Pharmaceutics最新文献

{"title":"Pharmacokinetic Monitoring of Methotrexate in Haematological Patients: Comparison of the Predictive Ability of Two Population-Based Models and Their Clinical Utility.","authors":"María López-Galán, Aida López-Gómez, Maria Antonia Pérez-Moreno, Marta Mejías-Trueba, María Dolores Vega-Coca, Laura Herrera-Hidalgo","doi":"10.3390/pharmaceutics18101255","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101255","url":null,"abstract":"<p><p><b>Background and Objectives:</b> Methotrexate (MTX) is a key drug for treating haematologic malignancies. Due to its narrow therapeutic window, Population pharmacokinetic (PopPK) models help predict MTX plasma concentrations (Cp) and optimize folinic acid rescue. This study evaluated and compared the predictive performance and clinical utility of two PopPK models in adults with lymphoma or acute lymphoblastic leukaemia (ALL). <b>Methods:</b> A retrospective PK study was conducted in adults with lymphoma/ALL treated with MTX. Cp at 24 h (lymphoma) and 42 h (ALL) were estimated by Bayesian forecasting using the Gallais et al. (2021) and Kawakatsu et al. (2019) PopPK models with Levenberg-Marquardt least squares (M2) and Strict Adaptive Metropolis (SAA), using frequency-based (FB) or concentration-based (CB) weighting. Predictive performance was assessed using median percentage error (MDiPE), median absolute percentage error (MDiAPE), and the percentage of individual prediction errors within ±20% (iF20) and ±30% (iF30) of observed concentrations. Clinical utility was evaluated by concordance with folinic acid rescue. <b>Results:</b> Thirty-seven patients (72 MTX cycles) were included: 17 with lymphoma (37 cycles; 52% men; median age of 66 (34-73) years) and 20 with ALL (35 cycles; 55% men; median age of 46 (17-68) years), with a median of two cycles per patient. In lymphoma, the Kawakatsu model showed the most favourable predictive performance with SAA-FB (MDiPE of 8.5%, MDiAPE of 30.3%, iF20 of 37.83%, and iF30 of 48.65%), whereas the Gallais model showed lower predictive accuracy across the evaluated approaches. Concordance with folinic acid rescue ranged from 75.68% to 86.49%, with the highest value observed with M2-CB. In ALL, both models showed lower and more variable predictive performance, with MDiAPE ranging from 43.0% to 73.8%, iF30 from 11.43% to 42.86%, and concordance with folinic acid rescue from 40.00% to 54.29%. <b>Conclusions:</b> PopPK models for MTX showed variable performance in external cohorts, with numerically more favourable results for the model by Kawakatsu et al. External validation is essential prior to clinical application, particularly given the relationship between MTX exposure, delayed clearance and toxicity. Validated models could contribute to safer monitoring and more personalised treatment, although larger studies are needed to confirm their clinical utility.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBPK Modeling Investigation of IVIVE-Observed Pharmacokinetic Divergence for VU0467319: A Mechanistic Refinement Workflow for Low-Solubility Compounds.","authors":"Akinwunmi A Abisogun, Srinivasan Krishnan, Craig W Lindsley, Olivier Boutaud","doi":"10.3390/pharmaceutics18101254","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101254","url":null,"abstract":"<p><p><b>Background/Objectives:</b> VU0467319 (VU319), an M1 muscarinic positive allosteric modulator evaluated in Phase 1 studies, exhibits subproportional dose-exposure scaling typical of poorly soluble compounds. This study applies physiologically based pharmacokinetic (PBPK) modeling to investigate the sources of divergence between IVIVE-based predictions and observed single ascending dose (SAD) clinical pharmacokinetics. <b>Methods:</b> A whole-body PBPK model was developed in Simcyp Simulator V24 using in vitro ADME and physicochemical inputs. Clinical pharmacokinetic data were used for sequential, hypothesis-driven model refinement of distribution, clearance, and absorption parameters. Model performance was evaluated at 60-600 mg fasted using virtual populations demographically matched to their corresponding clinical cohort. <b>Results:</b> A K_p scalar of 0.125 recovered model V_ss within the observed V_z/F bound; a 10.7-fold downward CL_int correction (32.2 to 3 µL/min/mg) reconciled clearance; and a 1 µm particle radius recovered AUC_0-∞ within 6% across 60-240 mg. The model met predefined performance thresholds across the four independent verification doses (geometric mean fold error 1.45 for AUC and 1.56 for C_max; three of four doses within 2-fold), with progressive underprediction at the highest doses (≥400 mg). Supersaturation-ratio analysis indicated that, within the model, sustained supersaturation was unlikely to explain the high-dose underprediction. The refined model reproduced the observed sub-proportional dose-exposure relationship through 240 mg, but underpredicted exposure at 400 and 600 mg. <b>Conclusions:</b> Structured PBPK refinement identified dissolution-limited absorption as the most likely primary contributor to IVIVE-observed divergence for VU319, with secondary contributions from clearance and distribution. These model-derived mechanisms remain hypotheses that require experimental confirmation. The workflow may provide a structured refinement framework for other low-solubility compounds where IVIVE assumptions diverge from observed pharmacokinetics.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Topical Vitamin D Analogs Beyond Psoriasis: Pharmacological Mechanisms, Cutaneous Drug Delivery, and Clinical Evidence.","authors":"Doris Laçej, Anna Pietrella, Nicole Zoratto, Marianna Lombardi, Chiara Di Meo, Pietro Matricardi","doi":"10.3390/pharmaceutics18101248","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101248","url":null,"abstract":"<p><p>Topical vitamin D analogs are well-established therapies for psoriasis, but their broader dermatologic potential increasingly depends not only on their biological activity but also on the ability of topical formulations to achieve effective and localized cutaneous delivery. This narrative review critically examines the emerging use of calcipotriol, tacalcitol, and calcitriol beyond psoriasis, with particular emphasis on formulation strategies, cutaneous drug delivery, and their relationship with clinical performance. Conventional topical dosage forms, including ointments, creams, and solutions, remain the principal delivery systems used in clinical studies. Their therapeutic performance is influenced by vehicle composition, skin-barrier integrity, local retention, application conditions, and the physicochemical properties of the vitamin D compound, which collectively determine cutaneous penetration, tolerability, and systemic exposure. Across the reviewed indications, formulations and treatment protocols vary considerably, contributing to heterogeneity in clinical outcomes. Vitiligo currently presents the strongest clinical evidence, particularly when topical vitamin D analogs are combined with narrowband ultraviolet B phototherapy, whereas encouraging results have been reported for morphea, acne vulgaris, and inherited ichthyoses. Evidence for atopic dermatitis, alopecia areata, and basal cell carcinoma remains limited or inconsistent. Beyond conventional vehicles, emerging delivery technologies including liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocarriers, hydrogels, and microneedle-assisted systems offer opportunities to enhance skin targeting, improve local drug retention and reduce systemic exposure. However, evidence specifically evaluating these advanced systems for vitamin D analogs remains predominantly preclinical. Future research should integrate clinical evaluation with formulation optimization, cutaneous pharmacokinetics, and comparative delivery studies, as accumulating evidence suggests that formulation-dependent skin delivery may be a critical determinant of therapeutic success beyond psoriasis.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Double-Edged Role of Enzyme Inhibition in Oral Anticancer Therapy.","authors":"Abdullah A Assiri","doi":"10.3390/pharmaceutics18101251","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101251","url":null,"abstract":"<p><p>Oral anticancer therapy is built on the deliberate inhibition of enzymes that drive malignant growth, among them protein kinases, poly(ADP-ribose) polymerases, cyclin-dependent kinases 4 and 6, the PI3K/AKT/mTOR and BRAF/MEK cascades, histone deacetylases and the proteasome. The same molecules are processed by the enzymes that metabolize drugs, and several of them inhibit or induce those enzymes in turn. Enzyme inhibition therefore carries two faces, and the objective of this review is to examine them as a single pharmacological phenomenon rather than as two separate subjects. The argument proposed is that the two are causally linked, because the structural features allowing a molecule to occupy a catalytic site also determine which metabolizing enzymes recognize it. Three consequences organize the review. Agents sharing a therapeutic target can differ by more than an order of magnitude in their dependence on one metabolizing enzyme, meaning that interaction liability is a property of the molecule rather than of its class. The mechanism of inhibition, whether reversible, covalent or time-dependent, governs how long an interaction persists. Several oral anticancer agents are themselves inhibitors or inducers of drug-metabolizing enzymes, acting as perpetrators rather than victims. Each point is quantified for representative agents from regulatory pharmacology data.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibacterial, Anti-Inflammatory, and Wound-Healing Effects of <i>Micromeria fruticosa</i> Essential Oil-Loaded Nanoemulsion in MRSA-Infected Diabetic Wounds: In Vitro and In Vivo Evaluation.","authors":"Azad Mammadov, Mehmet Çimentepe, Özge Öztürk Çimentepe, Serpil Demirci Kayiran, Umay Merve Güven Bolgen, Tilbe Çevikelli, Ahmet Alper Öztürk, Muhammet Bahaeddin Dörtbudak, Akın Yiğin, Metin Yildirim","doi":"10.3390/pharmaceutics18101252","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101252","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Diabetic foot ulcers infected with methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) heal poorly and respond inadequately to conventional antibiotic therapy. This study developed a <i>Micromeria fruticosa</i> essential oil-loaded nanoemulsion (Mf-NE) as a topical treatment for such wounds. <b>Methods:</b> The essential oil was obtained by hydrodistillation and analyzed by GC-MS. Nanoemulsions were developed from pseudoternary phase diagrams using oleic acid and a Cremophor^® EL/Tween 80-Transcutol^® system (2:1 surfactant/cosurfactant) and characterized physicochemically. Antibacterial activity against MRSA (ATCC 43300) was assessed by agar well diffusion and microdilution, antioxidant activity by DPPH and ABTS assays, and cytocompatibility by MTT assay on L929 fibroblasts. Efficacy was evaluated over 12 days in a streptozotocin-induced MRSA-infected diabetic wound model in rats. <b>Results:</b> Pulegone (42.81%) and piperitenone (29.73%) were the major constituents. Incorporation of 5% (<i>w</i>/<i>w</i>) essential oil raised the droplet size from 214.5 ± 14.4 to 292.9 ± 9.9 nm; both formulations had a dermatologically acceptable pH and Newtonian flow behavior. Mf-NE produced a 16.1 mm inhibition zone and a MIC of 1.25 mg/mL, whereas NE produced no inhibition zone and had a MIC of 5 mg/mL. Radical scavenging reached 61.5% by DPPH at 10 mg/mL and 71.5% by ABTS at 0.2 mg/mL, and cell viability remained above 87%. The NE and Mf-NE formulations also demonstrated good biocompatibility in L929 fibroblast cells. Topical Mf-NE reduced the remaining wound area to 4.8 ± 0.9% of the initial area by day 12, compared with 21.0 ± 1.9% for Fucidin, 26.1 ± 1.9% for NE and 57.2 ± 1.3% for the untreated group; bacterial colonization was almost completely suppressed, TNF-α and IL-1β expression was significantly decreased, and composite histopathological scores were lower than in the untreated group (<i>p</i> = 0.0007). <b>Conclusions:</b> Mf-NE is a promising topical candidate for MRSA-infected diabetic wounds. Formulation-specific dermal and systemic safety requires further evaluation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucoadhesive Chitosome-Based Buccal Delivery of Goat Placenta-Derived Bioactive Macromolecules: Effects on 5-Fluorouracil-Induced Gingival Fibroblast Injury.","authors":"Worranan Rangsimawong, Phaijit Sritananuwat, Sureewan Duangjit, Natawat Chankana, Praneet Opanasopit","doi":"10.3390/pharmaceutics18101246","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101246","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Goat placenta extract (GPE), enriched with bioactive macromolecules, exhibits regenerative potential in both healthy and damaged cells. To enable targeted transport of these macromolecules to the buccal mucosa, potential delivery systems are required. The study aimed to evaluate the bioactivity of GPE on human gingival fibroblasts (HGFs) and to develop a GPE-loaded chitosome (CTS) mucoadhesive system for buccal delivery. <b>Methods</b>: The bioactivity of GPE was assessed in normal and chemotherapy-damaged HGF cells. GPE-loaded CTS was prepared, lyophilized, and then incorporated into an oral gel. The <i>in vitro</i> buccal deposition was visualized by confocal laser scanning microscopy. <b>Results</b>: GPE showed no cytotoxic effects at a concentration of 4000 µg/mL and significantly promoted the viability of both normal and 5-fluorouracil (5-FU)-treated HGF cells (<i>p</i> < 0.05). The GPE-loaded CTS formed nanosized vesicles and a positive surface charge, which may facilitate interactions with mucin. CTS and its loaded oral gel enhanced the delivery of macromolecular proteins into the buccal mucosa compared with gel alone. <b>Conclusions</b>: GPE promoted HGF viability and facilitated the recovery of 5-FU-induced gingival fibroblast injury. The CTS-loaded oral gel enhanced the buccal delivery of macromolecular protein, representing a promising strategy for oral mucosal regeneration and supportive care in chemotherapy-induced mucosal injury.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the Role of Solvents in Hypromellose-Based Film-Forming Solutions for Topical Administration of Ketoprofen Through a Design of Experiments Approach.","authors":"Sandra Milinković, Ivana Kurćubić, Jelena Đuriš, Ljiljana Đekić","doi":"10.3390/pharmaceutics18101249","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101249","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Topical ketoprofen gels are limited by the need for frequent reapplication, short skin residence time, and the risk of sunlight-induced photoallergic dermatitis. Film-forming solutions (FFSs) allow for extended retention; however, the solvents used may affect the polymer film's characteristics. The present study aimed to elucidate the effect of macrogol 400 and isopropanol and develop a hypromellose-based ketoprofen FFS using a design of experiments (DoE) approach. <b>Methods</b>: A 3² full factorial design was applied to investigate the effects of macrogol 400 (0-5%, <i>w</i>/<i>w</i>) (X₁) and isopropanol (25-50%, <i>w</i>/<i>w</i>) concentrations (X₂) on film mechanical properties (tensile strength (Y₁), elongation at break (Y₂), and Young's modulus (Y₃)). The DoE-based placebo and ketoprofen-loaded FFSs were characterized for their physicochemical, rheological, and textural properties, while the corresponding films were evaluated for appearance, weight, stickiness, and mechanical properties. In vitro ketoprofen release from the drug-loaded FFS was also evaluated. <b>Results</b>: Macrogol 400 concentration was identified as a significant factor influencing film mechanical properties. As a film plasticizer, macrogol 400 improved film mechanical properties up to the optimal concentration (2.75%), whereas the water/isopropanol ratio mainly affected the applicative (rheological and textural) properties of the FFSs. Ketoprofen incorporation significantly reduced the film tensile strength and elongation at break. In vitro release testing demonstrated 58.52% ketoprofen release after 6 h, with the Weibull model showing the best fit to the release profile. <b>Conclusions</b>: Macrogol 400 and isopropanol have a complex, mutually conditioned influence on the application characteristics of hypromellose-based FFS and the mechanical characteristics of the films. Incorporation of ketoprofen into the selected placebo formulation significantly reduced film deformability but yielded a thin, transparent film with favorable in vitro drug-release characteristics. The developed FFS represents a promising topical dosage form for non-steroidal anti-inflammatory drugs and warrants further investigation, particularly in terms of skin retention and in vivo performance.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Body Weight and Combined <i>UGT1A1</i> and <i>NR1I2</i> Polymorphisms on Dolutegravir Pharmacokinetics Among Thai People Living with HIV: A Population Pharmacokinetic Analysis.","authors":"Anan Chanruang, Angela K Birnbaum, Sílvia M Illamola, Sasithorn Sirilun, Suthunya Chupradit, Sasiwimol Ubolyam, Napon Hiranburana, Yong-Soon Cho, Jae-Gook Shin, Anchalee Avihingsanon, Baralee Punyawudho","doi":"10.3390/pharmaceutics18101245","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101245","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Despite its role as a first-line therapy for Thai people living with HIV (PLWH), dolutegravir (DTG) exhibits significant pharmacokinetic (PK) variability influenced by both genetic and non-genetic factors. This variability may contribute to an increased incidence of neuropsychiatric adverse events (NP-AEs) at the standard 50 mg once daily (OD) dose. <b>Methods</b>: To evaluate the impact of relevant covariates, a population PK model of DTG was developed using 1122 DTG plasma concentrations from 221 Thai PLWH. Monte Carlo simulations were performed to evaluate the probability of target attainment for pre-defined efficacy and safety thresholds across different dosage regimens. <b>Results</b>: Data were analyzed using a one-compartment model with first-order absorption incorporating lag-time, and first-order elimination. Body weight (<61 kg) and a multigenic interaction were identified as significant covariates impacting DTG apparent clearance (CL/F). Specifically, individuals carrying both the UGT1A1 poor metabolizer phenotype and the <i>NR1I2</i> 63396 TT genotype resulted in a 25.1% reduction in DTG CL/F. Simulation results indicated that the standard dose achieved efficacy targets in > 95% of the population but resulted in a substantial proportion (30.46-85.68%) exceeding the safety threshold. In contrast, a reduced dose of 25 mg OD maintained high efficacy target attainment (>80%) while decreasing the proportion exceeding the safety threshold to <20% in most subgroups. <b>Conclusions</b>: These findings suggest that a reduced DTG dose may be a suitable alternative for Thai PLWH to mitigate the risk of NP-AEs, particularly among individuals with low body weight carrying the combined <i>UGT1A1</i> and <i>NR1I2</i> variants.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 GRPR-Targeted ^99mTc/¹⁸⁸Re Theranostic Pair Based on NOTA-P2-RM26.","authors":"Antonio Shegani, Nektarios Pirmettis, Sotiria Triantopoulou, Areti Titoni, Adrianna Travlou, Georgia I Terzoudi, Minas Papadopoulos, Ioannis Pirmettis, Charalampos Triantis","doi":"10.3390/pharmaceutics18101247","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101247","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Gastrin-releasing peptide receptor (GRPR)-targeted radioligands are promising tools for imaging and treatment of GRPR-expressing malignancies. This study aimed to develop a NOTA-P2-RM26-based &lt;sup&gt;99m&lt;/sup&gt;Tc/&lt;sup&gt;188&lt;/sup&gt;Re theranostic pair using the &lt;i&gt;fac&lt;/i&gt;-[M(CO)&lt;sub&gt;3&lt;/sub&gt;]&lt;sup&gt;+&lt;/sup&gt; core, with &lt;i&gt;fac&lt;/i&gt;-[&lt;sup&gt;99m&lt;/sup&gt;Tc][Tc(CO)&lt;sub&gt;3&lt;/sub&gt;(NOTA-P2-RM26)], &lt;sup&gt;99m&lt;/sup&gt;Tc2, as the diagnostic SPECT analogue and &lt;i&gt;fac&lt;/i&gt;-[&lt;sup&gt;188&lt;/sup&gt;Re][Re(CO)&lt;sub&gt;3&lt;/sub&gt;(NOTA-P2-RM26)], &lt;sup&gt;188&lt;/sup&gt;Re2, as the potential therapeutic counterpart. &lt;b&gt;Methods:&lt;/b&gt; NOTA-P2-RM26 was radiolabeled with the &lt;i&gt;fac&lt;/i&gt;-[&lt;sup&gt;99m&lt;/sup&gt;Tc(CO)&lt;sub&gt;3&lt;/sub&gt;(H&lt;sub&gt;2&lt;/sub&gt;O)&lt;sub&gt;3&lt;/sub&gt;]&lt;sup&gt;+&lt;/sup&gt;, &lt;sup&gt;99m&lt;/sup&gt;Tc1, precursor after systematic optimization of peptide amount, pH, buffer, temperature, and reaction time. The radioconjugate was purified by HPLC, reformulated by solid-phase extraction, and evaluated by radio-HPLC and radio-TLC. We assessed stability in the formulation, human serum, cysteine and histidine over 6 h. Lipophilicity was determined as logD&lt;sub&gt;7.4&lt;/sub&gt;. We evaluated in vitro specificity, cell association, and internalization in PC-3 cells. We performed biodistribution, blocking, dynamic imaging, and SPECT/CT imaging in PC-3 xenograft-bearing mice. The corresponding &lt;sup&gt;188&lt;/sup&gt;Re analog was prepared under analogous conditions and evaluated for physicochemical matching. &lt;b&gt;Results:&lt;/b&gt; Optimized labeling afforded &lt;sup&gt;99m&lt;/sup&gt;Tc2 with approximately 85% radiochemical conversion and &gt;97% radiochemical purity after purification. The compound remained stable in formulation, with 93% of the tracer intact after 6 h, and exhibited a hydrophilic profile (logD&lt;sub&gt;7.4&lt;/sub&gt; = -1.5 ± 0.2). In PC-3 cells, uptake reached 20.0 ± 1.0% of added activity and was reduced to 1.4 ± 0.3% under blocking conditions. In vivo, tumor uptake was 15.0 ± 1.0 %IA/g at 30 min and 17.0 ± 2.2 %IA/g at 1 h p.i. Blocking reduced tumor uptake to 0.84 ± 0.12 %IA/g, corresponding to approximately 95% inhibition. Pancreatic uptake decreased from 8.0 ± 0.4 %IA/g at 30 min to 3.0 ± 0.35 %IA/g at 1 h and was reduced to 0.20 ± 0.08 %IA/g after blocking. At 1 h p.i., tumor-to-blood, tumor-to-muscle, tumor-to-pancreas, and tumor-to-kidney ratios were approximately 21.3, 130.8, 5.7, and 3.6, respectively. SPECT/CT imaging confirmed clear, blockable visualization of the PC-3 tumor. The &lt;sup&gt;188&lt;/sup&gt;Re analog was obtained with approximately 80% radiochemical conversion and &gt;95% radiochemical purity post purification. It showed similar stability values to &lt;sup&gt;99m&lt;/sup&gt;Tc2 under the tested conditions and a logD&lt;sub&gt;7.4&lt;/sub&gt; of -1.6 ± 0.2. &lt;b&gt;Conclusions:&lt;/b&gt; Complex &lt;sup&gt;99m&lt;/sup&gt;Tc2 demonstrated efficient preparation, high stability, GRPR-mediated tumor uptake, favorable tumor-to-background ratios, and clear SPECT/CT visualization of PC-3 xenografts. The corresponding &lt;sup&gt;188&lt;/sup&gt;Re analog supports the feasibility of a chemically matched &lt;sup&gt;99m&lt;/su","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bench-to-Bedside Development of IMNN-001: A Non-Viral IL-12 Gene Therapy for Advanced Ovarian Cancer.","authors":"Khursheed Anwer, Subeena Sood, Jeff Sparks, Douglas V Faller, Ana Limon, Stacy R Lindborg","doi":"10.3390/pharmaceutics18101250","DOIUrl":"https://doi.org/10.3390/pharmaceutics18101250","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Interleukin-12 (IL-12) is a potent immunostimulatory cytokine with well-established antitumor activity, but systemic recombinant IL-12 administration has been constrained by inflammatory toxicity, high circulating cytokine peaks, and insufficient tumor-local exposure. IMNN-001 is a non-viral IL-12 gene therapy candidate based on the TheraPlas&lt;sup&gt;®&lt;/sup&gt; platform comprising an IL-12 expression plasmid formulated with synthetic polyethylene glycol-polyethyleneimine-cholesterol (PEG-PEI-cholesterol; PPC). Administered intraperitoneally, IMNN-001 is designed to enable regional transfection, localized IL-12 production for several days after a single injection, and repeatable pharmacodynamics activity within the peritoneal disease compartment. This review summarizes the rationale, formulation attributes, gene-transfer properties, pharmacodynamic durability, mechanism of action, biodistribution, toxicology, manufacturing controls, and clinical development of IMNN-001. Across preclinical and clinical studies, intraperitoneal delivery of IMNN-001 has produced preferential cytokine induction in ascites, with substantially higher IL-12 and interferon gamma (IFN-γ) levels in ascites than in blood. These effects were accompanied by immune remodeling including a favorable shift in the balance between immunostimulatory and immunosuppressive cells. In recurrent disease, activity varied by regimen and disease setting, whereas a randomized phase I/II study in newly diagnosed advanced ovarian cancer showed numerical differences in progression-free and overall survival that require confirmation in an adequately powered trial, currently in progress. Reported toxicities were predominantly local or attributable to combination therapy, although abdominal pain and catheter-related complications have been observed. An ongoing Phase III trial is evaluating whether adding IMNN-001 to standard chemotherapy improves clinical outcome. Objectives. The objective of this review is to place IMNN-001 within the broader challenge of developing safer and more effective IL-12-based cancer immunotherapies by examining how regional, non-viral gene delivery may overcome the limitations of systemic recombinant IL-12, including short circulating half-life, high systemic cytokine peaks, and dose-limiting inflammatory toxicity. Specifically, the review summarizes the IMNN-001 product rationale, formulation design, gene-transfer and transfection properties, pharmacodynamic durability, mechanism of action, immune remodeling, biodistribution, toxicology, manufacturing and stability attributes, and clinical development experience in ovarian cancer. By integrating preclinical, translational, CMC, and clinical findings, the article aims to define the scientific and clinical basis for IMNN-001 as a compartmentally targeted, durable, and repeatable IL-12 gene therapy strategy, while also positioning it within the broader landscape of emerging IL-12 delivery approaches and future therapeutic o","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"18 10","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149271852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}