Molecular Pharmaceutics最新文献

{"title":"Novel Radiofluorinated Nanobody PET Tracer for Preclinical Studies of TIM3 Expression.","authors":"Dongye Zheng, Yong Huang, Chengze Li, Yanye Lu, Zhaoheng Xie, Ying Liang, Qiushi Ren, Xiangxi Meng","doi":"10.1021/acs.molpharmaceut.5c00839","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00839","url":null,"abstract":"<p><p>T-cell immunoglobulin and mucin domain-3 (TIM3) is an inhibitory checkpoint glycoprotein expressed on immune cells, particularly tumor-infiltrating lymphocytes (TILs), and plays a critical role in suppressing antitumor immune responses. While dual blockade of TIM3 and programmed cell death protein 1 (PD1) has shown promising results in enhancing immune responses in advanced cancers, the lack of reliable, noninvasive methods for detecting TIM3 expression in tumors remains a major challenge. To address this, we developed and characterized a novel positron emission tomography (PET) tracer, [¹⁸F]AlF-RESCA-HVCR2N2, based on a TIM3-specific nanobody labeled via [¹⁸F]AlF radiochemistry. The tracer demonstrated high specificity and affinity for TIM3 (<i>K</i>_D = 4.644 nM) in vitro, enabling the clear visualization of TIM3-expressing lesions in tumor models through PET imaging. Dynamic imaging and kinetic analyses revealed favorable pharmacokinetics, and a preliminary correlation was observed between PET signal intensity and histologically assessed TIM3 expression in tumor tissues. These results highlight the potential of [¹⁸F]AlF-RESCA-HVCR2N2 as a sensitive and noninvasive tool for quantifying TIM3 expression in vivo, with significant implications for patient stratification, treatment monitoring, and the development of TIM3-targeted immunotherapies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005691","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 Preclinical Evaluation of Novel ^99mTc-Labeled Glucose Derivatives Containing Different Proline Analogs as Linker Moieties for Tumor Imaging.","authors":"Guangxing Yin, Junhong Feng, Qianna Wang, Yuhao Jiang, Peiwen Han, Dajie Ding, Junbo Zhang","doi":"10.1021/acs.molpharmaceut.5c01046","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01046","url":null,"abstract":"<p><p>2-[¹⁸F]Fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) is the most extensively utilized tumor imaging agent in clinical positron emission tomography (PET) applications. Nevertheless, no radiolabeled glucose derivatives for single-photon emission computed tomography (SPECT) imaging have achieved clinical usage comparable to that of [¹⁸F]FDG. Technetium-99m is a common single-photon-emitting radionuclide used in clinical practice and has potential for the development of novel radiopharmaceuticals. Proline is an advantageous linker because of its unique physicochemical profile. This study aimed to develop novel ^99mTc-labeled glucose derivatives containing different proline analogs as linker moieties for tumor imaging. Six ^99mTc-labeled glucose derivatives ([^99mTc]Tc-GL1-[^99mTc]Tc-GL6) incorporating different proline analog linkers were successfully prepared. These derivatives exhibited high hydrophilicity and good <i>in vitro</i> stability. Among them, [^99mTc]Tc-GL1 showed the highest tumor uptake (5.66 ± 0.46% ID/g) and tumor-to-nontarget ratios and was thus selected as a promising candidate radiotracer. Further mechanistic studies revealed that [^99mTc]Tc-GL1 was transported into cancer cells via glucose transporters (GLUTs). Additionally, a kit formulation for [^99mTc]Tc-GL1 was successfully developed and warrants further clinical exploration.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991060","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 Novel Peptide-Based ⁶⁸Ga-Labeled Radiotracers for Detecting ROR1 Expression in Tumors.","authors":"Shuhui Huang, Tian Tian, Mengfang Qi, Mufeng Li, Xiaoai Wu, Rui Huang","doi":"10.1021/acs.molpharmaceut.5c00917","DOIUrl":"10.1021/acs.molpharmaceut.5c00917","url":null,"abstract":"<p><p>The study aimed to develop a series of ⁶⁸Ga-labeled receptor tyrosine kinase orphan receptor 1 (ROR1)-targeted peptides and demonstrate the ability to evaluate the ROR1 expression of tumors. Three ROR1-targeted peptides (PR3, PR7, and 1036) were modified for connecting to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and then labeled with ⁶⁸Ga. The radiolabeling yields of ⁶⁸Ga-labeled ROR1-targeted peptides were assessed by high-performance liquid chromatography, and their stabilities were evaluated by thin-layer chromatography. In vitro, the specificity of ⁶⁸Ga-labeled ROR1-targeted peptides was demonstrated in NCI-H1975 and HepG2 cells. In vivo, NCI-H1975 and HepG2 tumor-bearing mice were established for micro-PET/CT imaging. All ⁶⁸Ga-labeled ROR1-targeted peptides had high radiolabeled yields and in vitro stability. The uptakes of ⁶⁸Ga-DOTA-PEG4-PR3 and ⁶⁸Ga-DOTA-PEG4-PR7 in NCI-H1975 tumor were significantly higher than those in HepG2 tumor at 15 and 30 min postinjection (all <i>P</i> < 0.05). After blocking with precursor, the NCI-H1975 tumor uptakes at 30 min of ⁶⁸Ga-DOTA-PEG4-PR3 and ⁶⁸Ga-DOTA-PEG4-PR7 at 30 min declined from 1.87 ± 0.32%ID/g to 1.02 ± 0.22%ID/g (<i>P</i> = 0.02) and from 1.53 ± 0.15%ID/g to 0.87 ± 0.24%ID/g (<i>P</i> = 0.011), respectively. However, there were no differences in the NCI-H1975 and HepG2 tumor uptakes of ⁶⁸Ga-DOTA-KGGG-1036, and it cannot be blocked by DOTA-KGGG-1036. Overall, ⁶⁸Ga-DOTA-PEG4-PR3 and ⁶⁸Ga-DOTA-PEG4-PR7 have the potential to noninvasively evaluate the expression of ROR1 and are expected to guide the therapy targeting ROR1.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936086","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":"Antitumor Activity of Alexidine Dihydrochloride Nanocarriers in Renal Cell Carcinoma.","authors":"Adan Sultan, Amani Zoabi, Anna Morshin, Ori Shalev, Philip Lazarovici, Katherine Margulis","doi":"10.1021/acs.molpharmaceut.5c00651","DOIUrl":"10.1021/acs.molpharmaceut.5c00651","url":null,"abstract":"<p><p>Renal cell carcinomas (RCC) have recently been shown to exhibit a high abundance of phosphatidylglycerols, which are products of the protein-tyrosine phosphatase mitochondrial 1 enzyme (PTPMT1) and precursors of cardiolipins. Effective treatments for RCC are still in need. This study evaluates the therapeutic effect of PTPMT1 inhibition using the poorly water-soluble inhibitor alexidine dihydrochloride, which has not previously been proposed for RCC treatment. Considering that this inhibitor is poorly water-soluble and has inconsistent antitumor activity in its pure form due to solubility limits, we incorporated it in nanocarriers composed of phosphatidylcholine and cholesterol. These solvent-free nanocarriers had an average size of 66 nm, a drug loading capacity of 21%, an encapsulation efficiency of 99%, a positive surface charge, and excellent storage stability. We assessed their safety and efficacy in two human RCC cell lines, 786O and A498, alongside the human non-neoplastic kidney cell line HEK293 as a control. Results revealed a marked antitumor activity of the nanocarriers and selectivity toward highly metabolically active RCC cells. Thus, after only 24 h of treatment, a significant decrease in the viability of 786O cells was recorded, while A498 and control cells exhibited only minimal reductions in viability. Advanced mass spectrometry imaging (DESI-MSI) revealed that untreated 786O cells had significantly higher levels of phosphatidylglycerols, cardiolipins, and 4-hydroxynonenal glutathione compared to A498 and HEK293. Treatment with nanocarriers markedly impacted the levels of these metabolites in RCC cells. In conclusion, RCC tumors with upregulated phosphatidylglycerol metabolism may be particularly sensitive to PTPMT1 inhibition by nanocarriers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936149","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, Radiolabeling, and Evaluation of a Dimeric Fibroblast Activation Protein Inhibitor with a Triazine Linker.","authors":"Xuran Zhang, Choong Mo Kang, Joon Young Choi, Yearn Seong Choe","doi":"10.1021/acs.molpharmaceut.5c00979","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00979","url":null,"abstract":"<p><p>Dimeric fibroblast activation protein inhibitor (FAPI) radioligands are promising candidates for theranostic applications because of their enhanced tumor uptake and prolonged retention compared to monomeric radioligands. Several linker strategies have been investigated to connect two FAPI motifs and a radiometal chelator in a dimer design. In this study, we report the development of a novel dimeric FAPI radioligand, [⁶⁸Ga]Ga-<b>1</b>, which utilizes a triazine core as a trifunctional linker. The ligand [^<i>nat</i>Ga/⁶⁸Ga]Ga-<b>1</b> was synthesized by chelating gallium or gallium-68 to 2-(DOTAGA-NH-ethyl-NH)-4,6-bis(Gly-FAPI)-1,3,5-triazine (<b>1</b>). [^<i>nat</i>Ga]Ga-<b>1</b>, a nonradioactive ligand, exhibited FAP-binding affinity comparable to that of FAPI-04 (IC₅₀ = 2.42 nM vs 1.57 nM). [⁶⁸Ga]Ga-<b>1</b> was synthesized in high decay-corrected radiochemical yields (91.7-94.7%) with high molar activities (40.8-50.0 GBq/μmol) and showed good stability in phosphate-buffered saline and fetal bovine serum. <i>In vitro</i> studies confirmed FAP-specific cellular uptake of [⁶⁸Ga]Ga-<b>1</b>. Positron emission tomography (PET) imaging and <i>ex vivo</i> biodistribution of [⁶⁸Ga]Ga-<b>1</b> in U87MG tumor-bearing mice demonstrated high tumor uptake and retention, which were significantly blocked by FAPI-04, confirming FAP specificity. Notably, [⁶⁸Ga]Ga-<b>1</b> demonstrated superior and more sustained tumor uptake than monomeric [⁶⁸Ga]Ga-FAPI-04, indicating improved pharmacokinetics. Altogether, the triazine linker is well suited for constructing dimeric FAPI radioligands, and [⁶⁸Ga]Ga-<b>1</b> holds potential as a FAP-targeted radioligand for theranostic applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936365","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":"Preparation and Evaluation of Upadacitinib-Loaded Binary Ethosomal Hydrogel: A Topical Delivery System with Enhanced Stratum Corneum Permeability for Improved Anti-Inflammatory Therapy in Psoriasis.","authors":"Zihao Xiong, Caiyu Song, Yingmiao Ou, Yishan Yan, Desheng Liang, Fan Liao, Yingying Zhang, Haijun Zhong, Feng Guo","doi":"10.1021/acs.molpharmaceut.5c00647","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00647","url":null,"abstract":"<p><p>Upadacitinib (UPA) is a potent antipsoriasis drug that can modulate the response of various pro-inflammatory cytokines by inhibiting the JAK-STAT pathway. The clinical application of UPA has been limited due to the systemic side effects associated with oral administration. The aim of this study was to develop upadacitinib-loaded ethanol-based carbomer hydrogel for the topical treatment of psoriasis and to improve the therapeutic efficacy against psoriasis. The ethosomes were prepared by the alcohol injection-sonication method with an average particle size of 114.42 ± 2.88 nm, an encapsulation rate of 73.75 ± 2.24%, and a drug loading capacity of 21.16 ± 0.49%. The penetration rate of binary ethosomal carbomer hydrogel was 7.04 μg/cm²·h, significantly higher than that of the cream formulation (3.12 μg/cm²·h), representing a 2.3-fold increase. Similarly, intradermal retention of the binary ethosomal carbomer hydrogel (52.19 ± 13.38 μg/cm²) was 2.9-fold greater than that of the cream (17.84 ± 9.09 μg/cm²). In vivo evaluations demonstrated that the binary ethosomal carbomer hydrogel significantly ameliorated skin phenotype and histopathologic features, while markedly suppressing pro-inflammatory cytokine levels: TNF-α decreased from 361.97 ± 17.53 to 262.11 ± 15.77 pg/mL (<i>p</i> < 0.01), IL-17 from 68.42 ± 11.59 to 49.68 ± 2.14 pg/mL (<i>p</i> < 0.05), and IL-23 from 62.64 ± 7.89 to 44.60 ± 3.08 pg/mL (<i>p</i> < 0.01) compared to the model group. In addition, upadacitinib binary ethosomal hydrogel did not show significant signs of irritation, indicating its safety for topical application. Therefore, the upadacitinib-loaded ethanol-based carbomer hydrogel developed in this study may be an effective strategy for the treatment of psoriasis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936240","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":"Characterizing ¹³C Spectral Assignments and Substituent Distributions of Hydroxypropylmethylcellulose Acetyl Succinate Using Dynamic Nuclear Polarization Nuclear Magnetic Resonance Spectroscopy.","authors":"Ronan P Cosquer, Arthur C Pinon, Mária Šoltésová, Lucy E Hawarden, Anuji Abraham, Mike Tobyn, Frédéric Blanc","doi":"10.1021/acs.molpharmaceut.5c00359","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00359","url":null,"abstract":"<p><p>Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available amorphous solid dispersions (ASDs), due to its ability to aid dissolution of poorly soluble drugs while impeding drug recrystallization. Nuclear magnetic resonance (NMR) spectroscopy is a well-suited approach to provide structural information on amorphous solids and access intermolecular interactions in multicomponent materials such as ASDs. The ¹³C spectral assignments for HPMC-AS differ in the literature, largely due to the significant structural complexity of this polymer, but are critical to identify drug-polymer interactions in ASDs containing HPMC-AS. A dynamic nuclear polarization (DNP) enhanced 2D ¹³C-¹³C refocused incredible natural abundance double quantum transfer experiment (INADEQUATE) spectrum is obtained to identify the one-bond ¹³C-¹³C connectivity in the polymer, which confirms the most recent ¹³C spectral assignments of HPMC-AS. Moreover, the spatial distribution of substituents in cellulose-based polymers is known to affect their physical properties and hence the dissolution or absorption of a formulated drug. Here, we use the definitive ¹³C spectral assignments of HPMC-AS and exploit the relayed-DNP of enhanced 1D cross-polarization (CP) spectra to determine that the HPMC-AS substituents are homogeneously distributed in three commercial grades of the polymer. Now, NMR experiments performed on ASDs containing HPMC-AS can more accurately correlate observed drug-polymer interactions to specific sites of the polymer. Therefore, a greater understanding into the mechanisms by which HPMC-AS stabilizes amorphous drugs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936111","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":"Intrapulmonary Spreading of Pharyngeally Instilled Liquids: Impact of Nanoparticle Concentration and PEG Lubrication in Polymer Lung Surfactant Solutions.","authors":"Taesuk Jun, Daniel J Fesenmeier, Sandra E Torregrosa-Allen, Xinzhe Jin, Sangyoon Kim, Hye Jin Oh, Seon Yeop Jung, Bennett D Elzey, Seyoung Kim, You-Yeon Won","doi":"10.1021/acs.molpharmaceut.5c00629","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00629","url":null,"abstract":"<p><p>The efficacy of surfactant replacement therapy (SRT) depends on the effective delivery of active ingredients─therapeutic lung surfactant (LS), specifically polymer lung surfactant (PLS) nanoparticles in this study─to their target site, the alveoli, in the lungs. This study examines how PLS concentration affects the spreading and distribution of PLS solutions in mouse lungs. A constant volumetric dose (∼80 μL, 4 mL/kg body weight) of PLS solutions at three polymer concentrations (0.6, 6.0, and 60 mg/mL in normal saline) was pharyngeally instilled into acid-injured mouse lungs, and X-ray computed tomography (CT) imaging was used for quantitative analysis. To enhance X-ray contrast, a nontoxic amount of the water-soluble contrast agent Iohexol (50 mg I/mL) was added to the PLS solution. Three-dimensional (3D) tomographic analysis revealed significant concentration-dependent differences in PLS distribution within the lungs. Mice receiving the lowest PLS concentration exhibited a notably higher increase in lung pixel intensity (gray value) compared to those at higher concentrations, indicating greater spreading of PLS into deeper lung regions. Simple calculations suggest this is likely due to lower solution viscosity at lower PLS concentrations, a factor previously overlooked in LS formulation design. Additionally, we investigated whether adding a small amount (0.1 or 1.0 mg/mL) of low-molecular-weight (1 kDa) poly(ethylene glycol) (PEG) to the PLS solution could further enhance spreading. Results showed that PEG significantly improved PLS distribution, particularly at higher PLS concentrations, likely due to interfacial lubrication induced by PEG homopolymers. This PEG-based enhancement strategy may also improve the delivery of commercial phospholipid-based LS formulations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936098","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":"Aggregate Suppression of Recombinant Human Serum Albumin (HSA) by Adenosine Triphosphate (ATP).","authors":"Nikita Vekaria, Shuyuan Tan, Eleonora Cerasoli, Peter Davis, Jason Cameron, Phil Morton, Matja Zalar, Robin A Curtis","doi":"10.1021/acs.molpharmaceut.5c00993","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00993","url":null,"abstract":"<p><p>Adenosine triphosphate (ATP), a key cellular energy metabolite, has been shown to modulate protein self-assembly processes such as amyloid formation and the behavior of biological condensates through nonspecific, proteome-wide mechanisms. Gaining mechanistic insight into these effects may enable the rational use of multivalent phosphate ions as stabilizing additives for biologics. The stabilizing properties of ATP are often attributed to its hydrotropic character, arising from its combination of a nonpolar adenosine moiety and a highly charged triphosphate group. However, this explanation has been questioned in cases where ATP behaves similarly to the simpler tripolyphosphate (TPP) ion. In this study, we compare the effects of ATP and TPP on the solution behavior of recombinant human serum albumin (HSA). A combination of ζ-potential measurements and saturation transfer difference (STD) NMR reveals that both ATP and TPP exhibit similar binding profiles, interacting with multiple sites on the protein with millimolar affinities. Thermal denaturation experiments indicate stronger binding to the unfolded state than to the native folded conformation, consistent with their equivalent effectiveness in suppressing aggregation under thermal stress. The stabilization effect arises from a dual mechanism: supercharging of the protein, which enhances colloidal stability, and attenuation of short-range attractive interactions. Notably, differences between ATP and TPP only emerge at elevated salt concentrations. These findings are interpreted in light of known interactions with intrinsically disordered protein regions, where ATP binds positively charged residues (particularly arginine) at submillimolar concentrations and interacts with aromatic residues at concentrations above 10 mM. Together, these results support a general framework in which multivalent anions such as ATP and TPP enhance the solubility of partially folded proteins, with implications for the design of next-generation excipients in biopharmaceutical formulations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936154","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":"Phase Transition and Permeability Behavior of Salicylic Acid Loaded Myristic Acid <i>In Situ</i> Gels: Insights from Molecular Dynamics and Confocal Imaging.","authors":"Napaphol Puyathorn, Poomipat Tamdee, Jitnapa Sirirak, Thawatchai Phaechamud, Sucharat Limsitthichaikoon","doi":"10.1021/acs.molpharmaceut.5c00711","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00711","url":null,"abstract":"<p><p>A solvent-exchangeable <i>in situ</i> gel (ISG) system was developed for the localized and sustained delivery of salicylic acid (SAL) using a myristic acid (MYR) based lipid matrix. Upon exposure to aqueous environments, the ISG undergoes a sol-to-gel transition, forming a semisolid matrix that enables prolonged drug retention and controlled release. Confocal laser scanning microscopy demonstrated effective permeation, while powder X-ray diffraction confirmed a reduction in crystallinity following gelation, evidenced by broad peaks around 8° 2θ indicative of amorphous or semicrystalline transformation. Molecular dynamics (MD) simulations were employed to investigate the phase behavior, structural organization, and drug release mechanisms of SAL-loaded MYR-based ISGs, particularly in the SN30M25 system. MD simulations (0-200 ns) revealed early stage solvent migration and molecular rearrangement. MYR and <i>N</i>-methyl-2-pyrrolidone (NMP) reached equilibrium rapidly (∼20 ns), while water (WAT) and SAL equilibrated more slowly (30 and 60 ns, respectively), suggesting greater molecular mobility of SAL and WAT. This was supported by diffusion coefficients, where SAL (6.2357 m²/s) and WAT (20.8941 m²/s) exhibited higher values than MYR (3.2271 m²/s) and NMP (1.5345 m²/s). Radius of gyration (<i>R</i>_g) analysis showed more extended conformations for SAL and WAT, whereas MYR and NMP exhibited compact structures, implying stronger molecular aggregation. These findings suggest that SAL disrupts MYR packing, enhances solvent diffusion, and influences the gel matrix behavior. Overall, this study provides molecular-level insights into the structural dynamics of lipid-based ISGs and supports their potential for targeted and sustained drug delivery in oral applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936190","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}