Molecular Pharmaceutics最新文献

{"title":"Development and Preclinical Evaluation of ¹⁸F-Labeled PEGylated Sansalvamide A Decapeptide for Noninvasive Evaluation of Hsp90 Status in Pancreas Cancer.","authors":"Xiaohui Wang, Zhijian Han, Jun Zhang, Ming Chen, Wenbo Meng","doi":"10.1021/acs.molpharmaceut.4c00643","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00643","url":null,"abstract":"<p><p>Heat shock protein 90 (Hsp90) is a promising target for cancer therapy and imaging. Accurate detection of Hsp90 levels in tumors via noninvasive PET imaging might be beneficial for management. To achieve this, the precursor compound Dimer-Sansalvamide A (Dimer-San A) was PEGylated and modified by conjugating it with the bifunctional chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The ¹⁸F-labeled PEGylated Dimer-SanA decapeptide (¹⁸F-PEGylated San A) was completed within 30 min using a two-step process. <i>In vitro</i> stability and specificity were assessed, including competition studies with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). MicroPET imaging was performed on PL45 tumor-bearing mice to evaluate probe accumulation and tumor-to-muscle ratios. Biodistribution studies determined the route of excretion. The probe resulted in a radiochemical yield of 23.11% with a purity exceeding 95%. <i>In vitro</i>, ¹⁸F-PEGylated San A exhibited high stability and selectively accumulated in Hsp90-positive PL45 cells, with binding effectively blocked by the Hsp90 inhibitor 17AAG, confirming its specificity. MicroPET imaging of PL45 tumor-bearing mice showed significant probe accumulation in tumor tissues at 1 and 2 h postinjection (4.06 ± 0.30 and 3.72 ± 0.61%ID/g, respectively), with optimal tumor-to-muscle ratios observed at 2 h postinjection (6.09 ± 1.92). While ¹⁸F-PEGylated San A demonstrates enhanced water solubility, as indicated by increased kidney uptake relative to liver accumulation. The study successfully incorporated PEG units to create the novel probe ¹⁸F-PEGylated San A targeting to Hsp90 without affecting its targeting capability, aimed at improving the pharmacokinetics and PET imaging of Hsp90 expression noninvasively.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306606","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":"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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-23","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":"Advancing the Harmonization of Biopredictive Methodologies through the Product Quality Research Institute (PQRI) Consortium: Biopredictive Dissolution of Dipyridamole Tablets.","authors":"Yasuhiro Tsume, Lee Ashworth, Marival Bermejo Sanz, Vincent Cicale, Jennifer Dressman, Masahiro Fushimi, Isabel Gonzalez-Alvarez, Pin-Syuan Haung, Corinne Jankovsky, Xiaohong Liu, Xujin Lu, Kazuki Matsui, Sanjaykumar Patel, Alejandro Ruiz-Picazo, Changquan Calvin Sun, Naveen Thakral, Laurin Zöller","doi":"10.1021/acs.molpharmaceut.4c00878","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00878","url":null,"abstract":"<p><p>Biorelevant dissolution and its concept have been widely accepted and further developed to meaningfully predict the bioperformance of oral drug products. Biorelevant methodologies have been applied to design and optimize oral formulations, to facilitate formulation bridging, and to predict the outcome of bioperformance by coupling the results with modeling. Yet, those methodologies have often been independently customized to align with specific aspects of the oral drug products being developed. Therefore, the evolution of biorelevant dissolution methodologies has taken slightly diverse pathways rather than being standardized like compendial quality control (QC) methodologies. This manuscript presents an effort through the Product Quality Research Institute (PQRI, https://pqri.org) consortium entitled: the standardization of \"<i>in vivo</i> predictive dissolution methodologies and <i>in silico</i> bioequivalent study working group\" to find the key parameters for biorelevant dissolution, to identify the best practices, and to move toward standardization of biorelevant dissolution methodologies. This working group is composed of members from 10 pharmaceutical companies and academic institutes. The consortium project will be accomplished in five phases, whereby the first two phases have already been completed and published. In this paper, the next two phases are addressed by reporting the biorelevant dissolution profiles of dipyridamole, a weak base model drug, then incorporating the dissolution results into physiologically based biopharmaceutics modeling (PBBM) to determine whether they would lead to bioequivalence (BE) or non-BE.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277345","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 Evaluation of a Radiolabeled Pan-RAF Inhibitor for RAF-Specific PET/CT Imaging","authors":"Wenhui Zhang, Shi Gao, Leqiang Wang, Xiaoguang Ge, Xiaonan Wu, Junzhi Liu, Jingbin Lu","doi":"10.1021/acs.molpharmaceut.4c00649","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00649","url":null,"abstract":"Abnormalities in the RAS–RAF signaling pathway occur in many solid tumors, leading to aberrant tumor proliferation, invasion, and metastasis. Due to the elusive pharmacology of RAS, RAF inhibitors have become the main targeted therapeutic drugs. Naporafenib (LXH-254) is a high-affinity pan-RAF inhibitor with FDA Fast Track Qualification. We sought to develop an ¹⁸F-labeled molecular probe from LXH-254 for PET imaging of tumors overexpressing RAF to noninvasively screen patients for susceptibility to targeted RAF therapy. To reduce the lipid solubility, LXH-254 was designed with triethylene glycol di(<i>p</i>-toluenesulfonate) (TsO-PEG₃-OTs) to obtain the precursor (LXH-254-OTs) and a nucleophilic substitution reaction with ¹⁸F to obtain the tracer ([¹⁸F]F-LXH-254). [¹⁸F]F-LXH-254 exhibited good molar activity (7.16 ± 0.81 GBq/μmol), radiochemical purity (&gt;95%), and stability. Micro-PET imaging revealed distinct radioactivity accumulation of [¹⁸F]F-LXH-254 in tumors in the imaging groups, whereas in the blocked group, the tumor radioactivity level was consistent with the background tissue, illustrating the affinity and specificity of [¹⁸F]F-LXH-254 in targeting RAF. Overall, [¹⁸F]F-LXH-254 is a promising radiotracer for screening and diagnosing patients with RAF-related disease and monitoring their treatment. This is the first attempt at using an ¹⁸F-labeled RAF-specific radiotracer.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249969","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":"Tumor-Targeted CO Nanodelivery System Design and Therapy for Hepatocellular Carcinoma","authors":"Congyi Zhang, Shizhuan Huang, Kunhao Ding, Haotian Wu, Minghui Li, Tianwei Li, Zibo Shen, Sheng Tai, Wenhua Li","doi":"10.1021/acs.molpharmaceut.4c00437","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00437","url":null,"abstract":"In recent years, carbon monoxide (CO) has garnered increased attention as a novel green therapy for hepatocellular carcinoma (HCC) treatment. However, the CO donor is still limited in clinical application due to its lack of targeted ability and unstable release rate. Here, self-assembled amphiphilic nanomicelles glucose-polyethylene glycol (PEG)–lipoic acid (LA)–Fe₂(CO)₆ (Glu-Fe₂(CO)₆) are first designed as a CO donor and synthesized via a chemical method, combining glucose with Fe₂(CO)₆ through PEG–LA. Some advantages of this tumor-targeted Glu-Fe₂(CO)₆ delivery system include (I) good water-solubility, (II) the glutathione responsive CO slow release, (III) the active tumor-targeted ability of glucose as targeted ligands, and (IV) outstanding efficacy of antitumor and safety of CO therapy of HCC both in vitro and in vivo. These findings suggest that Glu-Fe₂(CO)₆ nanomicelles hold promise for enhancing antitumor therapeutic capabilities, presenting a novel tumor-targeted delivery strategy in gas therapy for HCC treatment.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249946","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":"Lipid-Conjugated Reduced Haloperidol in Association with Glucose-Based Nanospheres: A Strategy for Glioma Treatment","authors":"Aasia Ansari, Tithi Bhattacharyya, Pritam Das, Yogesh Chandra, Tapas K. Kundu, Rajkumar Banerjee","doi":"10.1021/acs.molpharmaceut.4c00468","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00468","url":null,"abstract":"Aggressive glioma exhibits a poor survival rate. Increased tumor aggression is linked to both tumor cells and tumor-associated macrophages (TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively, for effective treatment, it is important to target both glioma cells and TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma receptor (SR), which is expressed in higher levels in both the cell types. Herein, we present the development of a novel cationic lipid-conjugated reduced haloperidol (±RHPC8), which aims to mediate the SR-targeted antiglioma effect. Hypothetically, ±RHPC8 would act simultaneously as an SR-targeting ligand and anticancer agent. As the blood–brain barrier (BBB) obstructs direct targeting of in situ glioma, we used BBB-crossing glucose-based carbon nanospheres (CSPs) to deliver ±RHPC8 within the glioma tumor-bearing mouse brain. The resultant ±RHPC8-CSP nanoconjugate targeted SR-expressing glioma cells. In both orthotopic and subcutaneous mouse tumor models, ±RHPC8-CSP prolonged survival and regressed tumors compared to other treated groups. Notably, ±RHPC8-CSP was significantly taken up by SR-expressing TAMs thus resulting in macrophage polarization from M2 to M1, as exhibited by markedly reduced expression of immunosuppressive cytokines released by TAMs, including TGF-β, IL-10, and VEGF. In conclusion, the designed ±RHPC8-CSP nanoconjugate presented an effective nanodrug delivery system for brain cancer treatment.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249968","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":"Prospective Study Comparing [99mTc]Tc-DP-FAPI Quantitative SPECT/CT with [68Ga]Ga-FAPI-04 PET/CT in Patients with Gastrointestinal Tumors","authors":"Cheng Zhou, Guoquan Li, Zhiyong Quan, Zongke Deng, Guiyu Li, Mingru Zhang, Fei Kang, Weidong Yang, Jing Wang","doi":"10.1021/acs.molpharmaceut.4c00783","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00783","url":null,"abstract":"Over the past decade, [⁶⁸Ga]Ga-FAPI-04 positron emission tomography (PET)/CT imaging has been widely used for the treatment of various tumors. However, the application of ^99mTC-labeled fibroblast activation protein inhibitors in tumors has been less studied. Our team previously demonstrated the safe biological distribution of [^99mTc]Tc-DP-FAPI in the human body. Based on this, this study reports the accuracy of [^99mTc]Tc-DP-FAPI in the imaging diagnosis of gastrointestinal tumors and compares it with that of [⁶⁸Ga]Ga-FAPI-04 to evaluate the differences. A total of 24 patients with clinically diagnosed gastrointestinal tumors were prospectively included. All patients received [^99mTc]Tc-DP-FAPI quantitative SPECT/CT imaging on the first day and [⁶⁸Ga]Ga-FAPI-04 PET/CT imaging on the second day. And the effectiveness of the two imaging probes in detecting suspicious lesions was analyzed and compared. The primary tumors of all 24 patients were well detected by two imaging probes, and the sensitivity of [^99mTc]Tc-DP-FAPI and [⁶⁸Ga]Ga-FAPI-04 to the primary lesions was 100%. [^99mTc]Tc-DP-FAPI examined 21 lymph nodes with a sensitivity and specificity of 32.8% and 10.9%, and [⁶⁸Ga]Ga-FAPI-04 detected 57 lymph nodes with a sensitivity and specificity of 89.1% and 67.2%, respectively. Three distant metastases were detected by [^99mTc]Tc-DP-FAPI and nine metastases by [⁶⁸Ga]Ga-FAPI-04. The study showed that [^99mTc]Tc-DP-FAPI is highly sensitive to detecting primary lesions of gastrointestinal tumors. Compared with [⁶⁸Ga]Ga-FAPI-04, [^99mTc]Tc-DP-FAPI has the same sensitivity in detecting primary tumors but has certain limitations in detecting metastases. [^99mTc]Tc-DP-FAPI is of great value for preliminary screening of tumor lesions and early diagnosis of disease in patients who are suspected of having gastrointestinal tumors.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249970","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 Evaluation of 99mTc-Labeled DPro-Gly-Containing Tracers Targeting PSMA","authors":"Zuojie Li, Yuhao Jiang, Qing Ruan, Guangxing Yin, Peiwen Han, Xiaojiang Duan, Junbo Zhang","doi":"10.1021/acs.molpharmaceut.4c00799","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00799","url":null,"abstract":"The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many ^99mTc-labeled PSMA-targeted tracers have been developed. However, the high renal uptake of these ^99mTc-labeled tracers is a common problem that limits their clinical application. In this work, the ligand (EUKPG) using _DPro-Gly as the linker was synthesized and three ^99mTc-labeled complexes ([^99mTc]Tc-EUKPG-EDDA, [^99mTc]Tc-EUKPG-TPPTS, [^99mTc]Tc-EUKPG-TPPMS) with different coligands were prepared and evaluated. Among them, [^99mTc]Tc-EUKPG-EDDA showed the most favorable pharmacokinetic properties, with significantly reduced uptake in the kidney (14.04 ± 0.23% ID/g), rapid clearance and low uptake in nontarget organs, thus making it to exhibit high tumor-to-background ratios (tumor/blood: 7.47, tumor/muscle: 12.65). Affinity studies have shown that it has high specificity for PSMA both <i>in vivo</i> and <i>in vitro</i>. Therefore, [^99mTc]Tc-EUKPG-EDDA has great potential as a promising molecular tracer to target PSMA for tumor imaging.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249971","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":"Amorphous Solid Dispersion Formation for Enhanced Release Performance of Racemic and Enantiopure Praziquantel","authors":"Hector Polyzois, Hanh Thuy Nguyen, Benedito Roberto de Alvarenga Junior, Lynne S. Taylor","doi":"10.1021/acs.molpharmaceut.4c00711","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00711","url":null,"abstract":"Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound (<i>RS</i>-PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the <i>S</i>-enantiomer. While many approaches have been explored for improving PZQ’s dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using <i>RS</i>-PZQ and <i>R</i>-PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for <i>RS</i>-PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of <i>RS</i>-PZQ and <i>R</i>-PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of <i>RS</i>-PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE <i>R</i>-PZQ ASDs with HPMCAS-MF released the drug as effectively as <i>RS</i>-PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the <i>R</i>-enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268394","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":"The Pharmacokinetics and Liver-Targeting Evaluation of Silybin Liposomes Mediated by the NTCP/OCTN2 Dual Receptors","authors":"Jian Cui, Zhiwei Wen, Huajie Huang, Shuilin Qin, Yanjie Luo, Wei Zhang, Wei Wu","doi":"10.1021/acs.molpharmaceut.3c01245","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.3c01245","url":null,"abstract":"The disadvantage of a traditional dosage regimen is the inability to deliver a sufficient drug concentration to the lesion site, which can result in adverse side effects due to nonspecific drug delivery. Actively targeting hepatic cells is a promising therapeutic strategy for liver disease. In this study, <span>l</span>-carnitine and a targeting peptide derived from the hepatitis B virus large envelope protein were used to modify liposomes for drug delivery to the liver through the sodium taurocholate cotransporting polypeptide (NTCP) and the organic cation/carnitine transporter 2 (OCTN2) receptors. Silybin was selected as the model drug. The solubility of silybin can reach 0.3 mg/mL after encapsulation in liposomes. The NTCP-specific and OCTN2-accelerated Myrcludex B and <span>l</span>-carnitine dual-modified liposomes were validated <i>in vitro</i>. The uptake of coumarin-6 in dual ligand-modified liposomes by hepatocytes was up to 2.36 μg/mg compared with unmodified liposomes (1.05 μg/mg). The pharmacokinetics and targeting abilities of various liposome formulations were evaluated in Kunming mice. Targeted liposomes increased the concentration of silybin and prolonged the drug’s retention time in the liver. The area under the liver’s pharmacokinetic curve of targeted liposomes was twice that of silybin injection, suggesting the promising application potential of silybin-loaded hepatotropic nanovesicles.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249973","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}