Molecular Pharmaceutics最新文献

{"title":"Engineering Multifunctional Peptide-Decorated Nanofibers for Targeted Delivery of Temozolomide across the Blood-Brain Barrier.","authors":"Rosa Bellavita, Teresa Barra, Simone Braccia, Marina Prisco, Salvatore Valiante, Assunta Lombardi, Linda Leone, Jessica Pisano, Rodolfo Esposito, Flavia Nastri, Gerardino D'Errico, Annarita Falanga, Stefania Galdiero","doi":"10.1021/acs.molpharmaceut.4c01125","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01125","url":null,"abstract":"<p><p>A nanoplatform based on self-assembling peptides was developed with the ability to effectively transport and deliver a wide range of moieties across the blood-brain barrier (BBB) for the treatment of glioblastoma. Its surface was functionalized to have a targeted release of TMZ thanks to the targeting peptide that binds to EGFRvIII, which is overexpressed on tumor cells, and gH625, which acts as an enhancer of penetration. Furthermore, the on-demand release of TMZ was achieved through matrix metalloproteinase-9 (MMP-9) cleavage. Nanofibers were characterized for their stability, critical aggregation concentration, and morphology. Next, the effect on both 2D and 3D glioblastoma/astrocytoma (U-87) and glioma (U-118) cell lines was evaluated. The Annexin V/Propidium iodide showed an increase in necrotic and apoptotic cells, and the morphological analysis allowed to discover that both U-118 and U-87 spheroids are smaller in surface, perimeter, and Feret's diameter when treated with NF-TMZ. The developed nanofiber was demonstrated to permeate the BBB <i>in vitro</i> in a 3D spheroidal biodynamic BBB model. Finally, there were no cytotoxic effects of nanofibers without the drug on spheroids, while a significant decrease in viability was observed when NF-TMZ was used. Overall, these results open new opportunities for the evaluation of the efficacy and safety of this nanoplatform in <i>in vivo</i> studies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646543","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 and Characterization of the [¹⁷⁷Lu]Lu-Labeled Anti-CDH17 Nanobody Derivative for Radioimmunotherapy in the Gastric Cancer Xenograft Model.","authors":"Chenkai Mao, Shicheng Li, Rencai Fan, Jiaqi Zhang, Xinying Fan, Zhen Shentu, Zhixiang Zhuang, Lei Gan","doi":"10.1021/acs.molpharmaceut.4c01285","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01285","url":null,"abstract":"<p><p>Cadherin 17 (CDH17) is highly expressed in digestive system cancers, and the potential of nanobodies targeting CDH17 as imaging probes and delivery vehicles for radioactive β-particles warrants exploration for their theranostic potential in CDH17-overexpressing gastric cancer (GC). In this study, we screened an anti-CDH17 nanobody library and constructed two antibodies: anti-CDH17 VHH (recombinant nanobody fused with a polyhistidine tag) and anti-CDH17 VHH-ABD (recombinant nanobody fused with an albumin-binding domain). VHH targeting CDH17 and its derivative VHH-ABD were conjugated with DOTA and labeled with radionuclide ¹⁷⁷Lu. The pharmacokinetics and theranostic efficacy of these agents were evaluated in the GC xenograft models. [¹⁷⁷Lu]Lu-VHH and [¹⁷⁷Lu]Lu-VHH-ABD exhibited high radiochemical purity (>99%, <i>n</i> = 3) and successfully delineated CDH17-positive gastric cancer tissues on SPECT/CT imaging. Compared with the rapid renal clearance of [¹⁷⁷Lu]Lu-VHH, [¹⁷⁷Lu]Lu-VHH-ABD demonstrated prolonged circulation times with increased and sustained tumor accumulation. Survival experiments in the MKN-45 tumor model revealed that two doses of [¹⁷⁷Lu]Lu-VHH-ABD effectively suppressed tumor growth, with limited systemic biotoxicity. Histological analysis using hematoxylin and eosin (H&E) staining and Ki67 immunohistochemistry confirmed structural disruption and low tumor cell proliferative activity in the tumor tissue. In preclinical studies, [¹⁷⁷Lu]Lu-anti-CDH17 VHH-ABD demonstrated substantial antitumor efficacy with manageable toxicity, offering promising clinical potential as a viable therapeutic option for CDH17-overexpressing GC.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633189","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":"Cancer Targeting Radiopeptidomimetics in Molecular Nuclear Medicine.","authors":"Drishty Satpati","doi":"10.1021/acs.molpharmaceut.4c01180","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01180","url":null,"abstract":"<p><p>Peptides are highly receptor-affine molecules exhibiting suitable pharmacokinetics. Additionally, low-cost production, simple protocols allowing easy modifications, and tolerance toward harsh reaction conditions make peptides ideal ligands for preparation of radiopharmaceuticals for cancer detection and treatment. However, natural peptides being substrates for enzymes are susceptible to proteolysis, which limits the <i>in vivo</i> lifetime and the target uptake. Therefore, the majority of peptides are not able to progress beyond preclinical research. Advancement of peptides for clinical analysis needs modification to instill improved features. Continuous increase and further expected rise in cancer cases in the next decade require development of more disease-directed and promising radiopharmaceuticals. Redesigned peptide, mimicking the original peptide with similar or improved affinity and high metabolic stability, shall have significant edge. This review outlines the design of peptidomimetics by incorporation of D-amino acids (inverso); reversal of D-amino acid sequence (retro-inverso), and reversal of L-amino acid sequence (retro). Clinically successful radiopeptidomimetics prepared using the three approaches have been elaborated to elucidate the important role of peptidomimetics in cancer management.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612840","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":"iBCS: 4. Application of the Inhalation Biopharmaceutics Classification System to the Development of Orally Inhaled Drug Products.","authors":"Ben Forbes, Per Bäckman, Antonio Cabal, Andy Clark, Carsten Ehrhardt, Jayne E Hastedt, Anthony J Hickey, Guenther Hochhaus, Wenlei Jiang, Stavros Kassinos, Philip J Kuehl, Bo Olsson, David Prime, Yoen-Ju Son, Simon Teague, Ulrika Tehler, Jennifer Wylie","doi":"10.1021/acs.molpharmaceut.4c01534","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01534","url":null,"abstract":"<p><p>This is the fourth paper in a series describing an inhalation biopharmaceutics classification system (iBCS), an initiative supported by the Product Quality Research Institute. The paper examines the application of the inhalation Biopharmaceutics Classification System (iBCS) through the drug discovery, development, and postapproval phases for orally inhaled drug products (OIDP) and for the development of generic OIDPs. We consider the implication of the iBCS class in terms of product performance and identify the practical gaps that must be filled to enable the classification system to be adopted into day-to-day practice. Consideration is given to the critical experimental data required and the methods for their generation with a focus on: (i) dose to the lungs, (ii) drug solubility in relevant media and methods to model the dissolution of respirable formulations, and (iii) pulmonary drug permeability. As described in three prior publications, the iBCS was developed to classify inhaled drugs based on physicochemical and biorelevant product attributes in a manner that will allow formulators and discovery chemists to identify and mitigate product development risks. It was not established to enable <i>in vitro</i> determination of bioequivalence between orally inhaled drug products. However, once analytical methods are in place to correctly classify inhaled drugs, the system has the potential to provide an understanding of the development risks associated with both establishing bioequivalence between two drug products and enabling postapproval changes based on product iBCS class.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612843","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":"Head-to-Head Comparison of the <i>in Vivo</i> Performance of Highly Reactive and Polar ¹⁸F-Labeled Tetrazines.","authors":"Lars Hvass, Marius Müller, Markus Staudt, Rocio García-Vázquez, Tobias K Gustavsson, Vladimir Shalgunov, Jesper T Jørgensen, Umberto M Battisti, Matthias M Herth, Andreas Kjaer","doi":"10.1021/acs.molpharmaceut.4c01129","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01129","url":null,"abstract":"<p><p>Pretargeted imaging harnessing tetrazine ligation has gained increased interest over recent years. Targeting vectors with slow pharmacokinetics may be visualized using short-lived radionuclides, such as fluorine-18 (¹⁸F) for positron emission tomography (PET), and result in improved target-to-background ratios compared to conventionally radiolabeled slowly accumulating vectors. We recently developed different radiochemical protocols enabling the direct radiofluorination of various tetrazine scaffolds, resulting in the development of various highly reactive and polar ¹⁸F-labeled tetrazines as lead candidates for pretargeted imaging. Here, we performed a direct head-to-head-comparison of our lead candidates to evaluate the most promising for future clinical translation. For that, all ¹⁸F-labeled tetrazine-scaffolds were synthesized in similar molar activity for improved comparability of their <i>in vivo</i> pretargeting performance. Intriguingly, previously reported dicarboxylic acid lead candidates with a net charge of -1 were outperformed by respective monocarboxylic acid derivatives bearing a net charge of 0, warranting further evaluation of such scaffolds prior to their clinical translation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622884","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 and Preliminary Evaluation of a ¹²⁵I-Labeled Radioligand ([¹²⁵I]iodotrazoline) for In Vitro Detection of Imidazoline-2 Binding Site in the Brain.","authors":"Donglan Huang, Yiming Guo, Mengchao Cui, Hualong Fu","doi":"10.1021/acs.molpharmaceut.4c01445","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01445","url":null,"abstract":"<p><p>Astrocytes exert multiple functions within the brain, including regulating neuroinflammation and maintaining homeostasis, and the reactive astrocytes are implicated in many neurodegenerative disorders. Imidazoline-2 binding site (I₂BS) has been established as a reliable biomarker for precisely quantifying reactive astrocytes. Here, we reported the development of [¹²⁵I]iodotrazoline ([¹²⁵I]<b>8</b>), a novel I₂BS radioligand with high affinity (<i>K</i>_i = 6.8 nM) and exceptional selectivity over α₂-adrenoceptors (>1400 folds). <i>In vitro</i> autoradiography (ARG) using rat brain sections revealed a heterogeneous distribution of [¹²⁵I]<b>8</b>, with high signals in the medulla, midbrain, pons, and hypothalamus. Pretreatment with unlabeled I₂BS-selective ligands, BU224 and FTIMD, reduced the binding by >30%, indicating high <i>in vitro</i> specificity for I₂BS. <i>Ex vivo</i> ARG results confirmed this distribution pattern in the rat brain. Biodistribution results in mice demonstrated a rapid brain uptake of [¹²⁵I]<b>8</b> (3.35% ID/g at 2 min postinjection) with slow washout. Metabolite analysis exhibited the desirable biostability of [¹²⁵I]<b>8</b> in the rat brain. Altogether, this work provides a new ¹²⁵I-labeled radioligand featuring a novel 2-trans-styryl-imidazoline scaffold, which shows significant specificity binding for I₂BS <i>in vitro</i>, serving as a valuable tool for I₂BS detection and astrocyte-related pathology research.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612841","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":"Is There Polyamorphism in Amorphous Indomethacin? Investigating the Physicochemical Properties of Amorphous Indomethacin with Different Thermal History.","authors":"Daniele Musumeci, Ji Zhou, Jiajun Xie He, Thomas Rades, Inês C B Martins","doi":"10.1021/acs.molpharmaceut.4c01276","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01276","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Polyamorphism in organic molecules is a poorly understood and controversial phenomenon related to amorphous materials. Although very few studies, including our own, have demonstrated the existence of polyamorphism in drug molecules, this solid-state phenomenon is still very elusive and the investigation of its occurrence in other drugs is fundamental to understand its formation. Indomethacin (IND) has been recently discussed in the literature as a potential drug exhibiting polyamorphism. Its amorphous forms obtained by quench-cooling (QC) at different temperatures have shown distinct dissolution and physical stability properties. However, temperature can induce degradation which can potentially influence the physicochemical properties of the drugs. Here we have investigated what role degradation products may play in the physicochemical properties of amorphous IND obtained at different QC temperatures and explored the potential formation of polyamorphism in IND. Amorphous IND obtained by QC at 165-220 °C revealed similar molecular near order, suggesting lack of structural variation between the differently prepared amorphous forms. The glass transition temperature slightly decreased when the QC temperature increased. Both the onset of crystallization and relaxation time consistently increased (being more notorious at a QC temperature of 180 °C), suggesting that the amorphous IND obtained at higher QC temperatures presents lower molecular mobility and as a consequence higher physical stability. Thermogravimetric analysis revealed that IND degradation starts to occur right after its melting temperature (i.e., 165 °C), being more evident after 180 °C. Considering that a melting point depression was observed for all amorphous IND samples, especially for the ones obtained at higher temperatures (i.e., higher than 180 °C), we hypothesized that the formation of degradation products is the cause for the observed differences in the thermal and physical stability properties of the amorphous IND obtained at different QC temperatures. Moreover, real-time dissolution experiments of amorphous IND films, QC from different temperatures, demonstrated that the dissolution performance decreased gradually, but substantially, as the preparation temperature of the samples increased. Similar experiments where amorphous IND was QC from different temperatures in the absence of oxygen and where amorphous IND was spiked with highly thermally degraded amorphous IND at 2%, 5% and 10% w/w prepared by QC from 165 °C to room temperature, unequivocally demonstrated that the degradation products formed during exposure of IND to high temperatures substantially inhibit the dissolution of amorphous IND. This study demonstrates that the differences in the physicochemical properties of differently prepared amorphous forms of drugs are not necessarily a result of polyamorphism and that special attention should be paid to the potential formation of degradation products and their inf","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612844","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":"Docetaxel-Loaded Electrospun Nanofibrous Mats for Local Chemotherapy Targeting Positive Surgical Margins in Prostate Cancer.","authors":"Xing Li, Kun Yuan, Yisheng Yin, Yiqun Tian, Zihao Guo, Zhenliang Qin, Xiaoyong Zeng","doi":"10.1021/acs.molpharmaceut.4c01440","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01440","url":null,"abstract":"<p><p>Positive surgical margins following radical prostatectomy significantly contribute to tumor recurrence. While systemic chemotherapy demonstrates limited efficacy in this context, local chemotherapy drug delivery systems based on nanomaterials offer promising strategies to address this issue by modifying drug release kinetics and distribution, thereby enhancing antitumor effects while minimizing the toxicities associated with systemic chemotherapy. In this study, we utilized electrospun nanofibrous mats loaded with docetaxel for sustained drug delivery. In vitro experiments demonstrated that these implantable drug-loaded nanofibrous mats effectively inhibited prostate cancer cell growth, induced cell cycle arrest, and promoted apoptosis. In animal models, these drug-loaded nanofibrous mats exhibited prominent therapeutic effects on positive surgical margins postoperatively. Importantly, docetaxel-loaded nanofibrous mats modulated the tumor immune microenvironment by suppressing M2-like macrophages, increasing the ratio between M1- and M2-like macrophages, and enhancing CD8+ T-cell infiltration. Local administration significantly reduced systemic toxicity compared to systemic chemotherapy. In summary, we developed an implantable electrospun drug-loaded nanofibrous mat for localized docetaxel delivery, which offers a prospective strategy for managing positive surgical margins after surgery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612842","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 a Radiogallium-Labeled Heterodivalent Imaging Probe Targeting Negative Charges and Integrin on the Surface of Cancer Cell Membranes.","authors":"Takeshi Fuchigami, Kohei Shimo, Toya Hiwatashi, Yuka Andoh, Masayuki Munekane, Kenji Mishiro, Hiroaki Echigo, Hiroshi Wakabayashi, Yoji Kitamura, Seigo Kinuya, Kazuma Ogawa","doi":"10.1021/acs.molpharmaceut.4c01263","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01263","url":null,"abstract":"<p><p>Radiopharmaceuticals targeting tumor-specific environments are powerful tools for cancer diagnosis and treatment. We previously demonstrated the considerable high tumor uptake of the cationic amphiphilic peptide, ⁶⁷Ga-NOTA-KV6, in vivo. However, because this radioligand shows a relatively rapid clearance from the tumor over time, further structural optimization is necessary. In this study, to enhance tumor accumulation and retention, we synthesized and evaluated a heterobivalent radiogallium-labeled radiotracer, [⁶⁷Ga]Ga-DOTA-KV6-Mal-c(RGDyK) ([⁶⁷Ga]<b>6a</b>), fusing the KV6 peptide targeting negatively charged sites on the cancer cell membrane and cyclic RGD peptide targeting integrin α_vβ₃ on the cancer cell membrane. Cellular uptake study revealed high accumulation of [⁶⁷Ga]<b>6a</b> in integrin α_vβ₃-expressing U-87MG cancer cells, but uptake was significantly inhibited in the presence of an excess of the cyclic RGD peptide, c(RGDyK) (<b>1</b>). Peptide <b>6a</b> exhibited integrin α_vβ₃-binding affinity comparable to those of RGD peptides <b>1</b> and DOTA-Mal-c(RGDyK) (<b>8</b>). In vivo biodistribution studies of U-87MG tumor-bearing mice revealed that [⁶⁷Ga]<b>6a</b> exhibited better accumulation and retention in tumor tissues than [⁶⁷Ga]Ga-DOTA-KV6-Mal-Et ([⁶⁷Ga]<b>6b</b>; without the RGD peptide motif) and [⁶⁷Ga]Ga-DOTA-Mal-c(RGDyK) ([⁶⁷Ga]<b>9</b>; without the KV6 peptide motif). Single-photon emission computed tomography analysis also revealed high signals of [⁶⁷Ga]<b>6a</b> in tumor tissues, which were significantly blocked in the presence of excess peptide <b>1</b>. Although reducing radiotracer accumulation in nontumor tissues, such as the kidneys, remains a challenge, our developed approach exhibits potential to enhance the selectivity and retention of radiopharmaceuticals in tumor tissues.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602939","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":"Mechanistic Investigation into the Phase Separation Behavior of Soluplus in the Presence of Biorelevant Media.","authors":"Justus Johann Lange, Malte Bøgh Senniksen, Nicole Wyttenbach, Susanne Page, Lorraine M Bateman, Patrick J O'Dwyer, Wiebke Saal, Martin Kuentz, Brendan T Griffin","doi":"10.1021/acs.molpharmaceut.4c01140","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01140","url":null,"abstract":"<p><p>More than a decade since its introduction, the polymeric excipient Soluplus continues to receive considerable attention for its application in the development of amorphous solid dispersions (ASDs) and its utility as a solubilizer for drugs exhibiting solubility limited absorption. While it is well-recognized that Soluplus forms micelles, the impact of its lower critical solution temperature of approximately 40 °C remains an underexplored aspect. This study investigated the phase behavior of Soluplus in fasted-state simulated intestinal fluid (FaSSIF-V1). It was demonstrated that Soluplus forms a dispersed polymer-rich coacervate phase, which coexists with Soluplus micelles at 37 °C. This behavior was confirmed by cloud point measurements, visually discernible phases after centrifugation, as well as multi-angle dynamic light scattering (MADLS) measurements, and quantitative ¹H-nuclear magnetic resonance (NMR) spectroscopy of Soluplus concentrations in the supernatant pre- and post-centrifugation. The practical relevance of these findings was contextualized by solvent shift experiments and dissolution testing of spray-dried ASD. The results demonstrated that the poorly water-soluble drug RO6897779 resided in a polymer-rich coacervate phase and was spun down during centrifugation, which resulted in an amorphous pellet exhibiting the characteristics of a viscous liquid. The entrapment of the drug within the polymer-rich phase was further analyzed by temperature- and time-dependent MADLS experiments. The findings of this study are of particular relevance for a mechanistic understanding, relevant to comprehending in vitro-in vivo relationships of Soluplus-based ASDs. Low sampled drug concentrations in FaSSIF-V1 at 37 °C may originate not only from limited drug release and precipitation but also from the formation of a drug-containing, polymer-rich Soluplus phase. Therefore, a liquid-liquid phase separation occurring from Soluplus-based formulations in a biorelevant medium can be excipient-driven, which is different from the common perception that phase separation in the solution state is triggered primarily by high drug concentrations exceeding their amorphous solubility.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595857","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}