Molecular Pharmaceutics最新文献

{"title":"Pathophysiology-Driven Approaches for Overcoming Nanomedicine Resistance in Pancreatic Cancer","authors":"Sreejith Thrivikraman Nair,&nbsp;C Abhi,&nbsp;Kaladhar Kamalasanan*,&nbsp;K. Pavithran,&nbsp;Ashok R. Unni,&nbsp;MS Sithara,&nbsp;Manjit Sarma and T S Mangalanandan,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0080110.1021/acs.molpharmaceut.4c00801","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00801https://doi.org/10.1021/acs.molpharmaceut.4c00801","url":null,"abstract":"<p >Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"5960–5988 5960–5988"},"PeriodicalIF":4.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756440","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":"Understanding the Impact of Lipids on the Solubilizing Capacity of Human Intestinal Fluids","authors":"Brecht Goovaerts,&nbsp;Joachim Brouwers,&nbsp;Zahari Vinarov,&nbsp;Marlies Braeckmans,&nbsp;Anura S. Indulkar,&nbsp;Alvaro Lopez Marmol,&nbsp;Thomas B. Borchardt,&nbsp;Jan Tack,&nbsp;Mirko Koziolek and Patrick Augustijns*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0094410.1021/acs.molpharmaceut.4c00944","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00944https://doi.org/10.1021/acs.molpharmaceut.4c00944","url":null,"abstract":"<p >Lipids in human intestinal fluids (HIF) form various structures, resulting in phase separation in the form of a lipid fraction and a micellar aqueous fraction. Currently used fed state simulated intestinal fluids (SIF) lack phase separation, highlighting the need for a deeper understanding of the effect of these fractions on intestinal drug solubilization in HIF to improve simulation accuracy. In this study, duodenal fluids aspirated from 21 healthy volunteers in fasted, early fed, and late fed states were used to generate 7 HIF pools for each prandial state. The apparent solubility of seven lipophilic model drugs was measured across these HIF pools, differentiating between the micellar fraction and the total sample (including both micellar and lipid fractions). The solubilizing capacities of these fluids were analyzed in relation to their composition, including total lipids, bile salts, phospholipids, total cholesterol, pH, and total protein. The solubility data generated in this work demonstrated that current fed state SIF effectively predicted the average solubility in the micellar fraction of HIF but failed to discern the considerable variability between HIF pools. Furthermore, the inclusion of a lipid fraction significantly enhanced the solubility of fed state HIF pools, resulting on average in a 13.9-fold increase in solubilizing capacity across the seven model compounds. Although the average composition of the fluids was consistent with previous studies, substantial variability was observed in micellar lipid concentrations, despite relatively stable total lipid concentrations. This variability is critical, as evidenced by the strong correlations between the solubilizing capacity of the micellar fraction and its micellar lipid concentrations. Additionally, this study identified that fluctuations in bile salt concentrations and pH contributed to the observed variability in micellar lipid concentration. In summary, the influence of the lipid fraction on solubility was 2-fold: it enhanced the solubility of lipophilic drugs in the total fluid, and contributed to the variability in the solubilizing capacity of the micellar fraction.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6398–6410 6398–6410"},"PeriodicalIF":4.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756568","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":"Dynamic Phase Behavior of Amorphous Solid Dispersions Revealed with In Situ Stimulated Raman Scattering Microscopy","authors":"Teemu Tomberg,&nbsp;Ilona Hämäläinen,&nbsp;Clare J. Strachan* and Bert van Veen,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0103210.1021/acs.molpharmaceut.4c01032","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01032https://doi.org/10.1021/acs.molpharmaceut.4c01032","url":null,"abstract":"<p >This study reports the application of <i>in situ</i> stimulated Raman scattering (SRS) microscopy for real-time chemically specific imaging of dynamic phase phenomena in amorphous solid dispersions (ASDs). Using binary ritonavir and poly(vinylpyrrolidone-vinyl acetate) films with different drug loadings (0–100% w/w) as model systems, we employed SRS microscopy with fast spectral focusing to analyze ASD behavior upon contact with a dissolution medium. Multivariate unmixing of the SRS spectra allowed changes in the distributions of the drug, polymer, and water to be (semi)quantitatively imaged in real time, both in the film and the adjacent dissolution medium. The SRS analyses were further augmented with complementary correlative sum frequency generation and confocal reflection for additional crystallinity and phase sensitivity. In the ASDs with drug loadings of 20, 40, and 60% w/w, the water penetration front within the film, followed by both surface-directed and bulk phase separation in the film, was apparent but differed quantitatively. Additionally, drug-loading and phase-dependent polymer and drug release behavior was imaged, and liquid–liquid phase separation was observed for the 20% drug loading ASD. Overall, SRS microscopy with fast spectral focusing provides quantitative insights into water-induced ASD phase phenomena, with chemical, solid-state, temporal, and spatial resolution. These insights are important for optimal ASD formulation development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6444–6457 6444–6457"},"PeriodicalIF":4.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c01032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756538","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,&nbsp;James G. Kempf,&nbsp;Yong Du,&nbsp;Paul Reichert,&nbsp;Chakravarthy Narasimhan,&nbsp;Rui Fang,&nbsp;Soonbum Kwon,&nbsp;Jing Ling,&nbsp;Ashley Lay-Fortenbery,&nbsp;Yongqian Zhang,&nbsp;Qing Zhe Ni,&nbsp;Aaron Cote and Yongchao Su*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0092910.1021/acs.molpharmaceut.4c00929","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00929https://doi.org/10.1021/acs.molpharmaceut.4c00929","url":null,"abstract":"<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 &amp; 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 (&lt;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":"21 12","pages":"6363–6375 6363–6375"},"PeriodicalIF":4.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756505","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":"Polyinosinic/Polycytidylic Lipid Nanoparticles Enhance Immune Cell Infiltration and Improve Survival in the Glioblastoma Mouse Model","authors":"Melanie M. T. Brüßeler,&nbsp;Alaa Zam,&nbsp;Víctor M. Moreno-Zafra,&nbsp;Nadia Rouatbi,&nbsp;Osama W. M. Hassuneh,&nbsp;Alessia Marrocu,&nbsp;Revadee Liam-Or,&nbsp;Hend Mohamed Abdel-Bar,&nbsp;Adam Alexander Walters and Khuloud T. Al-Jamal*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0087510.1021/acs.molpharmaceut.4c00875","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00875https://doi.org/10.1021/acs.molpharmaceut.4c00875","url":null,"abstract":"<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 &gt;75% and a size &lt;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":"21 12","pages":"6339–6352 6339–6352"},"PeriodicalIF":4.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00875","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756506","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":"Three Strikingly Different Crystal Habits of Tadalafil: Design, Characterization, Pharmaceutical Performance, and Computational Studies","authors":"Nagesh A. Bhale,&nbsp;Saurabh Shah,&nbsp;Avvaru Subha Jahnavi,&nbsp;Arti Vishwakarma,&nbsp;Tejender S. Thakur,&nbsp;Sajesh P. Thomas,&nbsp;Saurabh Srivastava and Amol G. Dikundwar*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0060110.1021/acs.molpharmaceut.4c00601","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00601https://doi.org/10.1021/acs.molpharmaceut.4c00601","url":null,"abstract":"<p >The present study aims at improving the physicochemical properties of a widely used drug Tadalafil through crystal habit modification, without changing the polymorphic form. Three distinct types of crystal habits, namely, needle, plate, and block, were obtained under controlled crystallization protocols with optimized solvent compositions. Complete characterization of these three crystal habits was carried out using powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Morphological features were studied by optical and scanning electron microscopy. Evaluation of the pharmaceutical performance of different crystal habits reveals significant improvement in compressibility and flow properties for the block-shaped crystals in comparison to the needle- and plate-shaped crystals. Also, a more linear tablet compression behavior was noted for the plate and block morphologies of the API compared to their needle counterpart. <i>In vitro</i> dissolution studies showed distinct release profiles for the same API form with different crystal habits, i.e., needle &gt; plate &gt; block. Insights into crystal growth mechanism and the role of solvents in affording the observed crystal habits are presented based on molecular dynamics simulations of intermolecular interactions with crystal facets, in conjunction with the experimental crystal face indexing of the single crystals of different habits. These observations were further supported by interaction topology analysis and the electrostatic features on different crystal facets.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6234–6244 6234–6244"},"PeriodicalIF":4.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756472","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":"Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine–Triazole Groups in Stable Crystal Form","authors":"Tetsuya Miyano*,&nbsp;Shigeru Ando,&nbsp;Daiki Nagamatsu,&nbsp;Yui Watanabe,&nbsp;Daichi Sawada and Hiroshi Ueda*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0110810.1021/acs.molpharmaceut.4c01108","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01108https://doi.org/10.1021/acs.molpharmaceut.4c01108","url":null,"abstract":"<p >Ensitrelvir is a nonpeptide 3CL protease inhibitor used for coronavirus disease 2019 treatment. Four crystalline forms of ensitrelvir, metastable (Form I), acetonate (Form II), stable (Form III), and hydrate (Form IV), have been analyzed as pharmaceutical crystals. Their rank order of solubility is Form I &gt; IV &gt; III. Form III is the stable crystal with a significantly lower solubility than that predicted from its log <i>P</i> value of 2.7. Here, single-crystal structural analysis revealed strong intermolecular interactions between the triazine (acidic) and triazole (basic) groups of Form III not Forms I and IV. Multicomponent crystals were also designed to improve the solubility by altering the intermolecular interactions in Form III. Slurry conversion with equal molar ratios of ensitrelvir and fumaric acid successfully induced the formation of a novel cocrystal (Form V). Fumaric acid inhibited the triazine–triazole interactions, and dissolution of Form V was approximately 8- and 13-fold higher than that of Form III in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited an approximately 16-fold higher flux value than that of Form III. Therefore, alterations in intermolecular interactions via cocrystallization significantly enhance the dissolution and permeation of ensitrelvir.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6473–6483 6473–6483"},"PeriodicalIF":4.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756499","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":"Divergent Proteomic Profiles and Uptake Mechanisms of Exosomes Derived from Human Dental Pulp Stem Cells, Endothelial Cells, and Fibroblasts","authors":"Siqi Zhang,&nbsp;Jun Chen,&nbsp;Yipu Cao,&nbsp;Yifan Cui,&nbsp;Mei Zhang,&nbsp;Chongxia Yue* and Bangcheng Yang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0091110.1021/acs.molpharmaceut.4c00911","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00911https://doi.org/10.1021/acs.molpharmaceut.4c00911","url":null,"abstract":"<p >Effective intercellular communication is crucial for tissue repair and regeneration, with exosomes playing a key role in mediating these processes by transferring proteins, lipids, and nucleic acids between cells. This study explored the mechanisms underlying the uptake of exosomes derived from human dental pulp stem cells (hDPSCs), human umbilical vein endothelial cells (HUVECs), and human fibroblasts (HFBs). Our findings revealed that hDPSCs exhibited the greatest capacity for exosome uptake across all three cell types. Moreover, exosomes originating from hDPSCs were also taken up in the highest amounts by all three cell types. Proteomic analysis uncovered significant differences in protein expression among exosomes from these different cell types, particularly in proteins related to endocytosis. Clathrin-dependent endocytosis emerged as the primary pathway for exosome uptake in hDPSCs and HUVECs, while HFBs appeared to use a different mechanism. Additionally, proteins such as fibronectin and tetraspanins were found to be highly expressed in hDPSC-derived exosomes, suggesting their potential involvement in exosome–cell interactions. This study offers new insights into exosome uptake mechanisms and highlights the potential of exosomes in advancing tissue engineering and regenerative medicine.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6353–6362 6353–6362"},"PeriodicalIF":4.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756497","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":"Trop2-Targeted Molecular Imaging in Solid Tumors: Current Advances and Future Outlook","authors":"Yongshun Liu,&nbsp;Wenpeng Huang,&nbsp;Rachel J. Saladin,&nbsp;Jessica C. Hsu,&nbsp;Weibo Cai* and Lei Kang*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0084810.1021/acs.molpharmaceut.4c00848","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00848https://doi.org/10.1021/acs.molpharmaceut.4c00848","url":null,"abstract":"<p >Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein, plays a dual role in physiological and pathological processes. In healthy tissues, Trop2 facilitates development and orchestrates intracellular calcium signaling. However, its overexpression in numerous solid tumors shifts its function toward driving cell proliferation and metastasis, thus leading to a poor prognosis. The clinical relevance of Trop2 is underscored by its utility as both a biomarker for diagnostic imaging and a target for therapy. Notably, the U.S. Food and Drug Administration (FDA) has approved sacituzumab govitecan (SG), a novel Trop2-targeted agent, for treating triple-negative breast cancer (TNBC) and refractory urothelial cancer, highlighting the significance of Trop2 in clinical oncology. Molecular imaging, a powerful tool for visualizing and quantifying biological phenomena at the molecular and cellular levels, has emerged as a critical technique for studying Trop2. This approach encompasses various modalities, including optical imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and targeted antibodies labeled with radioactive isotopes. Incorporating Trop2-targeted molecular imaging into clinical practice is vital for the early detection, prognostic assessment, and treatment planning of a broad spectrum of solid tumors. Our review captures the latest progress in Trop2-targeted molecular imaging, focusing on both diagnostic and therapeutic applications across diverse tumor types, including lung, breast, gastric, pancreatic, prostate, and cervical cancers, as well as salivary gland carcinomas. We critically evaluate the current state by examining the relevant applications, diagnostic accuracy, therapeutic efficacy, and inherent limitations. Finally, we analyze the challenges impeding widespread clinical application and offer insights into strategies for advancing the field, thereby guiding future research endeavors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"5909–5928 5909–5928"},"PeriodicalIF":4.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756496","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":"Immuno-PET Imaging of CD93 Expression with 64Cu-Radiolabeled NOTA-mCD93 ([64Cu]Cu-NOTA-mCD93) and Insulin-Like Growth Factor Binding Protein 7 ([64Cu]Cu-NOTA-IGFBP7)","authors":"Xiaoyan Li,&nbsp;Wenyu Song,&nbsp;Jonathan W. Engle,&nbsp;Jason C. Mixdorf,&nbsp;Todd E. Barnhart,&nbsp;Yi Sun,&nbsp;Yuwen Zhu* and Weibo Cai*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0098310.1021/acs.molpharmaceut.4c00983","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00983https://doi.org/10.1021/acs.molpharmaceut.4c00983","url":null,"abstract":"<p >CD93 is overexpressed in multiple solid tumor types, serving as a novel target for antiangiogenic therapy. The goal of this study was to develop a ⁶⁴Cu-based positron emission tomography (PET) tracer for noninvasive imaging of CD93 expression. Antimouse-CD93 mAb (mCD93) and the CD93 ligand IGFBP7 were conjugated to a bifunctional chelator, <i>p</i>-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (<i>p</i>-SCN-NOTA) and labeled with ⁶⁴Cu. To evaluate the pharmacokinetic properties and tumor-targeting efficacy of [⁶⁴Cu]Cu-NOTA-mCD93 and [⁶⁴Cu]Cu-NOTA-IGFBP7, PET imaging and biodistribution were performed on both 4T1 murine breast tumor-bearing mice and MDA-MB-231 human breast tumor-bearing mice. The tumor model HT1080-FAP, which does not overexpress CD93, was used as a negative control. Fluorescent immunostaining was conducted on different tissues to correlate radiotracer uptake with CD93 expression. ⁶⁴Cu-labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the <i>in vivo</i> performance of [⁶⁴Cu]Cu-NOTA-IGFBP7 was superior to that of [⁶⁴Cu]Cu-NOTA-mCD93, and that the tracer [⁶⁴Cu]Cu-NOTA-IGFBP7 exhibited elevated tumor uptake values and excellent tumor retention in MDA-MB-231 mice, rather than in 4T1 murine mice. The MDA-MB-231 tumor uptake of [⁶⁴Cu]Cu-NOTA-IGFBP7 was 2.85 ± 0.15, 3.69 ± 0.60, 6.91 ± 0.88, and 6.35 ± 0.55%ID/g at 1, 4, 24, and 48 h p.i., respectively, which were significantly higher than that in the CD93-negative HT1080-FAP tumor (0.73 ± 0.15, 0.97 ± 0.31, 1.00 ± 0.07, and 1.02 ± 0.11%ID/g, respectively). The significant difference between positive and negative tumors indicated [⁶⁴Cu]Cu-NOTA-IGFBP7 was specifically binding to CD93. Biodistribution data as measured by gamma counting were consistent with the PET analysis. <i>Ex vivo</i> histology further confirmed the high CD93 expression on MDA-MB-231 tumor tissues. Herein, we prepared two novel radiotracers, [⁶⁴Cu]Cu-NOTA-mCD93 and [⁶⁴Cu]Cu-NOTA-IGFBP7, for the first immune-PET imaging of CD93 expression. Our results suggest that [⁶⁴Cu]Cu-NOTA-IGFBP7 is a more potential radiotracer for visualizing angiogenesis due to its sensitive, persistent, and CD93-specific characteristics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6411–6422 6411–6422"},"PeriodicalIF":4.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756476","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}