Molecular Pharmaceutics最新文献

{"title":"Comparative Kidney Uptake of Nanobody-Based PET Tracers Labeled with Various Fluorine-18-Labeled Prosthetic Groups.","authors":"Colleen P Olkowski, Falguni Basuli, Bruna Fernandes, Behnaz Ghaemi, Jianfeng Shi, Hongwei H Zhang, Joshua M Farber, Freddy E Escorcia, Peter L Choyke, Orit Jacobson","doi":"10.1021/acs.molpharmaceut.4c01101","DOIUrl":"10.1021/acs.molpharmaceut.4c01101","url":null,"abstract":"<p><p>Nanobodies, or single-domain antibody fragments, are promising candidates for molecular imaging due to their small size, rapid tissue penetration, and high target specificity. However, a significant challenge in their use is high renal uptake and retention, which can limit the therapeutic efficacy and complicate image interpretation. This study compares five different fluorine-18-labeled prosthetic groups for nanobodies, aiming to optimize pharmacokinetics and minimize kidney retention while maintaining tumor targeting. Using an epidermal growth factor receptor (EGFR) targeting nanobody as a model, two labeling approaches were evaluated; direct labeling of RESCA (with and without polyethylene glycol (PEG))-conjugated nanobody using Al[¹⁸F]F and indirect labeling using ([¹⁸F]F-fluoropyridine ([¹⁸F]F-FPy)-based prosthetic groups (site-specific and nonsite-specific). Labeled nanobodies were characterized in vitro for binding affinity and cell uptake with in vivo behavior assessed in EGFR + A431 tumor-bearing mice using PET imaging and biodistribution studies. Labeling with Al[¹⁸F]F showed high renal retention, which was partially mitigated by PEGylation. However, PEGylation also led to a decreased tumor uptake, particularly with longer PEG chains. Labeling using [¹⁸F]F-FPy prosthetic groups exhibited the most favorable pharmacokinetics, with rapid renal clearance and minimal kidney retention while maintaining high tumor uptake. These constructs showed excellent tumor-to-background contrast as early as 1 h postinjection. The study confirms that the selection of the prosthetic group significantly impacts the in vivo behavior of nanobodies, particularly regarding kidney accumulation. [¹⁸F]F-FPy-based prosthetic groups show the most promising results, with high tumor and minimal kidney uptake. Robust production of [¹⁸F]F-FPy on Sep-Pak is adaptable to clinical translation. Moreover, the potential substitution of ¹⁸F with therapeutic radioisotopes such as ¹³¹I or ²¹¹At could expand the application of these nanobodies from diagnostics to targeted radionuclide therapy while maintaining a low kidney exposure. These findings have important implications for optimizing nanobody-based radiopharmaceuticals for molecular imaging and targeted radionuclide therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"533-543"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833141","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 Peptide-Based ⁶⁸Ga-Labeled Radiotracer for Preclinical Studies of TIM3 Expression.","authors":"Jinping Tao, Fei Wang, Ziqing Zeng, Wenyuan Zhou, Zilei Wang, Chengxue He, Jinyu Zhu, Chuanke Zhao, Hua Zhu","doi":"10.1021/acs.molpharmaceut.4c00884","DOIUrl":"10.1021/acs.molpharmaceut.4c00884","url":null,"abstract":"&lt;p&gt;&lt;p&gt;T-cell immunoglobulin and mucin domain-3 (TIM3) is an immune checkpoint that plays a negative regulatory role in the immune response. TIM3-targeted drugs inhibit this negative regulation, thereby modulating the level of immune response activation. In the previous investigation, several peptides targeting TIM3 were identified through screening from a phage peptide library. In this research, three peptides were selected to construct the radioactive molecular probes according to the characteristic that targeting TIM3 drugs would lead to the increase of interferon-γ (IFN-γ) secretion. Molecular docking was performed to assess the binding properties of the selected peptides with the TIM3 protein. To further enhance the targeting properties, one of the peptides with a higher-affinity peptide was structurally modified. Then, &lt;sup&gt;68&lt;/sup&gt;Ga was used to construct the peptide probe &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-peptide by labeling the six peptides with &lt;sup&gt;68&lt;/sup&gt;Ga riboprobes, and the binding affinity and specificity were assessed using TIM3 overexpressing cell line A549&lt;sup&gt;TIM3&lt;/sup&gt; and the parental A549 cells. In addition, in Micro-PET/CT imaging, transfected model mice were dynamically imaged for 30 min after injection of 3.7-7.4 MBq &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-peptides via the tail vein. Meanwhile, the same dose of molecular probes was injected in the MC38 model (colorectal cancer in mice) and the CCRCC (clear cell renal cell carcinoma) xenografted model, followed by static scans at 15, 30, and 60 min postinjection. Finally, immunohistochemical (IHC) staining was performed to assess TIM3 expression in the dissected tumor tissues. The molecular docking results showed that the binding energy of P26 to TIM3 protein was -6.5 kcal/mol, which was lower than that of P24 to TIM3 protein, -3.6 kcal/mol, indicating that the affinity of P26 peptide to TIM3 protein was higher than that of P24 and P20 peptide. After structural modification of the P26 peptide, P26NH&lt;sub&gt;2&lt;/sub&gt;, r-NH&lt;sub&gt;2&lt;/sub&gt;, and P26X&lt;sub&gt;2&lt;/sub&gt; were obtained, and the above peptides were successfully constructed into six targeting TIM3 peptide probes by &lt;sup&gt;68&lt;/sup&gt;Ga labeling. Cellular uptake experiments demonstrated that &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-P26, &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-P26NH&lt;sub&gt;2&lt;/sub&gt;, and &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-r-NH&lt;sub&gt;2&lt;/sub&gt; showed significantly higher uptake in A549&lt;sup&gt;TIM3&lt;/sup&gt; cells than in A549 cells and could be blocked by the unlabeled peptide. Micro-PET imaging experiments showed that the uptake of each probe in the A549&lt;sup&gt;TIM3&lt;/sup&gt; model tumor tissue was significantly higher than that in the A549 model tumor tissue, and a comparison of the tumor-to-cardiac uptake ratios of each group showed that the &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-P26 had a better tumor-to-cardiac uptake ratio in the A549&lt;sup&gt;TIM3&lt;/sup&gt; model than several other molecular probes, and in the MC38 model, similar results were obtained, with the difference that the &lt;sup&gt;68&lt;/sup&gt;Ga-DOTA-P26NH&lt;sub&gt;2&lt;/sub&gt; had the highest tumor-to-c","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"270-283"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602065","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 Matchmakers: Bioconjugation Techniques Enhance Prodrug Potency for Immunotherapy.","authors":"Yinuo Chen, Natalie Clay, Nathan Phan, Elijah Lothrop, Courtney Culkins, Blaise Robinson, Ariana Stubblefield, Alani Ferguson, Blaise R Kimmel","doi":"10.1021/acs.molpharmaceut.4c00867","DOIUrl":"10.1021/acs.molpharmaceut.4c00867","url":null,"abstract":"<p><p>Cancer patients suffer greatly from the severe off-target side effects of small molecule drugs, chemotherapy, and radiotherapy─therapies that offer little protection following remission. Engineered immunotherapies─including cytokines, immune checkpoint blockade, monoclonal antibodies, and CAR-T cells─provide better targeting and future tumor growth prevention. Still, issues such as ineffective activation, immunogenicity, and off-target effects remain primary concerns. \"Prodrug\" therapies─classified as therapies administered as inactive and then selectively activated to control the time and area of release─hold significant promise in overcoming these concerns. Bioconjugation techniques (e.g., natural linker conjugation, bioorthogonal reactions, and noncanonical amino acid incorporation) enable the rapid and homogeneous synthesis of prodrugs and offer selective loading of immunotherapeutic agents to carrier molecules and protecting groups to prevent off-target effects after administration. Several prodrug activation mechanisms have been highlighted for cancer therapeutics, including endogenous activation by hypoxic or acidic conditions common in tumors, exogenous activation by targeted bioorthogonal cleavage, or stimuli-responsive light activation, and dual-stimuli activation, which adds specificity by combining these mechanisms. This review will explore modern prodrug conjugation and activation options, focusing on how these strategies can enhance immunotherapy responses and improve patient outcomes. We will also discuss the implications of computational methodology for therapy design and recommend procedures to determine how and where to conjugate carrier systems and \"prodrug\" groups onto therapeutic agents to enhance the safety and control of these delivery platforms.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"58-80"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680131","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":"Highly Water-Soluble Microneedle Patch for Short Wear Time and Rapid Drug Delivery.","authors":"Amy J Wood-Yang, Abishek Sankaranarayanan, Max J Freidlin, Mark R Prausnitz","doi":"10.1021/acs.molpharmaceut.4c01207","DOIUrl":"10.1021/acs.molpharmaceut.4c01207","url":null,"abstract":"<p><p>Treatment of acute medical conditions such as pain would benefit from rapid drug delivery and improved ease of administration of local anesthetics that currently have a slow onset of action by topical or oral administration and require expert administration by injection. To address this need, microneedle (MN) patches containing needlelike projections made from a polymer/drug matrix can be painlessly pressed into the skin for local or systemic drug delivery. To improve the speed and ease of drug delivery, we present a rapidly dissolving, highly water-soluble MN patch, which minimizes the wear time to 10 s to improve drug delivery in situations where rapid delivery with simplified administration is needed. MNs were made of polyvinylpyrrolidone (PVP), which is soluble in both water (enabling dissolution in the skin) and polar organic solvents (facilitating coformulation with lidocaine (L)). The addition of a highly water-soluble salt, sodium bicarbonate (NaB), to PVP/L MNs allowed for 60% faster MN dissolution in porcine skin ex vivo. Further addition of citric acid to generate effervescence upon reaction with NaB did not further decrease the MN dissolution time in the pig skin and led to poor shelf-life stability due to premature effervescence during storage. The PVP/L/NaB MNs delivered 23.8 ± 3.5 μg lidocaine to the skin ex vivo, well above the expected dose for local analgesic effect. Our highly water-soluble PVP/L/NaB MN design enables shorter wear time for faster delivery compared to the oral or topical route and easier administration compared to injection currently used for the delivery of drugs needing a rapid onset of action.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"573-582"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764822","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":"Insights into Folding and Molecular Environment of Lyophilized Proteins Using Pulsed Electron Paramagnetic Resonance Spectroscopy.","authors":"Nikolay Isaev, Ken Lo Presti, Wolfgang Frieß","doi":"10.1021/acs.molpharmaceut.4c01008","DOIUrl":"10.1021/acs.molpharmaceut.4c01008","url":null,"abstract":"<p><p>There is still an insufficient understanding of how the characteristics of protein drugs are maintained in the solid state of lyophilizates, including aspects such as protein distances, local environment, and structural preservation. To this end, we evaluated protein folding and the molecules' nearest environment by electron paramagnetic resonance (EPR) spectroscopy. Double electron-electron resonance (DEER) probe distances of up to approximately 200 Å and is suitable to investigate protein folding, local concentration, and aggregation, whereas electron spin echo envelope modulation (ESEEM) allows the study of the near environment within approximately 10 Å of the spin label. We spin-labeled human serum albumin (HSA) and freeze-dried different concentrations with 100 g/L deuterated sucrose. DEER showed distinct local concentration behaviors for two folding states, directly correlating folding percentage with the interprotein distance, reaching 2 nm at an HSA concentration of 84 g/L. Interestingly, 50% of the HSA molecules showed partial structural perturbation already at 2.6 g/L, which corresponds to a molar ratio Suc/HSA of 7469. This percentage increased to 97% with an increase in the HSA concentration to 84 g/L. The degree of protein perturbation cannot be told, and no signs of unfolding are found after reconstitution. ESEEM demonstrated a higher sucrose concentration around the protein label compared to the HSA environment in highly concentrated sucrose solutions. The partial unfolding detected in DEER could lead to label exposure and explain the enhanced sucrose detection in the intimate shell. Our work provides new insights regarding sucrose enrichment in the nearest shell of proteins upon lyophilization. In addition, the results indicate substantial partial structural perturbation, even in the presence of enormous supplies of stabilizing sugars. Thus, pulse EPR spectroscopy allows additional understanding of the solid state of protein lyophilizates, which is complementary to SANS, FTIR, or ssNMR.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"424-432"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880698","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":"Effect of Moisture Sorption and Lactose Type on Tablet Quality: A Hygroscopicity Study between Lactose Powder and Tablets.","authors":"Chuting Shi, Ying Fang, Zhenda Liu, Youjie Wang, Lan Shen, Lijie Zhao","doi":"10.1021/acs.molpharmaceut.4c01164","DOIUrl":"10.1021/acs.molpharmaceut.4c01164","url":null,"abstract":"<p><p>Lactose is one of the most commonly used tablet diluents and fillers. However, the moisture sorption of lactose powder could exert detrimental effects on the excipient itself, as well as on the tablet quality. The effects of storage relative humidity (RH) conditions for different grades of lactose powders and tablets on compression behavior and tablet qualities were investigated. Four types of lactose were selected in this study: sieved lactose (Pharmatose 110M), granulated lactose (SuperTab 30GR), anhydrous lactose (SuperTab 21AN), and spray-dried lactose (SuperTab 14SD). These powders and tablets were stored at three RH levels (33, 58, 75%) for a certain period of time before determining their properties. For the moisture-sorbed powder, there was little change in the basic physical properties of lactose powder. Based on the dynamic vapor sorption (DVS) results, the lactose grades determined their hygroscopic properties. The reduction in mechanical strength of lactose powder during storage became less pronounced except for 14SD. But a reduction was observed in the tensile strength (TS) of the 14SD powder from 2.1 to 0.9 MPa after storage at 75% RH for 30 days. The fragmentation of lactose increased with increasing storage humidity. By using multivariate statistical analysis, the similarity and variation of powder properties between 14SD and other types of lactose were visualized. For the moisture-sorbed tablet, the TS became higher and the friability became lower. The TS of lactose tablets exhibited an increase of up to 59.8%. Whether water uptake occurred before or after compression adversely affected tablet disintegration. In conclusion, adverse phenomena during production and storage can be effectively minimized by a better understanding of the effects of moisture sorption on lactose powder and tablets.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"544-557"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890693","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":"Establishing a Pharmacoinformatics Repository of Approved Medicines: A Database to Support Drug Product Development.","authors":"Jack D Murray, Harriet Bennett-Lenane, Patrick J O'Dwyer, Brendan T Griffin","doi":"10.1021/acs.molpharmaceut.4c00991","DOIUrl":"10.1021/acs.molpharmaceut.4c00991","url":null,"abstract":"<p><p>Advanced predictive modeling approaches have harnessed data to fuel important innovations at all stages of drug development. However, the need for a machine-readable drug product library which consolidates many aspects of formulation design and performance remains largely unmet. This study presents a scripted, reproducible approach to database curation and explores its potential to streamline oral medicine development. The Product Information files for all centrally authorized drug products containing a small molecule active ingredient were retrieved programmatically from the European Medicines Agency Web site. Text processing isolated relevant information, including the maximum clinical dose, dosage form, route of administration, excipients, and pharmacokinetic performance. Chemical and bioactivity data were integrated through automated linking to external curated databases. The capability of this database to inform oral medicine development was assessed in the context of drug-likeness evaluation, excipient selection, and prediction of oral fraction absorbed. Existing filters of drug-likeness, such as the Rule of Five, were found to poorly capture the chemical space of marketed oral drug products. Association rule learning identified frequent patterns in tablet formulation compositions that can be used to establish excipient combinations that have seen clinical success. Binary prediction models of oral fraction absorbed constructed exclusively from regulatory data achieved acceptable performance (balanced accuracy_test = 0.725), demonstrating its modelability and potential for use during early stage molecule prioritization tasks. This study illustrates the impact of highly linked drug product data in accelerating clinical translation and underlines the ongoing need for accuracy and completeness of data reported in the regulatory datasphere.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"408-423"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869275","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":"Advances in Dendritic Systems and Dendronized Nanoparticles: Paradigm Shifts in Cancer Targeted Therapy and Diagnostics.","authors":"Pawan Kedar, Apeksha Saraf, Rahul Maheshwari, Mayank Sharma","doi":"10.1021/acs.molpharmaceut.4c00856","DOIUrl":"10.1021/acs.molpharmaceut.4c00856","url":null,"abstract":"<p><p>Cancer has emerged as a global health crisis, claiming millions of lives annually. Dendrimers and dendronized nanoparticles, a novel class of nanoscale molecules with highly branched three-dimensional macromolecular structures, have gained significant attention in cancer treatment and diagnosis due to their unique properties. These dendritic macromolecules offer a precisely controlled branching architecture, enabling functionalization with specific targeting molecules to enhance the selective delivery of therapeutic agents to tumor cells while minimizing systemic toxicity. Through surface modifications and the incorporation of various components, dendrimers demonstrate remarkable adaptability as nanocarriers for biomedical imaging and theranostic applications. Surface functionalization strategies, including PEGylation and ligand attachment (e.g., folic acid, RGD peptide, lactobionic acid), further enhance biocompatibility and facilitate targeted tumor cell imaging. Leveraging their improved biocompatibility and target specificity, dendritic nanosystems offer heightened sensitivity and precision in cancer diagnostics. Notably, the encapsulation of metal nanoparticles within dendrimers, such as gold nanoparticles, has shown promise in enhancing tumor imaging capabilities. Ongoing advancements in nanotechnology are poised to increase the sophistication and complexity of dendrimer-based systems, highlighting their potential as nanocarriers in drug delivery platforms, with a growing number of clinical trials on the horizon. This review provides a comprehensive overview of the potential and future prospects of dendrimers and dendrimer-based nanocarriers in targeted cancer therapy and diagnosis, exploring their ability to enhance biocompatibility, reduce toxicity, and improve therapeutic outcomes across various malignancies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"28-57"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870576","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 Characterization of Thallium-Texaphyrin Nanoparticles and Their Assessment as Potential Delivery Systems for Auger Electron-Emitting ²⁰¹Tl to Cancer Cells.","authors":"Katarzyna M Wulfmeier, Miffy H Y Cheng, Zhongli Cai, Samantha Y A Terry, Vincenzo Abbate, Philip J Blower, Gang Zheng, Raymond M Reilly","doi":"10.1021/acs.molpharmaceut.4c00873","DOIUrl":"10.1021/acs.molpharmaceut.4c00873","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Thallium-201 is an Auger electron-emitting radionuclide with significant potential for targeted molecular radiotherapy of cancer. It stands out among other Auger electron emitters by releasing approximately 37 Auger and Coster-Kronig electrons per decay, which is one of the highest numbers in its category. It has also a convenient half-life of 73 h, a stable daughter product, established production methods, and demonstrated high &lt;i&gt;in vitro&lt;/i&gt; radiotoxicity. However, its full potential in targeted radiotherapy remains unexplored, primarily due to the lack of available efficient chelators for [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;+&lt;/sup&gt; or [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;3+&lt;/sup&gt;. This study aims to assess texaphyrin for macrocycle chelation of [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;3+&lt;/sup&gt;. Texaphyrins are known for effective binding of trivalent metals with similar ionic radii, such as indium and gadolinium. Optimization of [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;+&lt;/sup&gt; to [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;3+&lt;/sup&gt; oxidation and subsequent chelation with texaphyrin-lipid conjugate were assessed using thin-layer chromatography. The formation and stability of nonradioactive Tl-texaphyrin-lipid complexes were confirmed by UV-Vis spectroscopy and ultrahigh performance liquid chromatography-mass spectrometry. [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl/Tl-texaphyrin-lipid nanoparticles (nanotexaphyrins) were assembled by using a microfluidic system, and their morphology and stability were evaluated by using dynamic light scattering and transmission electron microscopy. The uptake of these nanotexaphyrins in lung cancer and ovarian cancer cells was evaluated using both radioactive and nonradioactive methods. The conversion of [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;+&lt;/sup&gt; to [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;3+&lt;/sup&gt; in 0.25 M HCl achieved an average yield of 91.8 ± 3.1%, while the highest radiolabeling yield of the texaphyrin-lipid with [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;3+&lt;/sup&gt; was 25.5 ± 4.5%. Tl-texaphyrin-lipid conjugates were stable at room temperature for at least 72 h. These conjugates were successfully assembled into homogeneous nanotexaphyrins with an average hydrodynamic diameter of 147.4 ± 1.4 nm. Throughout a 72 h period, no changes in size or polydispersity of the synthesized nanoparticles were observed. [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl-nanotexaphyrins were synthesized with an average radiochemical purity of 77.4 ± 10.3% and a yield of 5.1 ± 4.4%. The release of [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;+&lt;/sup&gt; from [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl-nanotexaphyrins in phosphate-buffered saline exhibited a time- and temperature-dependent pattern, with a faster release observed at 37 °C than at room temperature. Additionally, the uptake of Tl-nanotexaphyrins and [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl-nanotexaphyrins in cancer cells was similar to that of unbound Tl&lt;sup&gt;+&lt;/sup&gt; and [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl&lt;sup&gt;+&lt;/sup&gt;. This is the first time that texaphyrins have been investigated as chelators for radiothallium. Although [&lt;sup&gt;201&lt;/sup&gt;Tl]Tl-nanotexaphyrins were found to be thermodynamically and kinetica","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"242-254"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833156","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":"High-Speed Imaging-Based Particle Attribute Analysis of Spray-Dried Amorphous Solid Dispersions Using a Convolution Neural Network.","authors":"Hang Hu, Sampada Koranne, Colton M Bower, Daniel Skomski, Matthew S Lamm","doi":"10.1021/acs.molpharmaceut.4c01092","DOIUrl":"10.1021/acs.molpharmaceut.4c01092","url":null,"abstract":"<p><p>Spray drying is a well-established method for preparing amorphous solid dispersion (ASD) formulations to improve the oral bioavailability of poorly soluble drugs. In addition to the characterization of the amorphous phase, particle attributes of spray-dried intermediates (SDIs), including particle size, morphology, and microstructure, need to be carefully studied and controlled for optimizing drug product performance. Although recent developments in microscopy technology have enabled the analysis of morphological attributes for individual SDI particles, a high-throughput method is highly desirable. In this work, a fingerprinting method exploiting high-speed dynamic imaging, laser diffraction (LD), and a convolutional neural network (CNN) was developed to characterize and quantify size and morphological distributions of particles in batches of spray-dried ASDs. This imaging technology enables the generation of hundreds of thousands of single-particle images in a few minutes that are analyzed by both unsupervised and supervised CNN models. The unsupervised data mining analysis demonstrated that a batch of SDI is a mixture of diverse particle subpopulations with varying sizes and morphological attributes. Motivated by this observation, we developed a CNN model that enabled rapid computation of the volumetric composition of the distinct particle subpopulations in a SDI batch, thus generating a morphological fingerprint. We implemented this high-speed imaging-based particle attribute analysis method to investigate SDIs containing hypromellose acetate succinate as a model system. The CNN fingerprint results enabled quantification of the changes in the morphological distribution of SDI batches prepared with variations in the spray drying process parameters, and the results were in line with the LD and electron microscopy data. Our experiments and analysis demonstrate the robustness and throughput of this fingerprinting approach for quantifying particle size and morphological distributions of individual SDI batches, which can help guide spray drying process development and thereby enable the development of a drug product with more robust process and optimized performance.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"488-497"},"PeriodicalIF":4.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764838","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}