Molecular Pharmaceutics最新文献

{"title":"Synthesis and Evaluation of ⁶⁸Ga- and ¹⁷⁷Lu-Labeled [Pro¹⁴]bombesin(8-14) Derivatives for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer.","authors":"Lei Wang, Hsiou-Ting Kuo, Devon E Chapple, Chao-Cheng Chen, Sara Kurkowska, Nadine Colpo, Carlos Uribe, François Bénard, Kuo-Shyan Lin","doi":"10.1021/acs.molpharmaceut.4c00952","DOIUrl":"10.1021/acs.molpharmaceut.4c00952","url":null,"abstract":"<p><p>The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz¹⁴) residue in our previously reported GRPR-targeted tracers with Pro¹⁴. The ⁶⁸Ga and ¹⁷⁷Lu labeling were conducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5) buffer, respectively, and the radiolabeled products were obtained in a 24-57% decay-corrected radiochemical yield and >92% radiochemical purity. The binding affinities (<i>K</i>_i) of Ga-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured via <i>in vitro</i> competition binding assays and were 12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ± 0.25 nM, respectively. The PET imaging and <i>ex vivo</i> biodistribution studies were conducted in PC-3 tumor-bearing mice at 1 h post injection. [⁶⁸Ga]Ga-ProBOMB5, [⁶⁸Ga]Ga-LW02056, and [⁶⁸Ga]Ga-LW02057 enabled clear tumor visualization in PET images. The tumor uptake values of [⁶⁸Ga]Ga-ProBOMB5, [⁶⁸Ga]Ga-LW02056, and [⁶⁸Ga]Ga-LW02057 were 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g, respectively, and their average pancreas uptake values were minimal (0.60-1.37%ID/g). Longitudinal SPECT imaging and <i>ex vivo</i> biodistribution studies were also conducted for [¹⁷⁷Lu]Lu-ProBOMB5 and clinically validated [¹⁷⁷Lu]Lu-RM2. Despite comparable tumor uptake at 1 h post injection ([¹⁷⁷Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [¹⁷⁷Lu]Lu-RM2:7.73 ± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was observed for [¹⁷⁷Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed dose delivered to tumors. Our data demonstrate that [⁶⁸Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for detecting GRPR-expressing tumor lesions. However, further optimizations are needed for [¹⁷⁷Lu]Lu-ProBOMB5 to prolong tumor retention for therapeutic applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6385-6397"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491115","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":"Synergistic Chemo-Immunotherapy Using pH-Responsive Nanoparticles in Breast Cancer Treatment: In Vitro and In Vivo Studies.","authors":"Kavya Sree Maravajjala, Milan Paul, Ritika Jaiswal, Vagesh Verma, Swati Biswas, Aniruddha Roy","doi":"10.1021/acs.molpharmaceut.4c00723","DOIUrl":"10.1021/acs.molpharmaceut.4c00723","url":null,"abstract":"<p><p>Recent research underscores the pivotal role of the heterogeneous multicellular interactome within the tumor microenvironment (TME) in tumor progression and survival. Tumor-associated macrophages (TAMs), among other nonmalignant cells in the TME, promote an immunosuppressive environment, fostering tumor cell survival, proliferation, and resistance. Hence, combining chemotherapy with immunomodulatory agents to transition TAMs to an immunostimulatory phenotype holds immense therapeutic potential. The present study focuses on developing tumor-responsive nanoparticles (NPs) for combined chemo-immunotherapy using resiquimod (RSQ), a TLR 7/8 agonist as an immunomodulator, and paclitaxel (PTX) as chemotherapeutics. A pH-responsive NP known as PHNP, tailored with a star-shaped PLGA conjugated with poly histidine, was engineered to selectively deliver a consistent ratio of PTX and RSQ directly to the tumor site. In vitro studies demonstrate enhanced drug release at pH 6.4, increased penetration in tumor spheroids, and increased cytotoxic efficacy against breast cancer cells. Furthermore, PHNPs activate macrophages for antitumor activity. In vivo studies demonstrated a notable rise in plasma AUC and improved delivery of drugs to the tumor using PHNPs, resulting in enhanced effectiveness against tumor growth in a mouse orthotopic breast cancer model. Notably, PHNP treatment elevated intratumoral ROS and apoptosis levels and inhibited lung metastasis. Overall, this study underscores the potential of the PTX and RSQ combination as a prospective combined chemo-immunotherapeutic modality.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6270-6289"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542900","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":"Glatiramer Acetate Complexes CpG Oligodeoxynucleotides into Nanoparticles and Boosts Their TLR9-Driven Immunity.","authors":"Huan Gong, J Daniel Griffin, Chad E Groer, Sa Wu, Grant M Downes, Grace Markum, Moustafa M Abdelaziz, Nabil A Alhakamy, M Laird Forrest, Cory J Berkland","doi":"10.1021/acs.molpharmaceut.4c00841","DOIUrl":"10.1021/acs.molpharmaceut.4c00841","url":null,"abstract":"<p><p>Unmethylated cytosine-guanine oligodeoxynucleotides (CpG ODNs) have a storied history as agonists for Toll-like receptor 9 (TLR9). CpG ODNs have shown promising antitumor effects in preclinical studies by inducing potent proinflammatory immune responses. However, clinical success has been hindered by inconsistent efficacy and immune-related toxicities caused by systemic exposure to CpG ODNs. We previously identified that glatiramer acetate (GA), an FDA-approved, lysine-rich polypeptide, could complex class B CpG into cationic nanoparticles which persist at the intratumoral injection site while mitigating the induction of systemic proinflammatory cytokines in mouse tumor models. To extend GA applications across subtypes of CpG ODN (class A, B, and C), we evaluated physiochemical properties and identified the immunological signaling of GA and its complexes with different classes of CpG ODNs. We compared the physiochemical characteristics of three types of GA-CpG nanoparticles, followed by assessments of cell uptake efficiency and endolysosomal trafficking. We then performed successive in vitro and in vivo assays to evaluate immunological discrepancies. Complexation with GA preserved the immunological activity of CpG ODN subtypes while encapsulating them into cationic spherical nanoparticles. GA improved the cellular uptake of CpG ODNs, generally increased retention in early endosomes, and amplified immunological responses. A subsequent in vivo experiment confirmed the achievement of potent tumor suppression while mitigating systemic immune-related toxicities. Together, these data help elucidate the noncanonical role of GA to serve as a nucleic acid delivery scaffold that can improve the efficacy and safety of CpG adjuvant for clinical cancer immunotherapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6323-6338"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556645","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 Application and Pharmaceutical Development of Etomidate: Challenges and Strategies.","authors":"Hao Zhang, Ailing Wu, Xichen Nan, Luhan Yang, Dan Zhang, Zhuo Zhang, Hao Liu","doi":"10.1021/acs.molpharmaceut.4c00325","DOIUrl":"10.1021/acs.molpharmaceut.4c00325","url":null,"abstract":"<p><p>Etomidate is a synthetic imidazole anesthetic that exerts hypnotic effects by potentiating the action of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) or directly activating the anionic GABA (GABA_A) receptor. It stands out among many anesthetics because of its multiple advantages, such as good hemodynamic stability and minimal inhibition of spontaneous respiration. However, its low water solubility and side effects, such as adrenal cortex inhibition and myoclonus, have limited the clinical application of this drug. To address these issues, extensive research has been conducted on the drug delivery of etomidate in recent decades, which has led to the emergence of different etomidate preparations. Despite so many etomidate preparations, so far some of the toxic side effects have not yet been effectively addressed. Herein we discuss the pharmaceutical design of etomidate that may resolve the above problem. We also propose targeted strategies for future research on etomidate preparations and discuss the feasibility of different administration routes and dosage forms to expand the application of this drug. Through this review, we hope to draw more attention to the potential of etomidate and its application challenges and provide valuable insights into the development of new etomidate preparations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5989-6006"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566412","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 Professor Joyann Marks, Who Develops Drug Delivery and Packaging Systems Using Sustainable Materials.","authors":"Joyann A Marks","doi":"10.1021/acs.molpharmaceut.4c01260","DOIUrl":"10.1021/acs.molpharmaceut.4c01260","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5907-5908"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589548","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":"Understanding the Impact of Lipids on the Solubilizing Capacity of Human Intestinal Fluids.","authors":"Brecht Goovaerts, Joachim Brouwers, Zahari Vinarov, Marlies Braeckmans, Anura S Indulkar, Alvaro Lopez Marmol, Thomas B Borchardt, Jan Tack, Mirko Koziolek, Patrick Augustijns","doi":"10.1021/acs.molpharmaceut.4c00944","DOIUrl":"10.1021/acs.molpharmaceut.4c00944","url":null,"abstract":"<p><p>Lipids in human intestinal fluids (HIF) form various structures, resulting in phase separation in the form of a lipid fraction and a micellar aqueous fraction. Currently used fed state simulated intestinal fluids (SIF) lack phase separation, highlighting the need for a deeper understanding of the effect of these fractions on intestinal drug solubilization in HIF to improve simulation accuracy. In this study, duodenal fluids aspirated from 21 healthy volunteers in fasted, early fed, and late fed states were used to generate 7 HIF pools for each prandial state. The apparent solubility of seven lipophilic model drugs was measured across these HIF pools, differentiating between the micellar fraction and the total sample (including both micellar and lipid fractions). The solubilizing capacities of these fluids were analyzed in relation to their composition, including total lipids, bile salts, phospholipids, total cholesterol, pH, and total protein. The solubility data generated in this work demonstrated that current fed state SIF effectively predicted the average solubility in the micellar fraction of HIF but failed to discern the considerable variability between HIF pools. Furthermore, the inclusion of a lipid fraction significantly enhanced the solubility of fed state HIF pools, resulting on average in a 13.9-fold increase in solubilizing capacity across the seven model compounds. Although the average composition of the fluids was consistent with previous studies, substantial variability was observed in micellar lipid concentrations, despite relatively stable total lipid concentrations. This variability is critical, as evidenced by the strong correlations between the solubilizing capacity of the micellar fraction and its micellar lipid concentrations. Additionally, this study identified that fluctuations in bile salt concentrations and pH contributed to the observed variability in micellar lipid concentration. In summary, the influence of the lipid fraction on solubility was 2-fold: it enhanced the solubility of lipophilic drugs in the total fluid, and contributed to the variability in the solubilizing capacity of the micellar fraction.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6398-6410"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666482","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":"Oral Administration of Bioactive Nanoparticulates for Inflammatory Bowel Disease Therapy by Mitigating Oxidative Stress and Restoring Intestinal Microbiota Homeostasis.","authors":"Hong Wu, Chengxin Shi, Qixin Li, Lizhao Wang, Ruochen Wang, Fangman Chen, Ruizhe Li, Xiaolong Guo, Yinnan Chen, Junjun She","doi":"10.1021/acs.molpharmaceut.4c00499","DOIUrl":"10.1021/acs.molpharmaceut.4c00499","url":null,"abstract":"<p><p>The management of inflammatory bowel disease (IBD) continues to pose significant challenges due to the absence of curative therapies and a high rate of recurrence. Therefore, it is imperative to explore novel approaches to enhance the efficacy of IBD therapy. Herein, a bioactive nanoparticulate s is tailored designed to achieve a \"Pull-Push\" approach for efficient and safe IBD treatment by integrating reactive oxygen species (ROS) scavenging (Pull) with anti-inflammatory agent delivery (Push) in the inflammatory microenvironment. The multifunctional nanomedicine, designated MON-PAMAM@SASP, is developed through the encapsulation of sulfasalazine (SASP), a widely utilized clinical drug for the treatment of IBD, within cationic diselenide-bridged mesoporous organosilica nanoparticles (MONs) that possess significant antioxidant properties. Herein, poly(amidoamine) (PAMAM) endows the original MONs with positive charge characteristics. The MON-PAMAM@SASP not only displays the remarkable capability of neutralizing ROS to ameliorates intestinal damage, but also achieves controllable release of SASP to mitigate intestinal inflammation. Consequently, this nanomedicine effectively mitigates IBD by colitis in mouse models, and our current research has not identified any significant drug toxicity. Beyond regulating inflammatory microenvironment in intestine, treatment with MON-PAMAM@SASP results in increased richness and restores intestinal microbiota homeostasis, thereby mitigating IBD to a certain extent. Together, our work provides a highly versatile \"Pull-Push\" approach for IBD management and encourages the development of similar nanomedicine to treating multiple inflammatory diseases of gastrointestinal tract.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6193-6205"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491113","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":"Correction to \"Understanding the Roles of Excipients in Moisture Management in Solid Dosage Forms\".","authors":"Natalia Veronica, Paul W S Heng, Celine V Liew","doi":"10.1021/acs.molpharmaceut.4c01201","DOIUrl":"10.1021/acs.molpharmaceut.4c01201","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6491"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563541","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":"Pathophysiology-Driven Approaches for Overcoming Nanomedicine Resistance in Pancreatic Cancer.","authors":"Sreejith Thrivikraman Nair, C Abhi, Kaladhar Kamalasanan, K Pavithran, Ashok R Unni, M S Sithara, Manjit Sarma, T S Mangalanandan","doi":"10.1021/acs.molpharmaceut.4c00801","DOIUrl":"10.1021/acs.molpharmaceut.4c00801","url":null,"abstract":"<p><p>Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5960-5988"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674434","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":"From Preformulative Design to <i>In Vivo</i> Tests: A Complex Path of Requisites and Studies for Nanoparticle Ocular Application. Part 1: Design, Characterization, and Preliminary <i>In Vitro</i> Studies.","authors":"Cinzia Cimino, Elide Zingale, Angela Bonaccorso, Teresa Musumeci, Claudia Carbone, Rosario Pignatello","doi":"10.1021/acs.molpharmaceut.4c00554","DOIUrl":"10.1021/acs.molpharmaceut.4c00554","url":null,"abstract":"<p><p>Ocular pathologies are widely diffused worldwide, and their effective treatment, combined with a high patient compliance, is sometimes challenging to achieve due to the barriers of the eye; in this context, the use of nanoparticles for topical ophthalmic application could represent a successful strategy. Aiming to develop nanoplatforms with potential clinical applications, great attention has to be paid to their features, in relation to the route of administration and to the pharmacopoeial requirements. This review (part 1) thus embraces the preliminary steps of nanoparticle development and characterization. At the beginning, the main barriers of the eye and the different administration routes are resumed, followed by a general description of the advantages of the employment of nanoparticles for ocular topical administration. Subsequently, the preformulative steps are discussed, deepening the choice of raw materials and determining the quantitative composition. Then, a detailed report of the physicochemical and technological characterization of nanoparticles is presented, analyzing the most relevant tests that should be performed on nanoparticles to verify their properties and the requisites (both mandatory and suggested) demanded by regulatory agencies. In conclusion, some preliminary noncellular <i>in vitro</i> evaluation methods are described. Studies from <i>in vitro</i> cellular assays to <i>in vivo</i> tests will be discussed in a separate (part 2) review paper. Hence, this overview aims to offer a comprehensive tool to guide researchers in the choice of the most relevant studies to develop a nanoplatform for ophthalmic drug administration.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6034-6061"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491109","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}