Molecular Pharmaceutics最新文献

{"title":"Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM): A Workshop Report.","authors":"Christer Tannergren, Sumit Arora, Andrew Babiskin, Luiza Borges, Parnali Chatterjee, Yi-Hsien Cheng, André Dallmann, Anitha Govada, Tycho Heimbach, Martin Hingle, Sivacharan Kollipara, Evangelos Kotzagiorgis, Anders Lindahl, Claire Mackie, Maria Malamatari, Amitava Mitra, Rebecca Moody, Xavier Pepin, James Polli, Kimberly Raines, Gregory Rullo, Maitri Sanghavi, Rajesh Savkur, Rajendra Singh, Erik Sjögren, Sandra Suarez-Sharp, Sherin Thomas, Shereeni Veerasingham, Kevin Wei, Fang Wu, Yunming Xu, Miyoung Yoon, Bhagwant Rege","doi":"10.1021/acs.molpharmaceut.4c01148","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01148","url":null,"abstract":"<p><p>This report summarizes the proceedings for Day 3 of the workshop titled \"<i>Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives</i>\". This day focused on the current and future drug product quality applications of PBBM from the innovator and generic industries as well as the regulatory agencies perspectives. The presentations, which included several case studies, covered the applications of PBBM in generic drug product development, applications of virtual bioequivalence trials to support formulation bridging and the utility of absorption modeling in clinical pharmacology assessments. In addition, recent progress in the prediction of colon absorption and <i>in vivo</i> performance of extended-release drug products was shared. The morning session was concluded by representatives from FDA, ANVISA, MHRA, Health Canada, EMA, and PMDA giving their perspectives on the application of PBBM in regulatory submissions. The afternoon breakout sessions focused on four parallel topics: 1) PBBM in generic drug product development; 2) virtual bioequivalence trials applications; 3) safe space and extrapolation; and 4) regional absorption and modified release PBBM applications. This allowed the participants to engage in in-depth discussions of best practices as well to identify key points of consideration to allow further progress on the applications of PBBM.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833143","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 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":"https://doi.org/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":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-16","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":"Rationalizing mAb Candidate Screening Using a Single Holistic Developability Parameter.","authors":"Leon F Willis, Isabelle Trayton, Janet C Saunders, Maria G Brùque, William Davis Birch, David R Westhead, Katie Day, Nicholas J Bond, Paul W A Devine, Christopher Lloyd, Nikil Kapur, Sheena E Radford, Nicholas J Darton, David J Brockwell","doi":"10.1021/acs.molpharmaceut.4c00829","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00829","url":null,"abstract":"<p><p>A framework for the rational selection of a minimal suite of nondegenerate developability assays (DAs) that maximize insight into candidate developability or storage stability is lacking. To address this, we subjected nine formulation:mAbs to 12 mechanistically distinct DAs together with measurement of their accelerated and long-term storage stability. We show that it is possible to identify a reduced set of key variables from this suite of DAs by using orthogonal statistical methods. We exemplify our approach by predicting the rank formulation:mAb degradation rate at 25 °C (determined over 6 months) using just five DAs that can be measured in less than 1 day, spanning a range of physicochemical features. Implementing such approaches focuses on resources, thus increasing sustainability and decreasing development costs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833144","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":"https://doi.org/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":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracranial Nanogel Pellets Carrying Temozolomide and Paclitaxel for Adjuvant Brain Cancer Therapy.","authors":"Hasan Slika, Aanya Shahani, Kranthi Gattu, Varsha Mundrathi, Ameilia A Solan, Brianna Gonzalez, Tasmima N Haque, Sadia Rahman, Vrashabh V Sugandhi, Jennifer Lee, Esteban Velarde, Safwan Alomari, Victor Lance Pacis, Henry Brem, Betty Tyler, Xiaoban Xin, Hyunah Cho","doi":"10.1021/acs.molpharmaceut.4c00708","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00708","url":null,"abstract":"<p><p>Glioblastoma multiforme is the most frequently diagnosed primary malignant brain tumor. Despite multimodal therapy with surgical resection, radiation therapy, and chemotherapy, recurrence of the tumor is almost always guaranteed due to the infiltrative nature of the disease. Moreover, the blood brain barrier imparts an additional layer of complexity by impeding the delivery of therapeutic agents to the tumor, hence limiting the efficacy of systemically delivered drugs. Hence, to overcome this obstacle and avoid treatment resistance, the local delivery of combination therapies has risen as an appealing adjuvant treatment. The present study describes the creation of a novel PLGA-PEG-PLGA-based nanogel pellet system for the interstitial delivery of Temozolomide (TMZ) and paclitaxel (PTX) to the brain. The nanogel pellet was shown to be stable as a pellet at ambient temperature, absorb water, change to a gel formulation at physiological temperature, and achieve gradual long-term release of TMZ and PTX in vitro. Additionally, in vivo testing of the TMZ/PTX-loaded nanogel pellets in an orthotopic CT2A mouse model and an orthotopic 9L rat model has shown an acceptable safety profile when implanted intracranially and a significant improvement in overall survival.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816788","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 Transferrin and Cell-Penetrating Peptide-Functionalized Liposomal Nanoparticles to Deliver Plasmid ApoE2 <i>In Vitro</i> and <i>In Vivo</i> in Mice.","authors":"Chinenye Edith Muolokwu, Avinash Gothwal, Takahisa Kanekiyo, Jagdish Singh","doi":"10.1021/acs.molpharmaceut.4c00870","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00870","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by the aggregation of amyloid-β plaques and neurofibrillary tangles in the brain, leading to synaptic dysfunction and neuronal degeneration. Recently, new treatment approaches involving drugs such as donanemab and lecanemab have been introduced for AD. However, these drug regimens have been associated with adverse effects, leading to the exploration of gene therapy as a potential treatment option. The apolipoprotein E (ApoE) isoforms (ApoE2, ApoE3, and ApoE4) play pivotal roles in AD pathology, with ApoE2 known for its protective effects against AD, making it a promising candidate for gene therapy interventions. However, delivering therapeutics across the blood-brain barrier (BBB) remains a crucial challenge in treating neurological disorders. Liposomes, lipid-based vesicles, are effective nanocarriers due to their ability to shield therapeutics from degradation, though they often lack specificity for brain delivery. To address this issue, liposomes were functionalized with cell-penetrating peptides such as penetratin (Pen), cingulin (Cgn), and a targeting ligand transferrin (T_f). This modification strategy aimed to enhance the delivery of therapeutic ApoE2 plasmids across the BBB to neurons, thereby increasing the level of ApoE2 protein expression. Experimental findings demonstrated that dual-functionalized liposomes (CgnT_f and PenT_f) exhibited higher cellular uptake, biodistribution, and transfection efficiency than single-functionalized (Pen, Cgn, or T_f) and nonfunctionalized liposomes. <i>In vitro</i> studies using primary neuronal cells, bEnd.3 cells, and primary astrocytes consistently supported these findings. Following a single dose treatment via tail vein administration in C57BL6/J mice, <i>in vivo</i> biodistribution results showed significantly higher biodistribution levels in the brain (∼12% ID/gram of tissue) for dual-functionalized liposomes. Notably, treatment with dual-functionalized liposomes resulted in a 2-fold increase in ApoE2 expression levels compared to baseline levels. These findings highlight the potential of dual-functionalized liposomes as an efficacious delivery system for ApoE2 gene therapy in AD, highlighting a promising strategy to address the disease's underlying mechanisms.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811476","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":"Preclinical Comparison of [¹¹¹In]In- and [²²⁵Ac]Ac-DOTA-Trastuzumab IgG, F(ab')₂ and Fab for Theranostic SPECT/CT Imaging and α-Particle Radioimmunotherapy of HER2-Positive Human Breast Cancer.","authors":"Misaki Kondo, Zhongli Cai, Conrad Chan, Madeline K Brown, Raymond M Reilly","doi":"10.1021/acs.molpharmaceut.4c01071","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01071","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Radioimmunotherapy (RIT) with α-particle-emitting, &lt;sup&gt;225&lt;/sup&gt;Ac complexed to trastuzumab may offer an alternative treatment for patients who progress on HER2-targeted therapies. Moreover, RIT with [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab could be combined with SPECT/CT imaging with [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab in a theranostic approach. In this study, we compared DOTA-conjugated trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab complexed to &lt;sup&gt;111&lt;/sup&gt;In or &lt;sup&gt;225&lt;/sup&gt;Ac for SPECT/CT imaging and α-particle RIT of subcutaneous (s.c.) HER2-positive 164/8-1B/H2N.luc&lt;sup&gt;+&lt;/sup&gt; human BC tumors in NRG mice. SPECT/CT imaging and tumor and normal tissue uptake were compared in NRG or NOD-SCID mice coinjected i.v. with [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab and [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab. Radiation absorbed doses in the tumor and normal organs for [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab were estimated based on the biodistribution of the [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab. Normal tissue toxicity was assessed by hematology and blood biochemistry analyses and monitoring body weight in NRG mice injected i.v. with 2 and 4 kBq of [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab separated by 8 d. RIT studies were performed in NRG mice with s.c. 164/8-1B/H2N.luc&lt;sup&gt;+&lt;/sup&gt; tumors injected i.v. with 2 kBq and 4 kBq of [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab separated by 8 d or irrelevant [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-IgG&lt;sub&gt;1&lt;/sub&gt;, two doses of unlabeled trastuzumab IgG or 0.9% NaCl. A tumor growth index (TGI) was plotted vs time (d) and Kaplan-Meier median survival estimated. [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab IgG or F(ab')&lt;sub&gt;2&lt;/sub&gt; exhibited 4.1-fold and 3.3-fold significantly greater tumor uptake at 2 d postinjection (p.i.) than Fab at 24 h p.i. However, spleen uptake at 2 d p.i. for [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab IgG was 3.3-fold significantly higher than F(ab')&lt;sub&gt;2&lt;/sub&gt; and 13.2-fold higher than Fab at 24 h p.i. [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab F(ab')&lt;sub&gt;2&lt;/sub&gt; and Fab exhibited higher kidney uptake than IgG. Tumors were imaged by SPECT/CT with [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab IgG and F(ab')&lt;sub&gt;2&lt;/sub&gt; but were not well-visualized with [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab Fab. The absorbed dose in the tumor was 2.2-fold greater for [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab F(ab')&lt;sub&gt;2&lt;/sub&gt; than IgG and 3.4-fold greater than Fab. Hematological toxicity was observed for [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab IgG but not for [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab. No kidney or liver toxicity or decreased body weight was observed for any RIT agent. Tumor growth was significantly inhibited by [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab IgG, F(ab')&lt;sub&gt;2&lt;/sub&gt; or Fab but [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab F(ab')&lt;sub&gt;2&lt;/s","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811475","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":"Calculating Apparent p<i>K</i>_a Values of Ionizable Lipids in Lipid Nanoparticles.","authors":"Nicholas B Hamilton, Steve Arns, Mee Shelley, Irene Bechis, John C Shelley","doi":"10.1021/acs.molpharmaceut.4c00426","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00426","url":null,"abstract":"<p><p>Creating new ionizable lipids for use in lipid nanoparticles (LNPs) is an active field of research. One of the critical properties for selecting suitable ionizable lipids is the apparent p<i>K</i>_a value of the lipid as formulated in an LNP. We have developed a structure-based, computational methodology for the prediction of the apparent p<i>K</i>_a value of ionizable lipids within LNPs and have tested it using the lipid formulations in the mRNA LNP COVID-19 vaccines COMIRNATY and Spikevax, and the siRNA LNP therapeutic Onpattro. The calculation was also applied to Lipid A, a variant of the ionizable lipid used in COMIRNATY.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798731","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":"Design and Bottom-up Production of an Aerosolizable Cannabidiol Nanosuspension.","authors":"Luca Casula, Michele Schlich, Maria Cristina Cardia, Eleonora Lai, Salvatore Marceddu, Rosa Pireddu, Donatella Valenti, Chiara Sinico, Francesco Lai, Elena Pini","doi":"10.1021/acs.molpharmaceut.4c01095","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01095","url":null,"abstract":"<p><p>Cannabidiol (CBD), a small nonpsychoactive molecule derived from <i>Cannabis sativa</i>, exerts a variety of therapeutic actions, such as anti-inflammatory, antioxidant, and antibacterial. Epidiolex is the only FDA-approved medicine containing pure CBD as an oral solution for seizure-controlling therapy. Nevertheless, the oral bioavailability of CBD is challenging due to its physical-chemical properties such as low solubility in water and high first-pass metabolism. By contrast, inhaled CBD has shown faster absorption and higher plasma concentration. Nanosuspensions represent an optimal strategy to obtain an effective aerosolizable formulation of poorly soluble drugs. In this study, a CBD nanosuspension was produced using a bottom-up technique, namely, a solvent/antisolvent nanoprecipitation. The obtained system was thoroughly characterized in terms of dimensions and ζ potential, nanocrystal morphology, and solid-state properties. The formulation was composed of homogeneously dispersed nanocrystals of approximately 88 nm, with a faster dissolution profile compared with the raw drug and the coarse suspension. The nebulization tests carried out using a Next Generation Impactor (NGI, Apparatus E Ph. Eu) highlighted optimal aerodynamic properties with high values of fine particle fraction and MMAD < 5 μm. Finally, the safety of the nanomedicine was assessed on human pulmonary cells demonstrating excellent biocompatibility.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805538","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":"https://doi.org/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":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-10","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}