International Journal of Pharmaceutics最新文献

{"title":"Unveiling the therapeutic potential of a Cu(II) complex with 1,10-phenanthroline and maleic acid: physicochemical characterization, DFT analysis, in silico pharmacokinetics, and evaluation of antitumor and antibacterial properties","authors":"Jad L.F. Simplicio ,&nbsp;João G. de Oliveira Neto ,&nbsp;Jailton R. Viana ,&nbsp;Ana L.A. Butarelli ,&nbsp;Ana P.S.A. dos Santos ,&nbsp;Richard P. Dutra ,&nbsp;Mateus R. Lage ,&nbsp;Eliana B. Souto ,&nbsp;Francisco F. de Sousa ,&nbsp;Adenilson O. dos Santos","doi":"10.1016/j.ijpharm.2025.126171","DOIUrl":"10.1016/j.ijpharm.2025.126171","url":null,"abstract":"<div><div>The crystal of a coordination compound of copper(II) with 1,10-phenanthroline (Phen) and maleic-acid (Mal) ligands, named as [Cu₂(Phen)₂(Mal)₂]2H₂O⋅CH₃OH, was obtained by slow solvent evaporation method. The obtained complex was physicochemically and structurally characterized by powder X-ray diffraction (PXRD), thermogravimetry (TG) and differential thermal analysis (DTA), and by Fourier-transform infrared (FT-IR), Raman and ultraviolet–visible (UV–Vis) spectroscopies. Theoretical predictions using density functional theory (DFT) were performed to study the geometric, thermodynamic, electronic, and spectroscopic properties of the complex. PXRD results showed that the crystal has a monoclinic structure (<em>C</em>2/<em>c</em>-space group). The vibrational bands observed in the Raman and FT-IR spectra were assigned with support from DFT calculations results, which also revealed the influence of water, methanol, and their 1:1 mixture on the spectral profiles. Thermoanalytical measurements confirmed that the complex retains its coordination stability under biologically relevant conditions (∼310 K). UV–Vis spectroscopy revealed its maximum absorption at 646 nm, typical of bands related to the <em>d</em>-<em>d</em> transitions of Cu²⁺ ions. The characterization of the binuclear complex was complemented with the <em>in silico</em> studies of absorption, distribution, metabolism, and excretion (ADME), suggesting the potential of the complex as drug candidate. <em>In vitro</em> cytotoxicity analysis on MCF-7, MDA-MB-231, and HeLa cell lines foresees its potential use as anticancer, whereas bactericidal effects on gram-positive and gram-negative bacteria point out the promising antimicrobial properties of the complex.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"685 ","pages":"Article 126171"},"PeriodicalIF":5.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102922","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":"Long-term controlled in vitro release of FITC-dextran using polymer-based drug delivery systems manufactured by semi-solid extrusion 3D printing","authors":"Juuso Pohjola ,&nbsp;Mika Jokinen ,&nbsp;Tero Soukka ,&nbsp;Mikael Stolt","doi":"10.1016/j.ijpharm.2025.126176","DOIUrl":"10.1016/j.ijpharm.2025.126176","url":null,"abstract":"<div><div>Controlled release drug delivery systems provide significant advantages over traditional therapeutic approaches by enabling continuous drug release over extended periods at a predetermined rate, thereby enhancing treatment efficacy and patient compliance. However, their performance is often limited due to the inability to account for individual patient characteristics. 3D printing of semi-solid inks has emerged as a promising method for the preparation of personalized medicine, addressing the need for customized designs and drug release properties. Despite the advantages of 3D printing, the commonly used materials and processing methods have demonstrated limited success in manufacturing of controlled release systems for macromolecule drugs, highlighting the need for further development. This study presents a method for creating macromolecule-releasing polymer-based drug delivery systems via semi-solid extrusion 3D printing. Fluorescein isothiocyanate-dextran model drug was encapsulated in PLGA microspheres, which were incorporated into extrudable Carbopol gel-based inks, either alone or blended with drug-free microspheres. Cylindrical models were printed at room temperature and exposed to solvent vapor to tailor the object porosity, followed by <em>in vitro</em> assessment of material degradation and drug release over three months. The results indicated that the system porosity significantly influenced the burst release and polymer degradation rate. Additionally, the drug release rate could be either accelerated, slowed, delayed, or entirely prevented by tailoring the ink composition and post-processing conditions. Given the growing interest in macromolecule drugs, the reported method demonstrates potential for the future development of controlled release systems for such molecules.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126176"},"PeriodicalIF":5.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102910","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":"Recent Advances in Vaccine Adjuvants: From Lab to Clinic","authors":"Akhilesh Vardikar ,&nbsp;Mahendra Kumar Prajapati ,&nbsp;Amol D. Gholap ,&nbsp;Satish Rojekar ,&nbsp;Roshan Keshari ,&nbsp;Harsha Jain ,&nbsp;Amarjitsing Rajput","doi":"10.1016/j.ijpharm.2025.126180","DOIUrl":"10.1016/j.ijpharm.2025.126180","url":null,"abstract":"<div><div>Adjuvants are critical components in modern vaccines, designed to enhance, modulate, and prolong immune responses to antigens. Over the decades, their evolution from conventional agents like aluminum salts to advanced nanocarrier-based systems has significantly improved vaccine efficacy and broadened their protective capabilities. This review highlights synthesizing the recent landscape of vaccine adjuvants, encompassing their physicochemical properties, immunostimulatory mechanisms, and classification. Key focus areas include traditional adjuvants and emerging materials such as chitosan, alginate, hyaluronic acid, and β-glucans, along with next-generation platforms like lipid nanoparticles, nanoemulsion, virosomes, and proteosomes. We critically examine their roles in antigen delivery and immune system modulation, drawing insights from recent preclinical and clinical developments. In this review, particular focus is placed on formulation design, stability, and scalability, as these attributes are essential for translating adjuvant technologies from laboratory research to clinical application and large-scale manufacturing. Regulatory perspectives and harmonization challenges are also discussed, positioning adjuvant development within the broader framework of pharmaceutical science. Furthermore, the review addresses the safety, tolerability, and regulatory status of clinically approved adjuvants alongside ongoing clinical trials and translational challenges. Emerging strategies such as electroporation, gene gun delivery, and self-assembling peptide systems are also discussed, highlighting innovations driving the next wave of vaccine technologies. By bridging foundational knowledge with recent advances, this review underscores the pivotal role of adjuvant science in shaping the future of global immunization strategies.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126180"},"PeriodicalIF":5.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102976","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":"Improving the oral bioavailability of berberine: A crystal engineering approach","authors":"Anuja Venkata Sai Durga Surampudi ,&nbsp;Sai Ram Prasad ,&nbsp;Pujitha Ramanujam ,&nbsp;Debasish Swain ,&nbsp;Bhagyashri N. Wadje ,&nbsp;Sandip B. Bharate ,&nbsp;Umanath Kamalakannan ,&nbsp;Muralidharan Kathirvel ,&nbsp;Sridhar Balasubramanian","doi":"10.1016/j.ijpharm.2025.126177","DOIUrl":"10.1016/j.ijpharm.2025.126177","url":null,"abstract":"<div><div>Berberine is a poorly bioavailable, naturally occurring therapeutic compound. Despite being marketed as a chloride salt, berberine shows poor solubility, and it has poor permeability owing to its ionic nature. This study focuses on enhancing the oral bioavailability of berberine by improving solubility, drug release profiles and permeability of berberine. To achieve that, the concept of cocrystallization is employed to alter the solid-state/physicochemical properties of berberine. A coformer, i.e., a secondcomponent having uses similar to a drug or whose nature will enhance the physicochemical properties of the drug, will be cocrystallized with the drug. In this study, berberine was cocrystallized with gallic acid, gentisic acid, and pamoic acid. The resultant new crystalline forms were identified as salts through single-crystal X-ray diffraction and the systems were characterized by DSC, TGA and IR spectroscopy. The stability, solubility, dissolution, permeability, oral LD50 and bioavailability studies were performed. Introduction of coformers like gallic acid and gentisic acid in crystal architecture of berberine has enhanced the solubility (1.7–2.0x) and dissolution (1.6–1.8x) of berberine in acidic media, while pamoic acid shows a decreased trend. In the GIT PAMPA studies, gentisic acid and pamoic acid systems supported in enhancing the permeability by1.42 and5.98-folds compared to berberine, whereas gallic acid exhibited a low permeability profile. The berberine-gentisic acid salt enhances the peak plasma concentration by 1.8-fold compared to berberine. Salt formation of berberine via cocrystallization is advantageous in tailoring the solid-state properties with improved solubility, dissolution, permeability, and peak plasma concentration of berberine.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"685 ","pages":"Article 126177"},"PeriodicalIF":5.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091551","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":"Fabrication of freezed-dried docetaxel liposomal powders through a microfluidic technology with enhanced blood circulation and antitumor efficacy","authors":"Li-Jing Lan ,&nbsp;Lian-Bing Long ,&nbsp;Ling-Zhi Shi ,&nbsp;Ming-Wei Huo ,&nbsp;Xiang-Xiang Huang ,&nbsp;Ya-Wen Liu ,&nbsp;Le-Yan Gu ,&nbsp;Jing-Yi Liu ,&nbsp;Ye-Chao Zhang ,&nbsp;Renyu Huang ,&nbsp;Qing-Ri Cao","doi":"10.1016/j.ijpharm.2025.126190","DOIUrl":"10.1016/j.ijpharm.2025.126190","url":null,"abstract":"<div><div>The industrial scalability and clinical translation of liposomal formulations are significantly hindered by challenges in stability and batch-to-batch variability. To address these limitations, docetaxel (DTX)-loaded long-circulating liposomal freeze-dried powders were engineered via a synergistic integration of microfluidic technology and lyophilization, optimized through an orthogonal experimental design focusing on particle size, polydispersity index (PDI), and entrapment efficiency (EE). The optimized formulation, incorporating hydroxypropyl-β-cyclodextrin (HP-β-CD) as a lyoprotectant, demonstrated nanoscale particle diameter (∼120 nm), monodisperse distribution (PDI &lt; 0.2), and elevated EE (&gt;90 %), with physicochemical integrity preserved post-lyophilization. Reconstituted DTX liposomes (DTX-Lip) exhibited pH-dependent sustained release kinetics, with enhanced drug elution at acidic pH (5.5) versus physiological pH (7.4). Solid-state characterization (XRD, FT-IR, DSC) confirmed molecular interactions between DTX and lipid-excipient matrices. <em>In vitro</em> cytotoxicity assays revealed superior apoptotic induction in A549 human lung carcinoma cells by DTX-Lip compared to free DTX solution (DTX-Sol). Pharmacokinetic profiling in vivo demonstrated prolonged systemic circulation of DTX-Lip, marked by significantly elevated area under the curve (AUC_0-∞), maximum drug concentration (C_max), mean retention time (MRT_0-∞), longer half-life (T_1/2), lower clearance (CL) and steady-state volume of distribution (V_ss) relative to DTX-Sol (p &lt; 0.05). In a C57BL/6 murine lung cancer model, DTX-Lip elicited significant tumor suppression (p &lt; 0.05) without mortality, underscoring enhanced therapeutic efficacy and mitigated systemic toxicity. Collectively, the engineered DTX-Lip system combines optimal nano-pharmaceutical attributes (size, homogeneity, EE), controlled release, and favorable in vitro-in vivo performance, offering a robust platform for industrial-scale production of stable, efficacious liposomal DTX formulations. These findings advance translational strategies for liposome-based chemotherapeutics with improved reproducibility and clinical safety.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126190"},"PeriodicalIF":5.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086229","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":"Deciphering the role of polyethylene glycol-lipid anchors in siRNA-LNP efficacy for P2y2 inhibition in bone marrow-derived macrophages","authors":"Sezen Gül ,&nbsp;Juliette Vergnaud ,&nbsp;Qinglin Wang ,&nbsp;Mélanie Hery ,&nbsp;Jhon Mino ,&nbsp;Jihana Achour ,&nbsp;Séverine Domenichini ,&nbsp;Claudine Delomenie ,&nbsp;Jean-Luc Perfettini ,&nbsp;François Fay ,&nbsp;Elias Fattal","doi":"10.1016/j.ijpharm.2025.126186","DOIUrl":"10.1016/j.ijpharm.2025.126186","url":null,"abstract":"<div><div>Macrophages play a vital role in controlling tissue homeostasis, yet their dysregulation can drive the pathogenesis of various diseases. In this context, P2Y2, a purinergic receptor that binds ATP, could be involved in several biological mechanisms in inflammatory, infectious, or cancer diseases. Lipid nanoparticles (LNPs) varying by the difference of lipid moiety of the polyethyleneglycol-lipid (PEG-lipid) conjugate entering their composition were prepared by microfluidic mixing technology and loaded with a siRNA targeting the <em>P2y2</em> mRNA. Three PEG-lipids with varying saturated alkyl chain lengths — DMG-PEG (C14), DPPE-PEG (C16), and DSPE-PEG (C18) — were evaluated for formulation optimization. The results showed that all siRNA-LNPs were efficiently taken up by unpolarized (M0) and M2-polarized bone marrow-derived macrophages (BMDMs). Despite comparable cellular uptake across formulations, their performance in gene silencing differed significantly. While (DMG-PEG)-LNPs demonstrated the highest efficacy in both cellular models, (DSPE-PEG)-LNPs remained ineffective in knocking down the target gene. Our findings further revealed that gene silencing is more efficient in M2 BMDMs than in M0 BMDMs, emphasizing the influence of macrophage polarization. Additionally, the PEG-lipid type notably influenced the intracellular distribution patterns of lipids and siRNA, with DPPE-PEG and DSPE-PEG formulations leading to higher siRNA compartmentalization. In contrast, the DMG-PEG formulation enabled more effective siRNA delivery to the cytoplasm. This research provides valuable insights into the impact of different PEG-lipid anchors on the performance of siRNA-LNPs targeting macrophages <em>in vitro</em>, paving the way for developing new macrophage-based immunotherapies.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126186"},"PeriodicalIF":5.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086203","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":"Inkjet-printed drug-loaded temporary tattoos for personalized pediatric pain treatment","authors":"Simone Eder ,&nbsp;Matthias Wolfgang ,&nbsp;Manuel Zettl ,&nbsp;Laura Wiltschko ,&nbsp;Reingard Raml ,&nbsp;Eva Roblegg ,&nbsp;Martin Spoerk","doi":"10.1016/j.ijpharm.2025.126188","DOIUrl":"10.1016/j.ijpharm.2025.126188","url":null,"abstract":"<div><div>Parents worldwide suffer from their children’s frequent refusal to take their medicine – even creams and patches may be refused due to tedious application, painful removal, and caprice. However, children find decorative tattoos appealing. Hence, a personalized drug-loaded temporary tattoo as a novel pediatric dosage form is presented. As a showcase, a pain treatment prototype tattoo based on a lidocaine/prilocaine eutectic was developed. By employing piezoelectric inkjet printing of the drug onto a decorative motif, which can be chosen based on the child’s personal preference, the drug content was tailored via variations in the number of deposited layers. To ensure the correct dispensed drug content, non-destructive near-infrared hyperspectral imaging was used and a linear correlation model covering drug doses ranging from 0 to 25 mg cm⁻² (R² 0.9925) was established. The drug-loaded tattoos were easily transferred onto the skin and revealed suitable ex-vivo drug permeation into human skin with 0.69 and 0.78 µg·g⁻¹ lidocaine and prilocaine found in the upper dermis after only 30 min. In a nutshell, we hereby introduce a well-controllable and highly acceptable pediatric treatment alternative based on a low-cost additive manufacturing technology.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"685 ","pages":"Article 126188"},"PeriodicalIF":5.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086222","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":"Unlocking ferulic acid for neurological diseases and tailoring of nanoformulations to advance its brain delivery","authors":"Paulo Ricardo Alves de Andrade ,&nbsp;Raíssa Coelho Motta ,&nbsp;Bruno Fonseca-Santos","doi":"10.1016/j.ijpharm.2025.126173","DOIUrl":"10.1016/j.ijpharm.2025.126173","url":null,"abstract":"<div><div>Mental disorders represent a significant global health challenge, with a high prevalence and substantial impact on individual well-being. Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS) and various mood disorders, contribute significantly to the burden of neurological conditions worldwide. Identifying novel drug targets and exploring natural product-based molecules have become essential priorities in advancing treatment strategies for these complex diseases. Nanoencapsulation technology has emerged as a valuable tool to increase the stability, solubility, and bioavailability of natural products, thus improving their efficacy in treating neurological disorders. By encapsulating natural compounds such as ferulic acid (FA) in nanoscale delivery systems, researchers have aimed to overcome challenges related to poor solubility and bioavailability, ultimately enhancing therapeutic outcomes. In this review, we examine recent advancements focused on the therapeutic potential of FA in AD, PD, MS, brain cancer, depression (DP), anxiety (AX), and epilepsy (EP). Furthermore, we explored the use of nanoscale delivery systems to optimise the delivery of FA for improved treatment efficacy. We aim to inspire discoveries and innovative approaches to address neurological diseases by highlighting current progress and future directions in this field with FA.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126173"},"PeriodicalIF":5.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085201","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":"Amino acid-equipped poly(ester amide) nanoparticles for improved encapsulation efficiency of lipophilic anti-inflammatory 6BIGOE based on molecular dynamic simulations","authors":"Jan Westhoff ,&nbsp;Christine Weber ,&nbsp;Vivien Bachmann ,&nbsp;Natalie E. Göppert ,&nbsp;Milica Peric ,&nbsp;Alan George ,&nbsp;Marek Sierka ,&nbsp;Stephanie Hoeppener ,&nbsp;Ivan Vilotijevic ,&nbsp;Ulrich S. Schubert ,&nbsp;Oliver Werz ,&nbsp;Dagmar Fischer","doi":"10.1016/j.ijpharm.2025.126182","DOIUrl":"10.1016/j.ijpharm.2025.126182","url":null,"abstract":"<div><div>The efficient delivery of lipophilic drugs still remains a major challenge in pharmaceutical nanotechnology, particularly due to limitations in drug loading, drug stability, and the biocompatibility of polymeric nanocarriers. Poly(ester amide)s represent a promising class of biodegradable materials and were investigated in the present study for the delivery of the anti-inflammatory, lipophilic drug 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE). Poly(ester amide)s incorporating the aromatic and non-aromatic α-amino acids <span>l</span>-phenylalanine or <span>l</span>-valine, next to glycolic acid as ester component, were synthesized by ring-opening polymerization and used to prepare nanoparticles <em>via</em> nanoemulsification in comparison to the widely used poly(lactic-<em>co</em>-glycolic acid) (PLGA). All polymers formed monodisperse nanoparticles of around 200 nm with anionic surfaces (ca. −20 mV) and comparable drug release profiles. Advantageously, the encapsulation efficiency of 6BIGOE was significantly improved to 63–78 % using poly(ester amide)s compared to 42 % for PLGA, confirmed by molecular dynamic simulations revealing enhanced interactions and miscibility between poly(ester amide)s and 6BIGOE. Poly(ester amide) nanoparticles showed higher glass transition temperatures compared to PLGA, indicating an improved thermo-mechanical stability. In human monocytes, 6BIGOE-loaded poly(ester amide) nanoparticles demonstrated excellent biocompatibility with pronounced anti-inflammatory activity by modulating pro- and anti-inflammatory mediators which highlights their potential as a versatile and tunable platform for the delivery of lipophilic anti-inflammatory drugs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126182"},"PeriodicalIF":5.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080689","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 BMX siRNA lipid nanoparticles using novel ionizable and cleavable lipids discovered through AI and experimentation for cancer therapy","authors":"Abdulaziz Alasmari ,&nbsp;Rwan Elsanhoury ,&nbsp;Avinash Kumar ,&nbsp;Rutesh Dave ,&nbsp;Mouhannad Jumaa ,&nbsp;Suliman Al-Fayoumi ,&nbsp;Sami Nazzal ,&nbsp;Ahmed Abu Fayyad","doi":"10.1016/j.ijpharm.2025.126183","DOIUrl":"10.1016/j.ijpharm.2025.126183","url":null,"abstract":"<div><div>In this work, ionizable and cleavable lipids were designed, synthesized, and characterized. The lipids were derived from the γ-T₃ isomer of vitamin E and were used to develop novel lipid nanoparticles (LNPs) targeting Bone Marrow on X chromosome (BMX). BMX is a promising and emerging target for the development of advanced cancer therapeutics. Our team recently reported on targeting BMX using small-molecule modalities. Here, we are expanding the modality of targeting employing BMX siRNA LNPs. AI and experimental design (QbD) were used to develop an optimal formulation for the BMX siRNA delivery. AI tools helped in designing the optimal ionizable lipid and further assisted in revealing the desired interaction between the ionizable lipids and the BMX siRNA. The BXM siRNA LNPs developed in this study were initially designed based on the compositions of the FDA-approved <em>Onpattro</em> formulation. The vitamin E-based ionizable and cleavable lipids were synthesized and chemically characterized using ¹H NMR. QbD played a crucial role in achieving the optimal formulation composition of the LNPs. The optimized BMX siRNA LNP compositions were prepared using methanol dilution and extrusion methods. The developed LNPs were characterized for their physicochemical properties, including particle size, zeta-potential, entrapment efficiency, and pH-dependent release. The <em>in-vitro</em> anticancer activity of the optimized BMX siRNA LPNs was also assessed. The particle size of the optimized BMX siRNA LNPs was in the range of 151 nm, with a zeta potential of 30 mV. The developed BMX siRNA LNPs exhibited a pH-dependent release profile, with the highest release occurring at an acidic pH of 5.5. The <em>in-vitro</em> anticancer activity of the developed BMX siRNA against two prostate cancer cell lines, DU145 and PC3, demonstrated statistically significant anticancer activity, as indicated by IC₅₀ values of 1.1 µM and 1.3 µM, respectively, compared to the control and <em>Onpattro</em>-composition like formulations. Furthermore, the BMX siRNA LNP designed using the novel lipids showed a significant reduction in BMX mRNA expression levels in DU145 and PC3 cell lines compared to the control or the <em>Onpattro</em>-like formulation. Profoundly, the novel LNPs showed significant <em>in-vivo</em> anticancer activity in the Castration-Resistant Prostate Cancer (CRPC) animal model compared to control or the <em>Onpattro</em>-like formulation. The results from this study further support the promise of such novel LNPs in cancer therapeutics development.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"684 ","pages":"Article 126183"},"PeriodicalIF":5.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080668","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}