Molecular Pharmaceutics最新文献

{"title":"Fabrication of Poly Lactic-co-Glycolic Acid Microneedles for Sustained Delivery of Lipophilic Peptide-Carfilzomib","authors":"Nisha Shrestha, Tanvi Karve, Thomas Kipping, Ajay K. Banga","doi":"10.1021/acs.molpharmaceut.4c00593","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00593","url":null,"abstract":"Transdermal drug delivery (TDD) is an attractive route of administration, providing several advantages, especially over oral and parenteral routes. However, TDD is significantly restricted due to the barrier imposed by the uppermost layer of the skin, the stratum corneum (SC). Microneedles is a physical enhancement technique that efficiently pierces the SC and facilitates the delivery of both lipophilic and hydrophilic molecules. Dissolving microneedles is a commonly used type that is fabricated utilizing various biodegradable and biocompatible polymers, such as polylactic acid, polyglycolic acid, or poly(lactide-<i>co</i>-glycolide) (PLGA). Such polymers also promote the prolonged release of the drug due to the slow degradation of the polymer matrix following its insertion. We selected carfilzomib, a small therapeutic peptide (<i>M</i>_W: 719.924 g/mol, log <i>P</i> 4.19), as a model drug to fabricate a microneedle-based sustained delivery system. This study is a proof-of-concept investigation in which we fabricated PLGA microneedles using four types of PLGA (50–2A, 50–5A, 75–5A, and 50–7P) to evaluate the feasibility of long-acting transdermal delivery of carfilzomib. Micromolding technique was used to fabricate the PLGA microneedles and characterization tests, including Fourier transform infrared spectroscopy, insertion capability using the skin simulant Parafilm model, histological evaluation, scanning electron microscopy, and confocal microscopy were conducted. <i>In vitro</i> release and permeation testing were conducted in vertical Franz diffusion cells. <i>N</i>-methyl pyrrolidone was utilized as the organic solvent and microneedles were solidified in controlled conditions, which led to good mechanical strength. Both <i>in vitro</i> release and permeation testing showed sustained profiles of carfilzomib over 7 days. The release and permeation were significantly influenced by the molecular weight of PLGA and the lipophilic properties of carfilzomib.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199980","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 Mechanisms of Antibody Binding to Alpha-Synuclein for the Treatment of Parkinson’s Disease","authors":"Malcolm C. Harrison, Pin-Kuang Lai","doi":"10.1021/acs.molpharmaceut.4c00879","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00879","url":null,"abstract":"Parkinson’s disease (PD) is an idiopathic neurodegenerative disorder with the second-highest prevalence rate behind Alzheimer’s disease. The pathophysiological hallmarks of PD are both degeneration of dopaminergic neurons in the substantia nigra pars compacta and the inclusion of misfolded α-synuclein (α-syn) aggregates known as Lewy bodies. Despite decades of research for potential PD treatments, none have been developed, and developing new therapeutic agents is a time-consuming and expensive process. Computational methods can be used to investigate the properties of drug candidates currently undergoing clinical trials to determine their theoretical efficiency at targeting α-syn. Monoclonal antibodies (mAbs) are biological drugs with high specificity, and Prasinezumab (PRX002) is an mAb currently in Phase II, which targets the C-terminus (AA 118–126) of α-syn. We utilized BioLuminate and PyMol for the structure prediction and preparation of the fragment antigen-binding (Fab) region of PRX002 and 34 different conformations of α-syn. Protein–protein docking simulations were performed using PIPER, and 3 of the docking poses were selected based on the best fit. Molecular dynamics simulations were conducted on the docked protein structures in triplicate for 1000 ns, and hydrogen bonds and electrostatic and hydrophobic interactions were analyzed using MDAnalysis to determine which residues were interacting and how often. Hydrogen bonds were shown to form frequently between the HCDR2 region of PRX002 and α-syn. Free energy was calculated to determine the binding affinity. The predicted binding affinity shows a strong antibody–antigen attraction between PRX002 and α-syn. RMSD was calculated to determine the conformational change of these regions throughout the simulation. The mAb’s developability was determined using computational screening methods. Our results demonstrate the efficiency and developability of this therapeutic agent.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199977","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":"Kinase Drug Discovery: Impact of Open Science and Artificial Intelligence.","authors":"Filip Miljković, Jürgen Bajorath","doi":"10.1021/acs.molpharmaceut.4c00659","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00659","url":null,"abstract":"<p><p>Given their central role in signal transduction, protein kinases (PKs) were first implicated in cancer development, caused by aberrant intracellular signaling events. Since then, PKs have become major targets in different therapeutic areas. The preferred approach to therapeutic intervention of PK-dependent diseases is the use of small molecules to inhibit their catalytic phosphate group transfer activity. PK inhibitors (PKIs) are among the most intensely pursued drug candidates, with currently 80 approved compounds and several hundred in clinical trials. Following the elucidation of the human kinome and development of robust PK expression systems and high-throughput assays, large volumes of PK/PKI data have been produced in industrial and academic environments, more so than for many other pharmaceutical targets. In addition, hundreds of X-ray structures of PKs and their complexes with PKIs have been reported. Substantial amounts of PK/PKI data have been made publicly available in part as a result of open science initiatives. PK drug discovery is further supported through the incorporation of data science approaches, including the development of various specialized databases and online resources. Compound and activity data wealth compared to other targets has also made PKs a focal point for the application of artificial intelligence (AI) in pharmaceutical research. Herein, we discuss the interplay of open and data science in PK drug discovery and review exemplary studies that have substantially contributed to its development, including kinome profiling or the analysis of PKI promiscuity versus selectivity. We also take a close look at how AI approaches are beginning to impact PK drug discovery in light of their increasing data orientation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138603","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":"Advances in Novel Biomaterial-Based Strategies for Spinal Cord Injury Treatment.","authors":"Nannan Zhang, Jiaqi Hu, Wenlong Liu, Wenjun Cai, Yun Xu, Xiaojuan Wang, Shun Li, Bin Ru","doi":"10.1021/acs.molpharmaceut.3c01104","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.3c01104","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a highly disabling neurological disorder. Its pathological process comprises an initial acute injury phase (primary injury) and a secondary injury phase (subsequent chronic injury). Although surgical, drug, and cell therapies have made some progress in treating SCI, there is no exact therapeutic strategy for treating SCI and promoting nerve regeneration due to the complexity of the pathological SCI process. The development of novel drug delivery systems to treat SCI is expected to significantly impact the individualized treatment of SCI due to its unique and excellent properties, such as active targeting and controlled release. In this review, we first describe the pathological progression of the SCI response, including primary and secondary injuries. Next, we provide a concise overview of newly developed nanoplatforms and their potential application in regulating and treating different pathological processes of SCI. Then, we introduce the existing potential problems and future clinical application perspectives of biomedical engineering-based therapies for SCI.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131181","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":"Research Progress on the Strategies for Crossing the Blood-Brain Barrier.","authors":"Li Qiao, Xiuwei Du, Hua Wang, Zhiyi Wang, Shijie Gao, Chun-Qin Zhao","doi":"10.1021/acs.molpharmaceut.4c00447","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00447","url":null,"abstract":"<p><p>Recently, the incidence of brain diseases, such as central nervous system degenerative diseases, brain tumors, and cerebrovascular diseases, has increased. However, the blood-brain barrier (BBB) limits the effective delivery of drugs to brain disease areas. Therefore, the mainstream direction of new drug development for these diseases is to engineer drugs that can better cross the BBB to exert their effects in the brain. This paper reviews the research progress and application of the main trans-BBB drug delivery strategies (receptor/transporter-mediated BBB crossing, focused ultrasound to open the BBB, adenosine agonist reversible opening of the BBB, aromatic resuscitation, transnasal administration, cell-mediated trans-BBB crossing, and viral vector system-mediated brain drug delivery). Meanwhile, the potential applications, advantages, and disadvantages of these strategies for crossing the BBB are analyzed. Finally, the future development prospects of strategies for crossing the BBB are also discussed. These strategies have potential value for treating brain diseases.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131182","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":"Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.","authors":"Mikolaj Milewski, Mikhail Murashov, Yash Kapoor, Jingtao Zhang, Wei Zhu, Maria A Cueto, Nicole Buist","doi":"10.1021/acs.molpharmaceut.4c00132","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00132","url":null,"abstract":"<p><p>Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124192","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":"Intradermal Injection of a Thermoresponsive Polymeric Dexamethasone Prodrug (ProGel-Dex) Ameliorate Dermatitis in an Imiquimod (IMQ)-Induced Psoriasis-like Mouse Model.","authors":"Haochen Jiang, Xin Fu, Gang Zhao, Xiaoqing Du, Corey Georgesen, Geoffrey M Thiele, Steven R Goldring, Dong Wang","doi":"10.1021/acs.molpharmaceut.4c00360","DOIUrl":"10.1021/acs.molpharmaceut.4c00360","url":null,"abstract":"<p><p>Psoriasis is a chronic immune-mediated inflammatory skin disease, affecting ∼ 3% of the US population. Although multiple new systemic therapies have been introduced for the treatment of psoriatic skin disease, topical and intralesional glucocorticoids (GCs) continue to be used as effective psoriasis therapies. Their clinical utility, however, has been hampered by significant adverse effects, including skin atrophy and pigmentation as well as elevated blood glucose levels and hypertension. To mitigate these limitations, we have developed a <i>N</i>-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug (ProGel-Dex) and assessed its therapeutic efficacy and safety in an imiquimod (IMQ)-induced psoriasis-like (PL) mouse model. ProGel-Dex was intradermally administered once at three dosing levels: 0.5, 1.0, and 2.0 mg/kg/day Dex equivalent at the beginning of the study. PL mice were also treated with daily topical saline or Dex, which were used as control groups. Treatment of PL mice with ProGel-Dex dosed at 0.5 mg/kg/day resulted in a significant reduction in scaling and erythema. Improvement in gross pathology scores, skin histological scores, and serum cytokine levels was also observed. Interestingly, for mice treated with ProGel-Dex at 1.0 and 2.0 mg/kg/day Dex equivalent, only improvement in skin erythema was observed. GC-associated side effects, such as elevation of serum alanine aminotransferase (ALT) and amylase levels and body weight loss, were not observed in mice treated with ProGel-Dex at 0.5 and 1.0 mg/kg/day Dex equivalent. Collectively, these results demonstrate the efficacy and improved safety of ProGel-Dex in treating psoriatic skin lesions when compared to topical Dex treatment, supporting its translational potential for clinical management of lesional skin psoriasis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118289","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":"Recent Advancement of Indocyanine Green Based Nanotheranostics for Imaging and Therapy of Coronary Atherosclerosis.","authors":"Nidhi Verma, Aseem Setia, Abhishesh Kumar Mehata, Nandini Randhave, Paresh Badgujar, Ankit Kumar Malik, Madaswamy S Muthu","doi":"10.1021/acs.molpharmaceut.4c00495","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00495","url":null,"abstract":"<p><p>Atherosclerosis is a vascular intima condition in which any part of the circulatory system is affected, including the aorta and coronary arteries. Indocyanine green (ICG), a theranostic compound approved by the FDA, has shown promise in the treatment of coronary atherosclerosis after incorporation into nanoplatforms. By integration of ICG with targeting agents such as peptides or antibodies, it is feasible to increase its concentration in damaged arteries, hence increasing atherosclerosis detection. Nanotheranostics offers cutting-edge techniques for the clinical diagnosis and therapy of atherosclerotic plaques. Combining the optical properties of ICG with those of nanocarriers enables the improved imaging of atherosclerotic plaques and targeted therapeutic interventions. Several ICG-based nanotheranostics platforms have been developed such as polymeric nanoparticles, iron oxide nanoparticles, biomimetic systems, liposomes, peptide-based systems, etc. Theranostics for atherosclerosis diagnosis use magnetic resonance imaging (MRI), computed tomography (CT), near-infrared fluorescence (NIRF) imaging, photoacoustic/ultrasound imaging, positron emission tomography (PET), and single photon emission computed tomography (SPECT) imaging techniques. In addition to imaging, there is growing interest in employing ICG to treat atherosclerosis. In this review, we provide a conceptual explanation of ICG-based nanotheranostics for the imaging and therapy of coronary atherosclerosis. Moreover, advancements in imaging modalities such as MRI, CT, PET, SPECT, and ultrasound/photoacoustic have been discussed. Furthermore, we highlight the applications of ICG for coronary atherosclerosis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118290","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 ImmunoPET Imaging Using a Zr-89-Labeled Anti-CD146 Monoclonal Antibody for Diagnosis of Melanoma.","authors":"Xiaoyi Guo, Muye Hu, Qian Zhang, Jiayue Liu, Jing Shi, Yanfang Tang, ShuHui Liu, Jun Guo, Yan Kong, Hua Zhu, Zhi Yang","doi":"10.1021/acs.molpharmaceut.4c00348","DOIUrl":"10.1021/acs.molpharmaceut.4c00348","url":null,"abstract":"<p><p>The aim of this study was to evaluate the preclinical efficacy of [⁸⁹Zr]Zr-DFO-Ab253 as a novel positron emission tomography (PET) tracer for CD146-positive malignant melanoma imaging. Considering the high expression of CD146 in malignant melanoma, this study investigated the effect of different CD146 expression levels on the tumor uptake of [⁸⁹Zr]Zr-DFO-Ab253. CD146 selectivity was investigated by using the CD146-positive human melanoma cell A375 and the CD146-negative human alveolar epithelial cell A549. The cell uptake of [⁸⁹Zr]Zr-DFO-Ab253 tracers was investigated, and receptor-binding affinities were measured by radioactive enzyme-linked immunosorbent assay. Biodistribution studies and micro-PET imaging of the radiotracers were performed on mice bearing A375 and A549 xenografts under baseline and blocking conditions. An immunohistochemical test was performed using A375 and A549 tissue sections for CD146 expression level analysis. [⁸⁹Zr]Zr-DFO-Ab253 was obtained with a high radiochemical yield (87.86 ± 4.66%) and a satisfactory radiochemical purity (>98.0%). The specificity and affinity of [⁸⁹Zr]Zr-DFO-Ab253 were confirmed in melanoma A375 cells and in vivo PET imaging of A375 tumor models. [⁸⁹Zr]Zr-DFO-IgG and A549 lung tumors were prepared as control radiotracers and negative models to verify the specificity of [⁸⁹Zr]Zr-DFO-Ab253 on CD146. [⁸⁹Zr]Zr-DFO-Ab253 has a <i>K</i>_d of 4.01 ± 0.50 nM. PET imaging and biodistribution showed a higher uptake of [⁸⁹Zr]Zr-DFO-Ab253 in A375 melanomas than that in A549 tumors (42.1 ± 4.04% vs 7.87 ± 1.30% ID/g at 120 h, <i>P</i> < 0.05). A low tumor uptake of [⁸⁹Zr]Zr-DFO-IgG was observed with uptakes of 1.91 ± 0.41 and 2.80 ± 0.14 ID%/g when blocked at 120 h. The radiation-absorbed dose was calculated to be 0.13 mSv/MBq. This study demonstrates the synthesis and preclinical evaluation of [⁸⁹Zr]Zr-DFO-Ab253 and indicates that the novel tracer has promising applications in malignant melanoma-specific PET imaging because of its high uptake and long-time retention in malignant melanoma. It also provides feasibility for the development of integrated molecular probes for diagnosis and treatment based on the CD146 target.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791328","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, Anna S Thickens, John A Kink, Eduardo Aluicio-Sarduy, Jonathan W Engle, Peiman Hematti, Reinier Hernandez","doi":"10.1021/acs.molpharmaceut.4c00298","DOIUrl":"10.1021/acs.molpharmaceut.4c00298","url":null,"abstract":"<p><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":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007857","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}