Molecular Pharmaceutics最新文献

{"title":"Development of Alginate-Based Biodegradable Radioactive Microspheres Labeled with Positron Emitter through Click Chemistry Reaction: Stability and PET Imaging Study.","authors":"Arun Gupta, Ji Yong Park, Hyunjun Choi, Tae Hyeon Choi, Yujin Chung, Dong-Hyun Kim, Yun-Sang Lee","doi":"10.1021/acs.molpharmaceut.4c00412","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00412","url":null,"abstract":"<p><p>Biodegradable radioactive microspheres labeled with positron emitters hold significant promise for diagnostic and therapeutic applications in cancers and other diseases, including arthritis. The alginate-based polymeric microspheres offer advantages such as biocompatibility, biodegradability, and improved stability, making them suitable for clinical applications. In this study, we developed novel positron emission tomography (PET) microspheres using alginate biopolymer radiolabeled with gallium-68 (⁶⁸Ga) through a straightforward conjugation reaction. Polyethylenimine (PEI)-decorated calcium alginate microspheres (PEI-CAMSs) were fabricated and further modified using azadibenzocyclooctyne-<i>N</i>-hydroxysuccinimide ester (ADIBO-NHS). Subsequently, azide-functionalized NOTA chelator (N₃-NOTA) was labeled with [⁶⁸Ga]Ga to obtain [⁶⁸Ga]Ga-NOTA-N₃, which was then reacted with the surface-modified PEI-CAMSs using strain-promoted alkyne-azide cycloaddition (SPAAC) reaction to develop [⁶⁸Ga]Ga-NOTA-PEI-CAMSs, a novel PET microsphere. The radiolabeling efficiency and radiochemical stability of [⁶⁸Ga]Ga-NOTA-PEI-CAMSs were determined using the radio-instant thin-layer chromatography-silica gel (radio-ITLC-SG) method. The <i>in vivo</i> PET images were also acquired to study the <i>in vivo</i> stability of the radiolabeled microspheres in normal mice. The radiolabeling efficiency of [⁶⁸Ga]Ga-NOTA-PEI-CAMSs was over 99%, and the microspheres exhibited high stability (92%) in human blood serum. PET images demonstrated the stability and biodistribution of the microspheres in mice for up to 2 h post injection. This study highlights the potential of biodegradable PET microspheres for preoperative imaging and targeted radionuclide therapy. Overall, the straightforward synthesis method and efficient radiolabeling technique provide a promising platform for the development of theranostic microspheres using other radionuclides such as ⁹⁰Y, ¹⁷⁷Lu, ¹⁸⁸Re, and ⁶⁴Cu.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015567","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":"Albumin-Mediated Drug Uptake by Organic Anion Transporter 1/3 Is Real: Implications for the Prediction of Active Renal Secretion Clearance","authors":"Shawn Pei Feng Tan,&nbsp;Annika Tillmann,&nbsp;Susan J. Murby,&nbsp;Amin Rostami-Hodjegan,&nbsp;Daniel Scotcher and Aleksandra Galetin*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0050410.1021/acs.molpharmaceut.4c00504","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00504https://doi.org/10.1021/acs.molpharmaceut.4c00504","url":null,"abstract":"<p >Modulation of the transport-mediated active uptake by human serum albumin (HSA) for highly protein-bound substrates has been reported and improved the <i>in vitro</i>-to-<i>in vivo</i> extrapolation (IVIVE) of hepatic clearance. However, evidence for the relevance of such a phenomenon in the case of renal transporters is sparse. In this study, transport of renal organic anion transporter 1 or 3 (OAT1/3) substrates into conditionally immortalized proximal tubular epithelial cells transduced with OAT1/3 was measured in the presence and absence of 1 and 4% HSA while keeping the unbound substrate concentration constant (based on measured fraction unbound, <i>f</i>_u,inc). In the presence of 4% HSA, the unbound intrinsic active uptake clearance (CL_int,u,active) of six highly protein-bound substrates increased substantially relative to the HSA-free control (3.5- to 122-fold for the OAT1 CL_int,u,active, and up to 28-fold for the OAT3 CL_int,u,active). The albumin-mediated uptake effect (fold increase in CL_int,u,active) was more pronounced with highly bound substrates compared to no effect seen for weakly protein-bound substrates adefovir (OAT1-specific) and oseltamivir carboxylate (OAT3-specific). The relationship between OAT1/3 CL_int,u,active and <i>f</i>_u,inc agreed with the facilitated-dissociation model; a relationship was established between the albumin-mediated fold change in CL_int,_u,active and <i>f</i>_u,inc for both the OAT1 and OAT3, with implications for IVIVE modeling. The relative activity factor and the relative expression factor based on global proteomic quantification of <i>in vitro</i> OAT1/3 expression were applied for IVIVE of renal clearance. The inclusion of HSA improved the bottom-up prediction of the level of OAT1/3-mediated secretion and renal clearance (CL_sec and CL_r), in contrast to the underprediction observed with the control (HSA-free) scenario. For the first time, this study confirmed the presence of the albumin-mediated uptake effect with renal OAT1/3 transporters; the extent of the effect was more pronounced for highly protein-bound substrates. We recommend the inclusion of HSA in routine <i>in vitro</i> OAT1/3 assays due to considerable improvements in the IVIVE of CL_sec and CL_r.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117153","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":"Correction to “Novel Synergistic Approach: Tazarotene-Calcipotriol-Loaded-PVA/PVP-Nanofiber Incorporated in Hydrogel Film for Management and Treatment of Psoriasis”","authors":"Sunita Thakur,&nbsp;Md Meraj Anjum,&nbsp;Shweta Jaiswal,&nbsp;Anand Kumar,&nbsp;Payal Deepak,&nbsp;Sneha Anand,&nbsp;Sanjay Singh and Paruvathanahalli Siddalingam Rajinikanth*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0063510.1021/acs.molpharmaceut.4c00635","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00635https://doi.org/10.1021/acs.molpharmaceut.4c00635","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117203","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":"Flow Activation Energy of High-Concentration Monoclonal Antibody Solutions and Protein–Protein Interactions Influenced by NaCl and Sucrose","authors":"Guangcui Yuan*,&nbsp;Paul F. Salipante,&nbsp;Steven D. Hudson,&nbsp;Richard E. Gillilan,&nbsp;Qingqiu Huang,&nbsp;Harold W. Hatch,&nbsp;Vincent K. Shen,&nbsp;Alexander V. Grishaev,&nbsp;Suzette Pabit,&nbsp;Rahul Upadhya,&nbsp;Sudeep Adhikari,&nbsp;Jainik Panchal*,&nbsp;Marco A. Blanco* and Yun Liu*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0046010.1021/acs.molpharmaceut.4c00460","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00460https://doi.org/10.1021/acs.molpharmaceut.4c00460","url":null,"abstract":"<p >The solution viscosity and protein–protein interactions (PPIs) as a function of temperature (4–40 °C) were measured at a series of protein concentrations for a monoclonal antibody (mAb) with different formulation conditions, which include NaCl and sucrose. The flow activation energy (<i>E</i>_η) was extracted from the temperature dependence of solution viscosity using the Arrhenius equation. PPIs were quantified via the protein diffusion interaction parameter (<i>k</i>_D) measured by dynamic light scattering, together with the osmotic second virial coefficient and the structure factor obtained through small-angle X-ray scattering. Both viscosity and PPIs were found to vary with the formulation conditions. Adding NaCl introduces an attractive interaction but leads to a significant reduction in the viscosity. However, adding sucrose enhances an overall repulsive effect and leads to a slight decrease in viscosity. Thus, the averaged (attractive or repulsive) PPI information is not a good indicator of viscosity at high protein concentrations for the mAb studied here. Instead, a correlation based on the temperature dependence of viscosity (i.e., <i>E</i>_η) and the temperature sensitivity in PPIs was observed for this specific mAb. When <i>k</i>_D is more sensitive to the temperature variation, it corresponds to a larger value of <i>E</i>_η and thus a higher viscosity in concentrated protein solutions. When <i>k</i>_D is less sensitive to temperature change, it corresponds to a smaller value of <i>E</i>_η and thus a lower viscosity at high protein concentrations. Rather than the absolute value of PPIs at a given temperature, our results show that the temperature sensitivity of PPIs may be a more useful metric for predicting issues with high viscosity of concentrated solutions. In addition, we also demonstrate that caution is required in choosing a proper protein concentration range to extract <i>k</i>_D. In some excipient conditions studied here, the appropriate protein concentration range needs to be less than 4 mg/mL, remarkably lower than the typical concentration range used in the literature.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117145","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":"Investigating the In Vivo Biodistribution of Extracellular Vesicles Isolated from Various Human Cell Sources Using Positron Emission Tomography","authors":"Zachary T. Rosenkrans,&nbsp;Anna S. Thickens,&nbsp;John A. Kink,&nbsp;Eduardo Aluicio-Sarduy,&nbsp;Jonathan W. Engle,&nbsp;Peiman Hematti and Reinier Hernandez*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0029810.1021/acs.molpharmaceut.4c00298","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00298https://doi.org/10.1021/acs.molpharmaceut.4c00298","url":null,"abstract":"<p >Positron emission tomography (PET) is a powerful tool for investigating the in vivo behavior of drug delivery systems. We aimed to assess the biodistribution of extracellular vesicles (EVs), nanosized vesicles secreted by cells isolated from various human cell sources using PET. EVs were isolated from mesenchymal stromal cells (MSCs) (MSC EVs), human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) by centrifugation and were conjugated with deferoxamine for radiolabeling with Zr-89. PET using conjugated and radiolabeled EVs evaluated their in vivo biodistribution and tissue tropisms. Our study also investigated differences in mouse models, utilizing immunocompetent and immunocompromised mice and an A375 xenograft tumor model. Lastly, we investigated the impact of different labeling techniques on the observed EV biodistribution, including covalent surface modification and membrane incorporation. PET showed that all tested EVs exhibited extended in vivo circulation and generally low uptake in the liver, spleen, and lungs. However, Mϕ EVs showed high liver uptake, potentially attributable to the intrinsic tissue tropism of these EVs from the surface protein composition. MSC EV biodistribution differed between immunocompetent and immunodeficient mice, with increased spleen uptake observed in the latter. PET using A375 xenografts demonstrated efficient tumor uptake of EVs, but no preferential tissue-specific tropism of A375 EVs was found. Biodistribution differences between labeling techniques showed that surface-conjugated EVs had preferential blood circulation and low liver, spleen, and lung uptake compared to membrane integration. This study demonstrates the potential of EVs as effective drug carriers for various diseases, highlights the importance of selecting appropriate cell sources for EV-based drug delivery, and suggests that EV tropism can be harnessed to optimize therapeutic efficacy. Our findings indicate that the cellular source of EVs, labeling technique, and animal model can influence the observed biodistribution.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117324","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":"Templated Nucleation of Clotrimazole and Ketoprofen on Polymer Substrates","authors":"Michael A. Bellucci,&nbsp;Lina Yuan,&nbsp;Grahame R. Woollam,&nbsp;Bing Wang,&nbsp;Liwen Fang,&nbsp;Yunfei Zhou,&nbsp;Chandler Greenwell,&nbsp;Sivakumar Sekharan,&nbsp;Xiaolan Ling* and GuangXu Sun*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0049110.1021/acs.molpharmaceut.4c00491","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00491https://doi.org/10.1021/acs.molpharmaceut.4c00491","url":null,"abstract":"<p >The use of different template surfaces in crystallization experiments can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). Consequently, templated nucleation is an attractive approach to enhance crystal nucleation kinetics and preferentially nucleate desired crystal polymorphs for solid-form drug molecules, particularly large and flexible molecules that are difficult to crystallize. Herein, we investigate the effect of polymer templates on the crystal nucleation of clotrimazole and ketoprofen with both experiments and computational methods. Crystallization was carried out in toluene solvent for both APIs with a template library consisting of 12 different polymers. In complement to the experimental studies, we developed a computational workflow based on molecular dynamics (MD) and derived descriptors from the simulations to score and rank API–polymer interactions. The descriptors were used to measure the energy of interaction (EOI), hydrogen bonding, and rugosity (surface roughness) similarity between the APIs and polymer templates. We used a variety of machine learning models (14 in total) along with these descriptors to predict the crystallization outcome of the polymer templates. We found that simply rank-ordering the polymers by their API–polymer interaction energy descriptors yielded 92% accuracy in predicting the experimental outcome for clotrimazole and ketoprofen. The most accurate machine learning model for both APIs was found to be a random forest model. Using these models, we were able to predict the crystallization outcomes for all polymers. Additionally, we have performed a feature importance analysis using the trained models and found that the most predictive features are the energy descriptors. These results demonstrate that API–polymer interaction energies are correlated with heterogeneous crystallization outcomes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117147","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":"Fabrication of Hybrid Coated Microneedles with Donepezil Utilizing Digital Light Processing and Semisolid Extrusion Printing for the Management of Alzheimer’s Disease","authors":"Paraskevi-Kyriaki Monou,&nbsp;Eleftherios G. Andriotis,&nbsp;Eirini Saropoulou,&nbsp;Emmanouil Tzimtzimis,&nbsp;Dimitrios Tzetzis,&nbsp;Georgios Komis,&nbsp;Chrysanthi Bekiari,&nbsp;Nikolaos Bouropoulos,&nbsp;Efterpi Demiri,&nbsp;Ioannis S. Vizirianakis and Dimitrios G. Fatouros*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0037710.1021/acs.molpharmaceut.4c00377","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00377https://doi.org/10.1021/acs.molpharmaceut.4c00377","url":null,"abstract":"<p >Microneedle (MN) patches are gaining increasing attention as a cost-effective technology for delivering drugs directly into the skin. In the present study, two different 3D printing processes were utilized to produce coated MNs, namely, digital light processing (DLP) and semisolid extrusion (SSE). Donepezil (DN), a cholinesterase inhibitor administered for the treatment of Alzheimer’s disease, was incorporated into the coating material. Physiochemical characterization of the coated MNs confirmed the successful incorporation of donepezil as well as the stability and suitability of the materials for transdermal delivery. Optical microscopy and SEM studies validated the uniform weight distribution and precise dimensions of the MN arrays, while mechanical testing ensured the MNs’ robustness, ensuring efficient skin penetration. In vitro studies were conducted to evaluate the produced transdermal patches, indicating their potential use in clinical treatment. Permeation studies revealed a significant increase in DN permeation compared to plain coating material, affirming the effectiveness of the MNs in enhancing transdermal drug delivery. Confocal laser scanning microscopy (CLSM) elucidated the distribution of the API, within skin layers, demonstrating sustained drug release and transcellular transport pathways. Finally, cell studies were also conducted on NIH3T3 fibroblasts to evaluate the biocompatibility and safety of the printed objects for transdermal applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117146","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":"Magnetic Resonance Imaging of Fibroblast Activation Protein Using a Targeted Gadolinium-Based Contrast Agent.","authors":"Dinghu Weng, Rong Guo, Changling Dong, Yuan Luo, Dasheng Qiu, Liying Xu, Guobin Xu","doi":"10.1021/acs.molpharmaceut.3c01250","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.3c01250","url":null,"abstract":"<p><p>The aim of this study was to synthesize a quinoline-based MRI contrast agent, Gd-DOTA-FAPI04, and assess its capacity for targeting fibroblast activation protein (FAP)-positive tumors in vivo. Gd-DOTA-FAPI04 was synthesized by attaching a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complex of gadolinium(III) to FAP inhibitor FAPI04. The longitudinal relaxation time (T1) of the contrast agent was measured using a Siemens Prisma 3.0T MR system, and the CCK-8 assay was performed to evaluate its potential cytotoxicity. Male nude mice bearing tumors grown from FAP-expressing fibrosarcoma cells were divided into experimental (<i>n</i> = 4) and control (<i>n</i> = 4) groups, and T1-weighted image enhancement was measured at different times (0, 10, 30, 60, 90, and 120 min) postinjection of Gd-DOTA-FAPI04. The control group received an additional preinjection of excess FAPI04. FAP expression in tumor tissue was investigated by using immunohistochemistry with an anti-FAP antibody. The longitudinal relaxivities of gadodiamide and Gd-DOTA-FAPI04 were measured to be 3.734 mM^-1 s^-1 and 5.323 mM^-1 s^-1, respectively. The CCK-8 assay demonstrated that Gd-DOTA-FAPI04 has minimal toxicity to cultured human fibrosarcoma cells. In vivo MRI showed that peak accumulation of Gd-DOTA-FAPI04 in FAP-expressing tumors occurred 1 h postinjection and could be blocked by preinjection of excess FAPI04. Immunohistochemical analysis of harvested tumor tissue supported the above findings. Gd-DOTA-FAPI04 is a promising contrast agent for in vivo imaging of FAP.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003009","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":"Patient-Centric Long-Acting Injectable and Implantable Platforms─An Industrial Perspective","authors":"Simone Alidori,&nbsp;Raju Subramanian and René Holm*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0066510.1021/acs.molpharmaceut.4c00665","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00665https://doi.org/10.1021/acs.molpharmaceut.4c00665","url":null,"abstract":"<p >The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients’ unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient’s provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations. In this work, a comprehensive analysis of marketed LAIs across therapeutic classes and technologies is conducted. The analysis demonstrated an increasing number of new LAIs being brought to the market, recently most as aqueous suspensions and one as a solution, but many other technology platforms were applied as well, in particular, polymeric microspheres and in situ forming gels. The analysis across the technologies provided an insight into to the physicochemical properties the compounds had per technology class as well as knowledge of the excipients typically used within the individual formulation technology. The principle behind the formulation technologies was discussed with respect to the release mechanism, manufacturing approaches, and the possibility of defining predictive in vitro release methods to obtain in vitro in vivo correlations with an industrial angle. The gaps in the field are still numerous, including better systematic formulation and manufacturing investigations to get a better understanding of potential innovations, but also development of new polymers could facilitate the development of additional compounds. The biggest and most important gaps, however, seem to be the development of predictive in vitro dissolution methods utilizing pharmacopoeia described equipment to enable their use for product development and later in the product cycle for quality-based purposes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c00665","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117299","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":"First-Generation Radiolabeled Cyclic Peptides for Molecular Imaging of Platelet-Derived Growth Factor Receptor α","authors":"Susan Pike,&nbsp;Melinda Wuest,&nbsp;Ana Lopez-Campistrous,&nbsp;Mi Yao Hu,&nbsp;Ratmir Derda,&nbsp;Frank Wuest* and Todd McMullen*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0054910.1021/acs.molpharmaceut.4c00549","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00549https://doi.org/10.1021/acs.molpharmaceut.4c00549","url":null,"abstract":"<p >Occult nodal spread and metastatic disease require longstanding imaging and biochemical assessments for thyroid cancer, a disease that has a propensity for diffuse, small-volume disease. We have developed a ⁶⁴Cu-labeled platelet-derived growth factor receptor α (PDGFRA) antibody for immuno-PET of PDGFRA in metastatic papillary thyroid cancer (PTC). The present work describes the discovery of small cyclic PDGFRA-targeting peptides, their binding features, and radiolabeling with positron emitter gallium-68 (⁶⁸Ga) for <i>in vitro and in vivo</i> characterization in thyroid cancer models. Phage-display technology with two separate libraries and seven different cell lines was used through three rounds of biopanning as well as flow cytometry and comparative analysis with recombinant protein to select specific peptide sequences. Phenotypic binding analysis was completed by using phosphorylation and cell migration assays. <i>In vitro</i> protein binding was analyzed with thermophoresis and flow cytometry using the fluorescent-labeled PDGFRA peptide. Peptide candidates were modified with the NOTA chelator for radiolabeling with ⁶⁸Ga. <i>In vitro</i> cell uptake was studied in various thyroid cancer cell lines. <i>In vivo</i> studies of ⁶⁸Ga-labeled peptides included metabolic stability and PET imaging. From the original library (10¹³ compounds), five different peptide groups were identified based on biopanning experiments with and without the α subunit of PDGFR, leading to ∼50 peptides. Subsequent phenotypic screening revealed two core peptide sequences (<b>CP16</b> and <b>CP18</b>) that demonstrated significant changes in the level of PDGFRA phosphorylation and cell migration. Alanine scan sublibraries were created from these two lead peptide sequences, and peptides were radiolabeled using ⁶⁸Ga-GaCl₃ at pH 4.5, resulting in RCP &gt; 95% within 34–40 min, including SPE purification. Cyclic peptide <b>CP18.5</b> showed the strongest effects on cell migration, flow cytometry, and binding by visual interference color assay. ⁶⁸Ga-labeled PDGFRA-targeting peptides showed elevated cell and tumor uptake in models of thyroid cancer, with ^<b>68</b><b>Ga-NOTA-CP18.5</b> being the lead candidate. However, metabolic stability <i>in vivo</i> was compromised for ^<b>68</b><b>Ga-NOTA-CP18.5</b> vs ^<b>68</b><b>Ga-NOTA-CP18</b> but without impacting tumor uptake or clearance profiles. First-generation radiolabeled cyclic peptides have been developed as novel radiotracers, particularly ^<b>68</b><b>Ga-NOTA-CP18.5</b>, for the molecular imaging of PDGFRA in thyroid cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117211","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}