Molecular Pharmaceutics最新文献

{"title":"Developing Multi-Component Solid Formulation Strategies for PROTAC Dissolution Enhancement.","authors":"Martin A Screen, Sean Askin, James F McCabe, Esther Jacobs, Akosua Anane-Adjei, Clare S Mahon, Mark R Wilson, Jonathan W Steed","doi":"10.1021/acs.molpharmaceut.5c01107","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01107","url":null,"abstract":"<p><p>PROTACs are an emerging class of beyond-rule-of-5 molecular drugs currently under clinical investigation for the treatment of malignant diseases and are capable of degrading previously \"undruggable\" protein targets. They are poorly crystallizable due to their structure, consisting of two ligands joined chemically by a flexible linker, yet the inherent insolubility of their amorphous phases hinders their development into sufficiently bioavailable medicines. Formulation approaches to improve the dissolution properties of PROTACs are required as a result, but research in this area is made even more challenging by the scarcity of available samples. In this work, amorphous solid dispersion (ASD) formulations of four cereblon-recruiting PROTACs 'AZ1-4' using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a polymer excipient are described. ASDs of AZ1 show up to a 2-fold increase in drug supersaturation compared to the pure amorphous API, observed up to a drug loading of 20% w/w. Preparing the ASDs by slurry conversion offers greater solubility enhancement over those prepared by solvent evaporation and maintains the dissolution advantage up to a higher drug load. Positive deviations from theoretical <i>T</i>_g values coupled with a lack of spectral evidence of drug-polymer hydrogen-bond interactions suggest that the ASDs may differ from ideal mixtures via predominantly dispersive drug-polymer interactions. ASDs that provide a dissolution enhancement were stored at elevated temperature and humidity for one month and showed no sign of plasticization or loss of physical stability. Coamorphous formulations using low-molecular-weight excipients, by contrast, showed no dissolution advantage despite evidence of drug-coformer hydrogen-bonding interactions. This work demonstrates that ASDs may be an effective strategy for improving PROTAC bioavailability and producing commercializable solid forms for oral administration despite the lack of well-behaved solid phases of PROTACs. It also highlights the need for a deeper understanding of how to develop successful formulation approaches for bRo5 compounds.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205148","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":"Enhancing Sonodynamic Therapy for Cervical Cancer Using Ultrasound-Activated BTO@PEG.","authors":"Chengqing Liu, Lu Ding, Shangke Chen, Lu Liu, Xiang Zeng, Qi Yan, Jiabo Wang, Nazila Saitiniaz, Nan Yang, Xiaoya Xu, Yuming Mu, Zhen Chen, Rong Li","doi":"10.1021/acs.molpharmaceut.5c00765","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00765","url":null,"abstract":"<p><p>Patients with advanced cervical cancer have a poor prognosis, and sonodynamic therapy (SDT) is expected to offer a new approach for improving the therapeutic outcome of cervical cancer due to its noninvasiveness and ability to penetrate deeply into tissues. In order to overcome the problems of the rapid elimination and low water solubility of organic acoustic sensitizers in SDT, DSPE-PEG₂₀₀₀-coated tetragonal-phase barium titanate nanoparticles (BTO@PEG) were employed in this study to replace the conventional nanoacoustic sensitizers. It was found that BTO@PEG could continuously generate ROS through SDT and the piezoelectric effect under ultrasound (US) stimulation, which subsequently promoted the apoptosis of cervical cancer cells and inhibited the growth of subcutaneously transplanted HeLa-derived cervical cancer tumors in nude mice. BTO@PEG showed good biocompatibility, as confirmed by cytology and animal experiments.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197379","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":"Salicylic Acid and Its Boron Complexes as Quorum Sensing Molecules.","authors":"Valery M Dembitsky, Alexander O Terent'ev, Leonid A Stolbov, Pavel V Pogodin, Dmitry A Filimonov, Vladimir V Poroikov","doi":"10.1021/acs.molpharmaceut.5c00848","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00848","url":null,"abstract":"<p><p>This perspective provides a comprehensive review of salicylic acid (SA) and its boron complexes, emphasizing their biological significance. Research suggests that SA forms boron complexes with water-soluble compounds, including sugars, glycerol, and organic acids, aiding in its systemic transport in plants via xylem and phloem saps. Moreover, SA possesses antibacterial properties, while its boron complexes display quorum sensing inhibition and antibiofilm activity. Through an in silico study using the self-consistent extreme classifier (SCEC), we analyzed the effects of these compounds on quorum sensing and biofilm formation. Our findings indicate that combining salicylic and boric acid derivatives may enhance their potential as quorum sensing modulators. Interestingly, certain compounds exhibited both inhibitory and activating effects, corroborating prior experimental observations on SA's dual role in biofilm regulation. Crucially, boron complexes enhance the biological activities of both salicylic acid and its conjugates with organic acids (e.g., malic, citric acids, or sugars). These complexes inhibit bacterial quorum sensing, blocking important signaling pathways in bacteria. This approach offers a new way to control bacterial pathogens without directly killing them. This could reduce the selective pressure for antibiotic resistance as these complexes enhance the antibacterial activity of SA.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197370","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":"Intravitreal Sustained Release of Dexamethasone from a Self-Healing Injectable Hydrogel: An In Vivo Safety and Release Study.","authors":"Ada Annala, Amir Sadeghi, Elisa Toropainen, Annika Valtari, Jooseppi Puranen, Jussi J Paterno, Lea Pirskanen, Kati-Sisko Vellonen, Wim E Hennink, Marika Ruponen, Tina Vermonden, Arto Urtti","doi":"10.1021/acs.molpharmaceut.5c00872","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00872","url":null,"abstract":"<p><p>Corticosteroids, such as dexamethasone, are clinically used in intravitreal injections for the treatment of inflammatory and age-related ocular diseases; however, frequent injections can cause complications. To prolong the retention of dexamethasone in the eye after intravitreal administration, sustained-release drug delivery systems have previously been investigated. The aim of this study was to evaluate the in vivo release of dexamethasone from a self-healing thermosensitive hydrogel consisting of a thermosensitive ABA triblock copolymer and to investigate its safety after its injection into the eyes of rats and rabbits. The polymer building block for hydrogel preparation was synthesized by copolymerization of a methacrylated dexamethasone prodrug (mDEX) with <i>N</i>-isopropylacrylamide (NIPAM) and <i>N</i>-acryloxysuccinimide (NAS) through reversible addition-fragmentation chain transfer (RAFT) polymerization, using poly(ethylene glycol) (PEG; 6 kDa) functionalized at both ends with a chain transfer agent (CTA). This yielded a thermosensitive triblock copolymer (p(NIPAM-<i>co</i>-NAS-<i>co</i>-mDEX)-PEG-P(NIPAM-<i>co</i>-NAS-<i>co</i>-mDEX) with a cloud point of 23 °C. Upon incubation of an aqueous solution of this polymer at 37 °C, thermogelation occurs. The resulting thermogel is chemically stabilized by cross-linking with cystamine, a compound with two amino groups that react with the succinimide functionalities present in the polymer chains. Intravitreal injections of a preformed fluorescently labeled hydrogel into rats were carried out, and hydrogel degradation and retinal health were followed using optical coherence tomography (OCT) and fundus imaging. The hydrogel started to degrade 2-3 weeks post injection, and it was cleared from the eye after 5 weeks. Adverse effects, mainly cataract and mild retinal bleeding, were observed, which were probably caused by injection trauma. No histological differences were seen between the treated and untreated eyes. In rabbits, unlabeled hydrogel was injected into the vitreous, and no side effects were observed in the animals. After 3 weeks, the hydrogels could not be seen by fundus imaging, but released dexamethasone was quantifiable with LC-MS/MS in the aqueous humor for 9 weeks post injection. A compartmental model fit of the experimental data showed that the in vivo release of dexamethasone followed first-order kinetics with a half-life of 16.5 days. The good tolerance of the formulation and the sustained dexamethasone release for 2 months make this delivery system an interesting candidate for further preclinical testing.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197462","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":"Manifold Embedding of Quantum Information as Molecule Representation to Predict Blood-Brain Barrier Permeability by Deep Learning.","authors":"Jiaqing Li, Koushiki Basu, Xiaoqing Chen, Tonglei Li","doi":"10.1021/acs.molpharmaceut.5c01196","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01196","url":null,"abstract":"<p><p>Neurological disorders continue to be a leading global health challenge, with the blood-brain barrier (BBB) presenting considerable obstacles to effective drug delivery for central nervous system (CNS) therapies. Accurately predicting BBB permeability is essential for the early stages of CNS drug design. This study utilizes Manifold Embedding of Molecular Surface (MEMS) as a quantum-informed molecule representation to improve log <i>BB</i> prediction using deep learning models. Employing the B3DB data set, our approach achieved competitive performance, with an average RMSE of 0.49 ± 0.06, MAE of 0.38 ± 0.05, and <i>R</i>² of 0.55. The ability of MEMS to authentically encode molecular interactions facilitates a more direct modeling of log <i>BB</i> compared to traditional descriptors. Still, as expected, model performance is influenced by the size and quality of the data, exhibiting notable variability across different B3DB groups and imbalances in the distribution of the log <i>BB</i> values. Additionally, although chirality significantly influences BBB permeability, the limited stereochemical data in the data set constrain its impact. Future efforts should focus on curating high-quality, stereochemically rich measurements and addressing data imbalances to train predictive models.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190444","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":"Colloidal Stability Assessment of a Model Antibody Oligonucleotide Conjugate.","authors":"Douglas D Banks, Jon F Cordia","doi":"10.1021/acs.molpharmaceut.5c01126","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c01126","url":null,"abstract":"<p><p>Antibody oligonucleotide conjugates (AOCs) are quickly gaining traction as a new modality within the biopharmaceutical industry for their ability to precisely deliver gene expression modulating therapeutic oligonucleotides to specific tissues for the treatment of a range of genetic diseases. To realize their full pharmaceutical potential, high-concentration liquid formulations will need to be developed to minimize manufacturing costs and enable patient-centric subcutaneous routes of administration. Motivated by this goal, the current report details, to the best of our knowledge, the first systematic comparison of the pH and ionic strength dependence of the colloidal stabilities of a model AOC with the unconjugated monoclonal antibody (mAb) using a design of experiment approach. Similar to past investigations, protein-protein interactions of the mAb native state, as assessed by polyethylene glycol-induced liquid-liquid phase separation and dynamic light scattering experiments, were minimized at low pH and ionic strength solvent conditions, where long-range net electrostatic repulsion was highest. In contrast, the AOC was the least colloidally stable in these same solvent conditions, and higher solution viscosities were observed with increasing AOC concentration. The greater protein-protein intermolecular interactions of the AOC native state are believed to be caused by short-range attractive electrostatic interactions between the localized negative charge of the oligonucleotide and positive surface charge of the mAb. These interactions could be effectively minimized by raising solution pH and/or screening charge by increasing the ionic strength.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190469","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":"Targeted Delivery of Anti-TGF-β₁-siRNA Using PDGFR-β Peptide-Modified Chitosan Nanoparticles for the Treatment of Liver Fibrosis.","authors":"Salma Mostafa, Maryam A Shetab Boushehri, Aya A Ezzat, Ralf Weiskirchen, Alf Lamprecht, Samar Mansour, Salma N Tammam","doi":"10.1021/acs.molpharmaceut.5c00715","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00715","url":null,"abstract":"<p><p>Activated hepatic stellate cells (aHSCs) are key players in the fibrotic cascade in inflamed livers, with transforming growth factor-beta 1 (TGF-β₁) being the most potent pro-fibrotic cytokine. Therefore, TGF-β₁ downregulation in aHSCs may serve as an interesting therapeutic approach for the treatment of liver fibrosis. However, excessive collagen deposition in the extracellular matrix (ECM) hinders drug delivery to aHSCs. Chitosan nanoparticles (CS-NPs) show intrinsic affinity for collagen, holding potential for drug delivery to fibrotic livers. In this study, CS-NPs were used for the <i>in vivo</i> delivery of anti-TGF-β₁ siRNA. To promote delivery into aHSCs, CS-NPs were modified with different densities of platelet-derived growth factor receptor-β (PDGF-β) binding peptides as the targeting moiety. The CS-NPs showed an average hydrodynamic diameter of 103 ± 7 nm, a zeta potential of 24 ± 1 mV, and an siRNA encapsulation efficiency of 92.39 ± 6.4%. In healthy mice, biweekly treatment of siRNA-free unmodified CS-NPs up to a concentration of 120 mg/kg for 4 weeks was well tolerated and caused no organ-specific toxicity. The biodistribution of the unmodified and peptide-modified CS-NPs was carried out to identify potential sites of accumulation in healthy and fibrotic mice, and histopathological studies confirmed the safety of the formulations in nontarget sites in the case of fibrotic animals. Cell culture experiments confirmed the affinity of unmodified CS-NPs to the collagenated ECM, whereas collagen density reduction with collagenase-loaded CS-NPs (Coll-NPs) was necessary to promote cellular uptake of the peptide-modified CS-NPs. When loaded with anti-TGF-β₁ siRNA and used for the treatment of the CCl₄ liver fibrosis model in mice, CS-NPs decorated with a high density of PDGF-β binding peptide could significantly reduce the hepatic TGF-β₁ (by approximately 65%) and fibronectin (by approximately 63%) levels. Pretreatment with Coll-NPs could contribute to a further reduction of both markers by around 10%. Histopathological evaluations with Masson Trichrome staining revealed a reduction in the aggregation of the portal inflammatory cells, an absence in the proliferation of the fibroblastic cells in between hepatocytes, and a decrease in collagen deposition in the liver following treatment with anti-TGF-β₁ siRNA-loaded peptide-modified CS-NPs, both with and without Coll-NP pretreatment. Accordingly, the results demonstrate the plausibility of anti-TGF-β₁-siRNA delivery to aHSCs using PDGF-β binding peptide-modified CS-NPs for the treatment of liver fibrosis.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Parameter-Fitted PC-SAFT Framework for Solubility Extrapolation in Drug-Polymer Systems.","authors":"Alex Mathers, Michal Fulem","doi":"10.1021/acs.molpharmaceut.5c00939","DOIUrl":"10.1021/acs.molpharmaceut.5c00939","url":null,"abstract":"<p><p>Accurate modeling of drug-polymer solubility is essential for the rational design of amorphous solid dispersions and other advanced pharmaceutical formulations. The perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state has emerged as a robust framework for capturing complex thermodynamic interactions in such systems. However, its predictive accuracy is often constrained by the limited availability of validated pure-component parameters and the frequent need to optimize the binary interaction parameter (<i>k</i>_ij) to match experimental data. In this study, we present a novel application of PC-SAFT as a data-driven extrapolation tool in which model parameters are directly regressed to experimental solubility data for specific drug-polymer pairs. This approach repositions PC-SAFT from a purely predictive model to a pragmatic extrapolative framework, enabling solubility estimation without reliance on pretabulated parameters or speculative <i>k</i>_ij adjustments. In a separate analysis, we further demonstrate that using arbitrary pure-component parameter values─when coupled with <i>k</i>_ij optimization─can achieve predictive performance comparable to that of literature-derived parameters. This finding underscores the dominant role of the binary interaction parameter and suggests that detailed pure-component calibration may not be essential for capturing the solubility behavior. Case studies confirm that both strategies reliably reproduce experimental trends and offer practical paths for bridging data gaps in the thermodynamic modeling of drug-polymer systems.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147169","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":"Defective Host Immunity in a Mouse Hindlimb Ischemia Model Attenuates the Blood Flow Recovery Promoted by an mRNA/LNP Formulation.","authors":"Hanae Toyonaga, Lei Cheng, Hirotsugu Tanaka","doi":"10.1021/acs.molpharmaceut.5c00982","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00982","url":null,"abstract":"<p><p>mRNA therapeutics represent a relatively new therapeutic modality with the potential for a diverse range of clinical applications, from vaccines to regenerative therapy. Recent clinical advances in mRNA-based vaccines have revealed that the inflammatory nature of lipid nanoparticle (LNP) formulations leads to acute side effects and plays an important adjuvant role in enhancing efficacy (i.e., immunogenicity). Therefore, understanding the biological responses associated with LNP formulations is broadly interesting for further advancing the therapeutic application of the mRNA platform while ensuring safety and efficacy. Here, we report that an intramuscularly administered firefly luciferase (Fluc) mRNA/LNP formulation enhanced proinflammatory responses, characterized by upregulation of proinflammatory chemokine expression and local leukocyte infiltration. Furthermore, in a mouse hindlimb ischemia (HLI) model, this mRNA/LNP formulation induced blood flow recovery without mRNA encoding any pro-angiogenic gene. In an attempt to mitigate the immune response, we employed severely immunocompromised NSG mice, which exhibit multiple defects in host immunity, as an HLI model and demonstrated that the mRNA/LNP formulation was unable to induce blood flow recovery in this condition. These findings suggest that the mRNA/LNP formulation can be the primary substance in enhancing the blood flow recovery after ischemia through immune activation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172125","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":"Bayesian Optimization for Efficient Multiobjective Formulation Development of Biologics.","authors":"Isabel Waibel, Timo N Schneider, Fiona J Fischer, Poonpat Dumnoenchanvanit, Alina Kulakova, Tin Duy Nguyen, Thomas Egebjerg, Søren Bertelsen, Nikolai Lorenzen, Paolo Arosio","doi":"10.1021/acs.molpharmaceut.5c00591","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00591","url":null,"abstract":"<p><p>Biologics, including emerging engineered formats, can often exhibit poor developability profiles, complicating their translation into successful therapeutics. While formulation design can substantially mitigate some developability issues, it represents a highly complex optimization challenge due to the need to simultaneously improve multiple biophysical properties, navigate a vast design space, and account for nonlinear or synergistic interactions among excipients. Traditional design of experiments methods can reduce experimental effort but are limited by difficulties in managing high-order complexities and a propensity to become trapped in local optima. In response, machine learning techniques combined with (high-throughput) screenings have emerged as powerful strategies to overcome these limitations, dramatically reducing the number of required experiments. The ability of these models to capture nonlinear relationships and interactions among multiple features enables efficient navigation in a high-dimensional design space. We present a combined Bayesian optimization and experimental screening method that concurrently optimizes three key biophysical properties of a monoclonal antibody─melting temperature <i>T</i>_m, diffusion interaction parameter <i>k</i>_D, and stability against air-water interfaces. We demonstrate its effectiveness through the identification of highly optimized formulation conditions in just 33 experiments. Furthermore, our approach can account for essential formulation constraints such as osmolality and pH, ensuring practical applicability. We show that beyond optimization, our method provides valuable insights into the influence of individual excipients on each biophysical property across formulations. Furthermore, it highlights the need to balance trade-offs between conflicting properties, such as the opposing effects of pH on <i>T</i>_m and <i>k</i>_D.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147138","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}