b> exhibited significant inhibition of lung and breast tumor growth, with inhibition rates of 94.6% and 97.3%, respectively. Therefore, the Ru(II) complexes we designed, as effective type-I/-II photosensitizers and potential immunoactivators, demonstrate multiple antitumor mechanisms, warranting further study.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925829","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":"Comparison of a Series of ⁶⁸Ga-Labeled DOTA-LLP2A Conjugates for Positron Emission Tomography Imaging of Very Late Antigen-4 in Melanoma.","authors":"Peng Zhou, Yujing Wu, Guoqing Han, Juntao Jiang, Hongyong Wang, Chunxiong Lu, Yaling Liu, Jun Wu, Pei Zou, Hao Wu","doi":"10.1021/acs.molpharmaceut.4c01204","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01204","url":null,"abstract":"<p><p>Melanoma, with its steadily rising global incidence, is characterized by high invasiveness, leading to poor prognosis in advanced stages. There remains an unmet clinical need for the development of radiolabeled PET imaging probes for the early diagnosis of melanoma. Integrin VLA-4, a key factor in melanoma metastasis, presents a promising protein target to address the specificity shortcomings of existing probes in melanoma imaging. This study evaluates ⁶⁸Ga-labeled DOTA-LLP2A PET probes for melanoma imaging by modifying different carboxyl sites and employing various polyethylene glycol (PEG) linkers based on the structure of the high-affinity ligand LLP2A for VLA-4. The ligand intermediates LLP2A-NH₂ and LLP2A(<i>t</i>Bu)-OH, as well as their conjugates (probe precursors), were synthesized via solid-phase synthesis. The specificity and cytotoxicity of the probes were assessed in VLA-4-positive B16F10 cells and VLA-4-negative A375 cells. Targeting efficacy of the probes in B16F10 and A375 xenograft models was compared through PET imaging and biodistribution studies. VLA-4 expression in tissues was evaluated via immunofluorescence, while H&E staining was employed to assess the safety profile of the probes. The probe ([⁶⁸Ga]Ga-T-CH) modified at the Aminocyclohexane carboxylic acid (Ach) exhibited greater signal accumulation in B16F10 melanoma (3.90 ± 0.43%ID/g at 1 h) compared to the 2-aminoadipic acid (Aad) side-chain-modified probe ([⁶⁸Ga]Ga-T-AD) (1.43 ± 0.23%ID/g at 1 h). PET images of the three PEG conjugates derived from the Ach demonstrated bright tumor signals and low background noise, showing a progressive increase in tumor signal intensity from [⁶⁸Ga]Ga-T6 to [⁶⁸Ga]Ga-T4 and [⁶⁸Ga]Ga-T2. Tumor uptake, tumor-to-muscle ratio, and tumor-to-blood ratio from biodistribution were significantly higher for [⁶⁸Ga]Ga-T2 than for [⁶⁸Ga]Ga-T4 and [⁶⁸Ga]Ga-T6 (tumor: 3.58 ± 0.28 vs 2.90 ± 0.16 vs 1.87 ± 0.22%ID/g at 1 h; tumor/muscle: 13.38 ± 0.43 vs 10.62 ± 0.70 vs 7.19 ± 1.15 at 1 h; tumor/blood: 8.64 ± 1.12 vs 5.32 ± 0.91 vs 4.36 ± 0.59 at 1 h; <i>P</i> < 0.05). These data suggest that the series of PEG derivatives [⁶⁸Ga]Ga-T2, [⁶⁸Ga]Ga-T4, and [⁶⁸Ga]Ga-T6, linked at the Ach site, are excellent ⁶⁸Ga-labeled probes for melanoma and other potential VLA-4-positive tumors. Among them, [⁶⁸Ga]Ga-T2 shows the highest tumor-to-background contrast for melanoma, positioning it as the most promising candidate for clinical translation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918677","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":"Nanosystems at Nexus: Navigating Nose-to-Brain Delivery for Glioblastoma Treatment.","authors":"Tejas Girish Agnihotri, Akanksha Dahifale, Shyam Sudhakar Gomte, Biswajit Rout, Vasu Peddinti, Aakanchha Jain","doi":"10.1021/acs.molpharmaceut.4c00703","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00703","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is considered to be one of the most devastating brain tumors with a shorter life expectancy. Several factors contribute to the dismal prognosis of GBM patients including the complicated nature of GBM, the ability of tumor cells to resist treatment, and the difficulty of delivering drugs to the brain because of barriers like the blood-brain barrier (BBB) and blood-tumor barrier (BTB). The unique challenges posed by the BBB in delivering therapeutic agents to the brain have led to the development of innovative nanotechnology-based approaches. By exploiting the olfactory/trigeminal pathway, nanosystems offer a promising strategy for targeted drug delivery to the brain, glioblastoma tumors in particular. This review contemplates varied nanocarriers, including polymeric nanoparticles, lipid-based nanosystems, in situ gel formulations, peptide, and stem cell-based nanoformulations, signifying their utility in brain targeting with minimal systemic side effects. Emerging trends in gene therapy and immunotherapy in the context of GBM treatment have also been discussed. Since safety is a paramount aspect for any drug product to get approved, this review also delves into toxicological considerations associated with intranasal delivery of nanosystems. Regulatory aspects and critical factors for the successful development of intranasal products are also explored in this review. Overall, this review underscores the significant advancements in nanotechnology for nose-to-brain delivery and its potential impact on GBM management.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918680","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":"Subcutaneous Administration of Therapeutic Monoclonal Antibody Drug Products Using a Syringe in Blinded Clinical Trials: Advances and Key Aspects Related to Blinding/Matching/Masking Strategies for Placebo Formulation.","authors":"Kashappa Goud Desai","doi":"10.1021/acs.molpharmaceut.4c01166","DOIUrl":"10.1021/acs.molpharmaceut.4c01166","url":null,"abstract":"<p><p>Therapeutic monoclonal antibody (mAb) drug products are increasingly used to treat both chronic and acute diseases. These mAb drug products are often developed for subcutaneous (SC) injection to simplify dosing compared with intravenous (IV) infusion. For SC injection, the mAb liquid drug product is typically filled in a vial for use with a syringe or in a prefilled syringe, which can then be assembled into a safety syringe device or an autoinjector for direct administration. A placebo is an inert formulation (one without an active ingredient) that lacks pharmacological activity or a therapeutic effect. It serves as a control in blinded clinical trials to evaluate the efficacy of a new treatment. A suitable blinding/matching/masking strategy is crucial to ensure that study participants cannot distinguish between the active mAb formulation and the placebo. The success of these strategies is pivotal in ensuring the accuracy and reliability of clinical trial results. This Review summarizes recent advances and key considerations related to placebo strategies. It covers the benefits and challenges of SC injection of therapeutic mAbs compared to IV infusion, the placebo effect, the significance of blinding/matching/masking, and various strategies. Strategies discussed include the use of traditional placebos (e.g., normal saline, 5% w/v dextrose solution, and formulation buffer of the active mAb), syringe blinding, the use of different gauge syringe needles, novel (custom) placebos, dilution, independent administration, and multiple injections. Additional topics covered include the incidence of antidrug antibodies (ADAs), the benefits and challenges associated with different strategies, and regulatory expectations regarding custom placebos. By addressing these critical aspects, the Review aims to contribute to the growing body of knowledge and ongoing efforts to enhance the effectiveness of formulation blinding, matching, and masking in clinical trials.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913255","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":"Comparative Study of Dimeric Fibroblast Activation Protein-Targeting Radioligands Labeled with Fluorine-18, Copper-64, and Gallium-68.","authors":"Xuran Zhang, Kyo Chul Lee, Joon Young Choi, Kyung-Han Lee, Yearn Seong Choe","doi":"10.1021/acs.molpharmaceut.4c01080","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01080","url":null,"abstract":"<p><p>Fibroblast activation protein inhibitors (FAPIs) labeled with gallium-68 and lutetium-177 show potential for use in the diagnosis and treatment of various cancers expressing FAP. However, ¹⁷⁷Lu-labeled FAPIs often exhibit short tumor retention time, limiting their therapeutic applications. To improve tumor retention, we synthesized three radiolabeled dimeric FAPIs, [¹⁸F]<b>1</b>, [⁶⁴Cu]<b>2</b>, and [⁶⁸Ga]<b>3</b>. These were prepared by chelating Al[¹⁸F]F to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-l-glutamic acid (E)-(FAPI)₂ and copper-64 or gallium-68 to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-E-(FAPI)₂. NOTA-E-(FAPI)₂ and DOTA-E-(FAPI)₂ showed higher binding affinities for FAP compared with that of FAPI-04 (IC₅₀ = 0.47 and 0.16 nM vs 0.89 nM, respectively). All radioligands were synthesized in high decay-corrected radiochemical yields (59-96%) and were stable in fetal bovine serum and phosphate-buffered saline. The more hydrophilic radioligand, [⁶⁸Ga]<b>3</b>, was selected for cellular uptake studies, which confirmed FAP-specific uptake. Positron emission tomography imaging and ex vivo biodistribution studies in U87MG tumor-bearing mice revealed high tumor uptake of all three radioligands, with significant blocking observed after preinjection of FAPI-04. [⁶⁴Cu]<b>2</b> and [⁶⁸Ga]<b>3</b> exhibited favorable in vivo pharmacokinetics compared to those of [¹⁸F]<b>1</b>. Notably, [⁶⁸Ga]<b>3</b> showed lower normal organ uptake than did the other two radioligands, and moreover, it exhibited higher, more prolonged tumor uptake than its monomeric counterpart [⁶⁸Ga]Ga-FAPI-04 over a 3 h period, suggesting its potential as a promising FAP-specific theranostic radioligand.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906225","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}