Molecular Pharmaceutics最新文献

{"title":"Octa-Arginine-Conjugated Liposomal Nimodipine Incorporated in a Temperature-Responsive Gel for Nasoencephalic Delivery.","authors":"Shuai Hong, Changxiu Lin, Junsheng Hu, Jingshu Piao, Ming Guan Piao","doi":"10.1021/acs.molpharmaceut.4c00634","DOIUrl":"10.1021/acs.molpharmaceut.4c00634","url":null,"abstract":"<p><p>Nimodipine is the primary clinical drug used to treat cerebral vasospasm following subarachnoid hemorrhage. Currently, tablets have low bioavailability when taken orally, and injections contain ethanol. Therefore, we investigated a new method of nimodipine administration, namely, nasoencephalic administration. Nasal administration of nimodipine was carried out by attaching the cell-penetrating peptide octa-arginine (R8) to liposomes of nimodipine and incorporating it into a temperature-sensitive in situ gel. The prepared liposomes and gels underwent separate evaluations for in vitro characterization. In vitro release exhibited a significant slow-release effect. In vitro toad maxillary cilia model, RPMI 2650 cytotoxicity, and in vivo SD rat pathological histotoxicity experiments showed that all the dosage from the groups had no significant toxicity to toad maxillary cilia, RPMI 2650 cells, and SD rat tissues and organs, and the cilia continued to oscillate up to 694 ± 10.15 min, with the survival rate of the cells being above 85%. A transwell nasal mucosa cell model and an isolated porcine nasal mucosa model were established, and the results showed that the osmolality of the R8-modified nimodipine liposomal gel to nasal mucosal cells and isolated porcine nasal mucosa was 30.41 ± 2.14 and 65.9 ± 7.34 μg/mL, respectively, which was significantly higher than that of the NM-Solution and PEGylated nimodipine liposome gel groups. Animal fluorescence imaging studies revealed that the R8-modified nimodipine liposomal gel displayed increased brain fluorescence intensity compared to the normal liposomal gel. Pharmacokinetic results showed that after transnasal administration, the AUC_(0-∞) of the R8-modified nimodipine liposomal gel was 11.662 ± 1.97 μg·mL^-1, which was significantly higher than that of the plain nimodipine liposomal gel (5.499 ± 2.89 μg·mL^-1). Brain-targeting experiments showed that the brain-targeting efficiencies of the PEGylated nimodipine liposome gel and R8-modified PEGylated nimodipine liposome gels were 20.44 and 33.45, respectively, suggesting that R8/PEG/Lip-NM-TSG significantly increased the brain-targeting of the drug.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5217-5237"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054247","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":"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":"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":" ","pages":"5005-5014"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","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":"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":"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":" ","pages":"4764-4785"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","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":"Voices in <i>Molecular Pharmaceutics</i>: Meet Dr. Malcolm Lim, Who Advances Treatment for Brain Metastases with Targeted Radiopharmaceuticals.","authors":"Malcolm Lim","doi":"10.1021/acs.molpharmaceut.4c01026","DOIUrl":"10.1021/acs.molpharmaceut.4c01026","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"4762-4763"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337300","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":" ","pages":"4995-5004"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","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":"Kinase Drug Discovery: Impact of Open Science and Artificial Intelligence.","authors":"Filip Miljković, Jürgen Bajorath","doi":"10.1021/acs.molpharmaceut.4c00659","DOIUrl":"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":" ","pages":"4849-4859"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","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":"Unravelling Microarray Patch Performance: The Role of <i>In Vitro</i> Release Medium and Biorelevant Testing.","authors":"Maja Railic, Abina M Crean, Sonja Vucen","doi":"10.1021/acs.molpharmaceut.4c00459","DOIUrl":"10.1021/acs.molpharmaceut.4c00459","url":null,"abstract":"<p><p>The absence of established protocols for studying the <i>in vitro</i> performance of dissolvable microarray patches (MAPs) poses a significant challenge within the field. To overcome this challenge, it is essential to optimize testing methods in a way that closely mimics the skin's environment, ensuring biorelevance and enhancing the precision of assessing MAP performance. This study focuses on optimizing <i>in vitro</i> release testing (IVRT) and <i>in vitro</i> permeation testing (IVPT) methods for MAPs containing the antihistamine drugs loratadine (LOR) and chlorpheniramine maleate (CPM). Our primary objective is to investigate the impact of the composition of <i>in vitro</i> release media on the drug release rate, penetration through the skin, and permeation into the release medium. Artificial interstitial fluid is introduced as a biorelevant release medium and compared with commonly used media in IVRT and IVPT studies. Prior to these studies, we evaluated drug solubility in different release media and developed a method for LOR and CPM extraction from the skin using a design of experiment approach. Our findings highlight the effect of the <i>in vitro</i> release medium composition on both LOR and CPM release rate and their penetration through the skin. Furthermore, we identified the importance of considering the interplay between the physicochemical attributes of the drug molecules, the design of the MAP formulation, and the structural properties of the skin when designing IVRT and IVPT protocols.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5028-5040"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078503","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":"Brain Exposure to the Macrocyclic ALK Inhibitor Zotizalkib is Restricted by ABCB1, and Its Plasma Disposition is Affected by Mouse Carboxylesterase 1c.","authors":"Jamie Rijmers, Rolf W Sparidans, Manon Acda, Nancy H C Loos, Emmanouela Epeslidou, Viët Bui, Maria C Lebre, Matthijs Tibben, Jos H Beijnen, Alfred H Schinkel","doi":"10.1021/acs.molpharmaceut.4c00542","DOIUrl":"10.1021/acs.molpharmaceut.4c00542","url":null,"abstract":"<p><p>Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC). We here evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux transporters, OATP1 influx transporters and the metabolizing enzymes CES1 and CYP3A in plasma and tissue disposition of zotizalkib after oral administration in relevant mouse models. Zotizalkib was efficiently transported by hABCB1 in vitro. In vivo, a significant ∼9-fold higher brain-to-plasma ratio was observed in <i>Abcb1a/b</i>^-/- and <i>Abcb1a/b;Abcg2</i>^-/- compared to wild-type mice. No change in brain disposition was observed in <i>Abcg2</i>^-/- mice, suggesting that mAbcb1a/b markedly restricts the brain accumulation of zotizalkib. ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities. In <i>Oatp1a/b</i>^-/- mice, no marked changes in plasma exposure or tissue-to-plasma ratios were observed, indicating that zotizalkib is not a substantial <i>in vivo</i> substrate for mOatp1a/b. Zotizalkib may further be metabolized by CYP3A4 but only noticeably at low plasma concentrations. In <i>Ces1</i>^-/- mice, a 2.5-fold lower plasma exposure was seen compared to wild-type, without alterations in tissue distribution. This suggests increased plasma retention of zotizalkib by binding to the abundant mouse plasma Ces1c. Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5159-5170"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306605","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":"A Pharmaceutical Scientist's Journey: My Path to an Academic Career.","authors":"Tze Ning Hiew","doi":"10.1021/acs.molpharmaceut.4c00860","DOIUrl":"10.1021/acs.molpharmaceut.4c00860","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"4759-4761"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992192","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":"Additive Manufacturing of SmartEx QD 100 Designed Oral Three-Dimensional Printlets Containing Isoniazid for Immediate Gastric Release by Selective Laser Sintering.","authors":"Tukaram Karanwad, Sachin B Jorvekar, Santa Mandal, Roshan M Borkar, Subham Banerjee","doi":"10.1021/acs.molpharmaceut.4c00693","DOIUrl":"10.1021/acs.molpharmaceut.4c00693","url":null,"abstract":"<p><p>The selection of appropriate materials and compatibility of selected materials with drugs and formulations are limiting steps in three-dimensional printing technology. In this study, SmartEx QD 100 (SM QD 100) was introduced as a novel, coprocessed, unexplored excipient that can be used in SLS-mediated 3D printing. The current study aimed to evaluate the feasibility of fabricating SM QD 100 containing INH-embedded SLS-mediated immediate gastric release tablets. The prepared physical mixtures were subjected to the fabrication of 3D printlets by using SLS-mediated 3D printing. The fabricated 3D printlets were subjected to physicochemical characterization by using various analytical techniques. After oral administration of sintered 3D printlets to rabbits, samples were collected and pharmacokinetic parameters were analyzed using the developed LC-APCI-MS/MS method. The optimized batch was able to release 100% INH within 15 min, which confirmed the immediate gastric release. Similarly, sintered 3D printlets were stable under accelerated stability conditions for three months. Finally, the pharmacokinetic parameters revealed the rate and extent of absorption of INH from sintered 3D printlets. As evidenced by <i>in vitro</i> and <i>in vivo</i> analyses, SM QD 100 was able to sinter SLS-mediated INH-embedded stable immediate gastric release tablets. SM QD 100 is a novel material for SLS-mediated 3D printing in pharmaceutical applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5272-5284"},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078502","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}