Pub Date : 2025-03-07DOI: 10.1016/j.ijpharm.2025.125438
Huihui Li , Kang Liu , Zexin Yang , Quanwei Sun , Wencui Shang , Yunlong Li , Mingjing Wang , Ye Yang , Hanmeng Liu , Dengke Yin , Wei Shen
Although vascular disrupting agents (VDAs) can induce shutdown of blood flow and necrosis in the tumor core, eradicating tumor rim cells remains a significant challenge. Recently, researchers have developed various combination treatment strategies to improve the efficacy of VDAs. However, the aggravated hypoxic tumor microenvironment following vascular disruption limits the effectiveness of conventional therapeutic approaches. Here, we developed an ε-polylysine-derived oncolytic polymer (named OPAA) with membrane lytic activity. Its cytotoxic effect on tumor cells is largely unaffected by hypoxic conditions, as evidenced by the ratio of its IC50 value for 4 T1 cells under normoxic conditions to that under hypoxic conditions, which is 0.98. Subsequently, a pH-responsive combretastatin A4 phosphate disodium salt (CA4P)-loaded nanoparticle (OPAA@CA4P NPs) has been designed to efficiently deliver OPAA and CA4P to solid tumors. OPAA@CA4P NPs exhibited a prolonged serum half-life (t1/2 = 3.15 h) compared to CA4P (t1/2 = 0.31 h) and an enhanced tumor accumulation. In addition, CA4P can be responsively released within the tumor microenvironment, leading to necrosis in the tumor center. Concurrently, OPAA released from the nanoparticles eradicated the surviving cancer cells at the tumor periphery, thereby improving the overall therapeutic effect. Notably, compared to the CA4P + doxorubicin group (tumor suppression rates, TSR = 36.17 %), the OPAA@CA4P NPs group demonstrated superior therapeutic outcomes (TSR = 60.30 %). Overall, the introduction of oncolytic polymers provides new insights into the potential future applications of VDAs.
{"title":"Oncolytic polymer-mediated combretastatin A4 phosphate delivery for enhancing vascular disrupting therapy","authors":"Huihui Li , Kang Liu , Zexin Yang , Quanwei Sun , Wencui Shang , Yunlong Li , Mingjing Wang , Ye Yang , Hanmeng Liu , Dengke Yin , Wei Shen","doi":"10.1016/j.ijpharm.2025.125438","DOIUrl":"10.1016/j.ijpharm.2025.125438","url":null,"abstract":"<div><div>Although vascular disrupting agents (VDAs) can induce shutdown of blood flow and necrosis in the tumor core, eradicating tumor rim cells remains a significant challenge. Recently, researchers have developed various combination treatment strategies to improve the efficacy of VDAs. However, the aggravated hypoxic tumor microenvironment following vascular disruption limits the effectiveness of conventional therapeutic approaches. Here, we developed an ε-polylysine-derived oncolytic polymer (named OPAA) with membrane lytic activity. Its cytotoxic effect on tumor cells is largely unaffected by hypoxic conditions, as evidenced by the ratio of its IC50 value for 4 T1 cells under normoxic conditions to that under hypoxic conditions, which is 0.98. Subsequently, a pH-responsive combretastatin A4 phosphate disodium salt (CA4P)-loaded nanoparticle (OPAA@CA4P NPs) has been designed to efficiently deliver OPAA and CA4P to solid tumors. OPAA@CA4P NPs exhibited a prolonged serum half-life (t<sub>1/2</sub> = 3.15 h) compared to CA4P (t<sub>1/2</sub> = 0.31 h) and an enhanced tumor accumulation. In addition, CA4P can be responsively released within the tumor microenvironment, leading to necrosis in the tumor center. Concurrently, OPAA released from the nanoparticles eradicated the surviving cancer cells at the tumor periphery, thereby improving the overall therapeutic effect. Notably, compared to the CA4P + doxorubicin group (tumor suppression rates, TSR = 36.17 %), the OPAA@CA4P NPs group demonstrated superior therapeutic outcomes (TSR = 60.30 %). Overall, the introduction of oncolytic polymers provides new insights into the potential future applications of VDAs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125438"},"PeriodicalIF":5.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585642","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}
Pub Date : 2025-03-07DOI: 10.1016/j.ijpharm.2025.125435
Eren Aytekin , Melih Zeki Kaya , Göksu Eylül İlkar , Heybet Kerem Polat , Naile Öztürk , İmran Vural , Hasan Basri Çakmak , Mustafa Çelebier , Erhan Palaska , Sema Çalış , Sibel Bozdağ Pehlivan
Keratoconus is a progressive disease characterized by corneal thinning and conical deformation. Corneal cross-linking, a common treatment, strengthens collagen fibers using vitamin B2 (riboflavin) and UVA light. However, the surgical removal of the corneal epithelium (Epi-Off) required for riboflavin penetration causes complications and may affect treatment success. To address this, research has focused on delivering riboflavin without removing the epithelium (Epi-On). In this study, riboflavin-based hydrogel and co-crystal formulations were developed and evaluated through in vitro, ex vivo, and in vivo studies.
Co-crystals were prepared using trehalose, dextrose, mannitol, and nicotinamide as agents, employing solvent evaporation and co-mixing methods. These formulations were characterized using DSC (Differential Scanning Calorimetry), XRD (X-Ray Diffraction), and FTIR (Fourier Transform Infrared Spectroscopy), identifying 1R1N (1 unit mol riboflavin and 1 unit mol nicotinamide co-crystals) and 1R1M (1 unit mol riboflavin and 1 unit mol mannitol co-crystals) groups as promising candidates. Thermosensitive hydrophilic gels containing riboflavin or riboflavin-5-phosphate sodium and Transcutol P (a permeation enhancer) were also developed, using Pluronic F-127 as the polymer. The 18 % Pluronic F-127 gel formed at 31.4 ± 0.2 °C. Drug release studies showed faster release from riboflavin-5-phosphate sodium formulations, while ex vivo retention studies revealed higher corneal retention for co-crystals. In vivo studies on rat corneas demonstrated superior drug concentrations for riboflavin formulations compared to riboflavin-5-phosphate sodium, with hydrophilic gels showing prolonged corneal contact time.
The THJ-TP formulation (Riboflavin-5-phosphate sodium and permeation enhancer (Transcutol P) containing hydrophilic gel formulations), containing riboflavin-5-phosphate sodium and Transcutol P, emerged as the most promising candidate. This research represents a significant advancement towards a non-invasive riboflavin-based treatment for keratoconus.
{"title":"Optimizing riboflavin delivery with co-crystal and in situ hydrogel formulations for management of keratoconus: A comprehensive investigation with in vitro, ex vivo and in vivo studies","authors":"Eren Aytekin , Melih Zeki Kaya , Göksu Eylül İlkar , Heybet Kerem Polat , Naile Öztürk , İmran Vural , Hasan Basri Çakmak , Mustafa Çelebier , Erhan Palaska , Sema Çalış , Sibel Bozdağ Pehlivan","doi":"10.1016/j.ijpharm.2025.125435","DOIUrl":"10.1016/j.ijpharm.2025.125435","url":null,"abstract":"<div><div>Keratoconus is a progressive disease characterized by corneal thinning and conical deformation. Corneal cross-linking, a common treatment, strengthens collagen fibers using vitamin B2 (riboflavin) and UVA light. However, the surgical removal of the corneal epithelium (Epi-Off) required for riboflavin penetration causes complications and may affect treatment success. To address this, research has focused on delivering riboflavin without removing the epithelium (Epi-On). In this study, riboflavin-based hydrogel and co-crystal formulations were developed and evaluated through in vitro, ex vivo, and in vivo studies.</div><div>Co-crystals were prepared using trehalose, dextrose, mannitol, and nicotinamide as agents, employing solvent evaporation and co-mixing methods. These formulations were characterized using DSC (Differential Scanning Calorimetry), XRD (X-Ray Diffraction), and FTIR (Fourier Transform Infrared Spectroscopy), identifying 1R1N (1 unit mol riboflavin and 1 unit mol nicotinamide co-crystals) and 1R1M (1 unit mol riboflavin and 1 unit mol mannitol co-crystals) groups as promising candidates. Thermosensitive hydrophilic gels containing riboflavin or riboflavin-5-phosphate sodium and Transcutol P (a permeation enhancer) were also developed, using Pluronic F-127 as the polymer. The 18 % Pluronic F-127 gel formed at 31.4 ± 0.2 °C. Drug release studies showed faster release from riboflavin-5-phosphate sodium formulations, while ex vivo retention studies revealed higher corneal retention for co-crystals. In vivo studies on rat corneas demonstrated superior drug concentrations for riboflavin formulations compared to riboflavin-5-phosphate sodium, with hydrophilic gels showing prolonged corneal contact time.</div><div>The THJ-TP formulation (Riboflavin-5-phosphate sodium and permeation enhancer (Transcutol P) containing hydrophilic gel formulations), containing riboflavin-5-phosphate sodium and Transcutol P, emerged as the most promising candidate. This research represents a significant advancement towards a non-invasive riboflavin-based treatment for keratoconus.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125435"},"PeriodicalIF":5.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585645","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}
Pub Date : 2025-03-07DOI: 10.1016/j.ijpharm.2025.125437
Min Jiao , Weiwen Kong , Wenjuan Liu , Zirong Dong , Jinlong Yang , Zibo Wei , Xinrui Lu , Yuning Wei , Jie Zhuang
The advent of bacterial resistance has led to a notable challenge in effectively treating bacterial infections. This highlights the urgent need for the development of novel and effective drugs to combat bacterial infections. Medicinal plants, with their rich and diverse natural compounds, represent a valuable source for the discovery of novel antibacterial agents. Many of these natural compounds exhibit strong antibacterial functions, offering a promising direction for the development of antibacterial drugs. Furthermore, the application of nanotechnology in the development of antibacterial natural products has become a topic of considerable interest due to the advantages it offers, including the potential to enhance drug solubility. The efficacy of natural antibacterial agents is significantly enhanced through nanotechnology. This review offers a comprehensive overview of recent advances in the delivery of natural antibacterial compounds using a range of nanoformulation strategies.
{"title":"Boosting the antibacterial potency of natural products through nanotechnologies","authors":"Min Jiao , Weiwen Kong , Wenjuan Liu , Zirong Dong , Jinlong Yang , Zibo Wei , Xinrui Lu , Yuning Wei , Jie Zhuang","doi":"10.1016/j.ijpharm.2025.125437","DOIUrl":"10.1016/j.ijpharm.2025.125437","url":null,"abstract":"<div><div>The advent of bacterial resistance has led to a notable challenge in effectively treating bacterial infections. This highlights the urgent need for the development of novel and effective drugs to combat bacterial infections. Medicinal plants, with their rich and diverse natural compounds, represent a valuable source for the discovery of novel antibacterial agents. Many of these natural compounds exhibit strong antibacterial functions, offering a promising direction for the development of antibacterial drugs. Furthermore, the application of nanotechnology in the development of antibacterial natural products has become a topic of considerable interest due to the advantages it offers, including the potential to enhance drug solubility. The efficacy of natural antibacterial agents is significantly enhanced through nanotechnology. This review offers a comprehensive overview of recent advances in the delivery of natural antibacterial compounds using a range of nanoformulation strategies.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125437"},"PeriodicalIF":5.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585631","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}
Pub Date : 2025-03-06DOI: 10.1016/j.ijpharm.2025.125422
Katharina Tatjana Kopp , Maarten De Beer , Jody Voorspoels , Dorien Van Lysebetten , Guy Van den Mooter
Protein stability in solution state is often poor due to the intrinsic instability of proteins. A solution is to solidify them by using techniques like freeze or spray drying (SD). To shield therapeutic proteins from stress (e.g., heat or shear stress) related to the solidification process, suitable buffers and excipients are added during formulation development. In this work, buffers and excipients were identified for the stabilization of three protein model compounds (BSA, IgG and lysozyme) in solution state using a design of experiments (DoE) approach based on screening results from differential scanning fluorimetry (DSF) combined with static light scattering (SLS). The aim was to investigate whether it is possible to predict protein stability in solid state using data from protein stabilization in solution state according to DSF/SLS. Therefore, three concepts per protein were analyzed after SD, two of which were expected to stabilize the protein, and one less stabilizing and compared these results to screening results obtained in solution state. Analytical techniques prior to and post SD were reversed-phase and size-exclusion chromatography (RPC and SEC, respectively), dynamic light scattering (DLS), UV and circular dichroism (CD). Furthermore, yield and residual moisture were analyzed. BSA and lysozyme showed high stability during SD and therefore only minor changes were observed. IgG was more affected by solidification which partly resulted in a loss of more than 15 % of the initial protein concentration in comparison to before SD. In future studies, the use of analytical techniques that do not require reconstitution would give additional value.
{"title":"The value of spray drying as stabilization process for proteins","authors":"Katharina Tatjana Kopp , Maarten De Beer , Jody Voorspoels , Dorien Van Lysebetten , Guy Van den Mooter","doi":"10.1016/j.ijpharm.2025.125422","DOIUrl":"10.1016/j.ijpharm.2025.125422","url":null,"abstract":"<div><div>Protein stability in solution state is often poor due to the intrinsic instability of proteins. A solution is to solidify them by using techniques like freeze or spray drying (SD). To shield therapeutic proteins from stress (e.g., heat or shear stress) related to the solidification process, suitable buffers and excipients are added during formulation development. In this work, buffers and excipients were identified for the stabilization of three protein model compounds (BSA, IgG and lysozyme) in solution state using a design of experiments (DoE) approach based on screening results from differential scanning fluorimetry (DSF) combined with static light scattering (SLS). The aim was to investigate whether it is possible to predict protein stability in solid state using data from protein stabilization in solution state according to DSF/SLS. Therefore, three concepts per protein were analyzed after SD, two of which were expected to stabilize the protein, and one less stabilizing and compared these results to screening results obtained in solution state. Analytical techniques prior to and post SD were reversed-phase and size-exclusion chromatography (RPC and SEC, respectively), dynamic light scattering (DLS), UV and circular dichroism (CD). Furthermore, yield and residual moisture were analyzed. BSA and lysozyme showed high stability during SD and therefore only minor changes were observed. IgG was more affected by solidification which partly resulted in a loss of more than 15 % of the initial protein concentration in comparison to before SD. In future studies, the use of analytical techniques that do not require reconstitution would give additional value.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125422"},"PeriodicalIF":5.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585648","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}
Front-of-the-eye (FOTE) droplet-based drug delivery presents a challenging fluid dynamics phenomenon, where many patients either miss their target or blink prematurely, leading to significant drug wastage and poor bioavailability. In this study, we investigate the influence of fluid properties and impact speed on the impact-spreading process on eyeball replica substrates in the context of both drops and jets to identify optimal parameters for maximum spreading, which has implications for bioavailability. Additionally, we investigate the role of the micro-scale protective tear film by coating the substrates with artificial tears. Our findings reveal that the presence of a tear film enhances the spreading of eye drops, and the spreading dynamics of various Newtonian and non-Newtonian fluids on both dry and wet substrates can be described by a universal scaling law.
{"title":"Delivery of viscous drops and jets to eyeball replicas","authors":"Idera Lawal , Pankaj Rohilla , Eliana Rodriguez, Phuong Pham, Jeremy Marston","doi":"10.1016/j.ijpharm.2025.125400","DOIUrl":"10.1016/j.ijpharm.2025.125400","url":null,"abstract":"<div><div>Front-of-the-eye (FOTE) droplet-based drug delivery presents a challenging fluid dynamics phenomenon, where many patients either miss their target or blink prematurely, leading to significant drug wastage and poor bioavailability. In this study, we investigate the influence of fluid properties and impact speed on the impact-spreading process on eyeball replica substrates in the context of both drops and jets to identify optimal parameters for maximum spreading, which has implications for bioavailability. Additionally, we investigate the role of the micro-scale protective tear film by coating the substrates with artificial tears. Our findings reveal that the presence of a tear film enhances the spreading of eye drops, and the spreading dynamics of various Newtonian and non-Newtonian fluids on both dry and wet substrates can be described by a universal scaling law.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125400"},"PeriodicalIF":5.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585635","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}
Pub Date : 2025-03-05DOI: 10.1016/j.ijpharm.2025.125434
Ana Martins , Cláudia Moura , João Henriques , João A. Lopes
The pharmaceutical industry has been shifting towards continuous manufacturing, specifically for tablet production. Compared to batch processing, continuous tableting exhibits higher process efficiency, better process control, reduced footprint, and consistent product quality. Understanding mass flow variability and feed factor profile of raw materials in the loss-in-weight feeding process is essential for controlling continuous processes. Current literature has highlighted correlations between material properties and feeding performance. However, research still lacks an assessment of how feeder set-up options impact this performance. This paper aims to fill the existing gap between material properties and feeder output to expedite the process development stage. A selection of commercially available excipients, crystalline APIs, spray-dried excipients, and protein-based excipients (nineteen in total) were characterized in terms of physical properties and rheological behavior. Volumetric feeding trials were conducted in a loss-in-weight feeder to obtain the feeding performance (mass flow RSD and feed factor profile curve). Partial least squares regression demonstrated that feeder performance can be estimated from material density, flowability, cohesion, charge density, and porosity. Additionally, experiments were conducted to assess the impact of feeding set-up options on feeding dynamics, enabling the development of a workflow for set-up and operating range definition. Applying this workflow to five different materials demonstrated sufficient accuracy in defining the feeder set-up parameters when compared to the experimental data results. The developed data-driven approach minimizes both material and time requirements, making it more efficient than a trial-and-error approach, which is essential for accelerating development.
{"title":"Methodology for rapid development of a continuous loss-in-weight feeding process","authors":"Ana Martins , Cláudia Moura , João Henriques , João A. Lopes","doi":"10.1016/j.ijpharm.2025.125434","DOIUrl":"10.1016/j.ijpharm.2025.125434","url":null,"abstract":"<div><div>The pharmaceutical industry has been shifting towards continuous manufacturing, specifically for tablet production. Compared to batch processing, continuous tableting exhibits higher process efficiency, better process control, reduced footprint, and consistent product quality. Understanding mass flow variability and feed factor profile of raw materials in the loss-in-weight feeding process is essential for controlling continuous processes. Current literature has highlighted correlations between material properties and feeding performance. However, research still lacks an assessment of how feeder set-up options impact this performance. This paper aims to fill the existing gap between material properties and feeder output to expedite the process development stage. A selection of commercially available excipients, crystalline APIs, spray-dried excipients, and protein-based excipients (nineteen in total) were characterized in terms of physical properties and rheological behavior. Volumetric feeding trials were conducted in a loss-in-weight feeder to obtain the feeding performance (mass flow RSD and feed factor profile curve). Partial least squares regression demonstrated that feeder performance can be estimated from material density, flowability, cohesion, charge density, and porosity. Additionally, experiments were conducted to assess the impact of feeding set-up options on feeding dynamics, enabling the development of a workflow for set-up and operating range definition. Applying this workflow to five different materials demonstrated sufficient accuracy in defining the feeder set-up parameters when compared to the experimental data results. The developed data-driven approach minimizes both material and time requirements, making it more efficient than a trial-and-error approach, which is essential for accelerating development.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125434"},"PeriodicalIF":5.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-04DOI: 10.1016/j.ijpharm.2025.125432
A. Locks , B.J. Bowles , S. Brown , H.C. Hailes , S.T. Hilton
Despite advances in the range of materials that can be used in 3D printing and their applications across numerous scientific disciplines, the controlled breakdown of their solid structures after printing remains challenging. In this study we report the development of tuneable degradable 3D printed formulations, that could be 3D printed using standard digital light processing (DLP) and then degraded as required under mild conditions. Thirteen thiol-ene and thiol-yne formulations were designed to provide a range of tailored mechanical properties, with controlled degradation rates, and specific thermal behaviours with potential relevance to biomedical applications. The formulations ranged from ones with high stiffness for structural applications, through to those capable of rapid degradation. These formulations demonstrate full degradability and stability in physiological conditions, showing potential for future drug delivery applications pending further toxicity and release studies. This balance of degradability and mechanical robustness offers significant potential for enhancing patient safety and reducing the invasiveness of surgical treatments as directed by clinical needs.
{"title":"3D Printing with tuneable degradation: Thiol-ene and thiol-yne containing formulations for biomedical applications","authors":"A. Locks , B.J. Bowles , S. Brown , H.C. Hailes , S.T. Hilton","doi":"10.1016/j.ijpharm.2025.125432","DOIUrl":"10.1016/j.ijpharm.2025.125432","url":null,"abstract":"<div><div>Despite advances in the range of materials that can be used in 3D printing and their applications across numerous scientific disciplines, the controlled breakdown of their solid structures after printing remains challenging. In this study we report the development of tuneable degradable 3D printed formulations, that could be 3D printed using standard digital light processing (DLP) and then degraded as required under mild conditions. Thirteen thiol-ene and thiol-yne formulations were designed to provide a range of tailored mechanical properties, with controlled degradation rates, and specific thermal behaviours with potential relevance to biomedical applications. The formulations ranged from ones with high stiffness for structural applications, through to those capable of rapid degradation. These formulations demonstrate full degradability and stability in physiological conditions, showing potential for future drug delivery applications pending further toxicity and release studies. This balance of degradability and mechanical robustness offers significant potential for enhancing patient safety and reducing the invasiveness of surgical treatments as directed by clinical needs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125432"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lipoplexes are non-viral lipid vectors that effectively form complexes with genetic material, positioning them as promising alternatives to viral vectors in gene therapy. Their advantages include lower toxicity, reduced immunogenicity, improved targetability, and ease of large-scale production. A typical lipoplex is composed of cationic lipids, neutral lipids, and anionic nucleic acids (e.g., DNA, mRNA, miRNA, siRNA, shRNA). Neutral lipids play an auxiliary role and are often used as transfection enhancers. Enhancing lipoplex efficiency often involves modifying the cationic lipid structure through functional groups like PEG polymers and targeting ligands. The assembly of lipoplexes occurs spontaneously. This process involves the binding of the positively charged polar head group of the cationic lipid to the negatively charged DNA spontaneously as a result of electrostatic interaction, then irreversible rearrangement and condensation of the lipoplex occurs to form either lamellar or hexagonal structures. The transfection process encompasses several steps: cellular entry, endosomal escape and cargo release, cytoplasmic trafficking, and nuclear entry. The physicochemical and biological properties of lipoplexes are influenced by factors such as lipid structure, charge ratio, and environmental conditions. Despite certain limitations like low gene transfer efficiency and rapid clearance by serum proteins, lipoplexes show promise for clinical applications. They can be administered through various routes, offering potential treatments for diseases such as cancer, bone damage, infection, and cystic fibrosis. The study aims to examine the potential of lipoplexes as a promising vehicle for delivering therapeutic agents and their progression from theoretical concepts to practical clinical applications.
{"title":"Exploring the promise of lipoplexes: From concept to clinical applications","authors":"Alaa M. Al-Shihabi , Mazen Al-Mohaya , Mohamed Haider , Burcu Demiralp","doi":"10.1016/j.ijpharm.2025.125424","DOIUrl":"10.1016/j.ijpharm.2025.125424","url":null,"abstract":"<div><div>Lipoplexes are non-viral lipid vectors that effectively form complexes with genetic material, positioning them as promising alternatives to viral vectors in gene therapy. Their advantages include lower toxicity, reduced immunogenicity, improved targetability, and ease of large-scale production. A typical lipoplex is composed of cationic lipids, neutral lipids, and anionic nucleic acids (e.g., DNA, mRNA, miRNA, siRNA, shRNA). Neutral lipids play an auxiliary role and are often used as transfection enhancers. Enhancing lipoplex efficiency often involves modifying the cationic lipid structure through functional groups like PEG polymers and targeting ligands. The assembly of lipoplexes occurs spontaneously. This process involves the binding of the positively charged polar head group of the cationic lipid to the negatively charged DNA spontaneously as a result of electrostatic interaction, then irreversible rearrangement and condensation of the lipoplex occurs to form either lamellar or hexagonal structures. The transfection process encompasses several steps: cellular entry, endosomal escape and cargo release, cytoplasmic trafficking, and nuclear entry. The physicochemical and biological properties of lipoplexes are influenced by factors such as lipid structure, charge ratio, and environmental conditions. Despite certain limitations like low gene transfer efficiency and rapid clearance by serum proteins, lipoplexes show promise for clinical applications. They can be administered through various routes, offering potential treatments for diseases such as cancer, bone damage, infection, and cystic fibrosis. The study aims to examine the potential of lipoplexes as a promising vehicle for delivering therapeutic agents and their progression from theoretical concepts to practical clinical applications.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125424"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563281","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}
Purpose: Patients with pulmonary fibrosis are prone to developing lung cancer. Pulmonary fibrosis and lung cancer have many common pathogenic factors and similar pathological features. For patients with IPF combined with lung cancer, there is currently no better treatment method available now. The purpose of this study is to develop a rapamycin pulmonary administration preparation that can treat lung cancer with pulmonary fibrosis, thereby overcoming the limitations of rapamycin treatment.
Methods: In this study, rapamycin-loaded mixed micelle nanoparticles (TPGS/F127@RAPA) were first prepared by the film dispersion method. Then biomimetic nanoparticles (MM@TPGS/F127@RAPA) were obtained by coating the surface of TPGS/F127@RAPA with macrophage membranes (MM) using a co-incubation method.
Results: TPGS/F127@RAPA and MM@TPGS/F127@RAPA showed particle sizes of about 15 nm and 260 nm respectively. Transmission electron microscope results showed that TPGS/F127@RAPA and MM@TPGS/F127@RAPA had homogeneous spherical shape morphologies and that the TPGS/F127@RAPA core was successfully covered with the macrophage membrane. In vitro studies demonstrated that MM@TPGS/F127@RAPA could effectively inhibit the excessive proliferation and migration of A549 cells and activated-Mlg cells. Moreover, MM@TPGS/F127@RAPA could increase the uptake of rapamycin by cells. By inhibiting the TGF-β1/Smad3 and PI3K/AKT/mTOR signaling pathways, TPGS/F127@RAPA and MM@TPGS/F127@RAPA could further reduce collagen deposition, inhibit tumor cell proliferation and improve lung function. Mice suffering from lung cancer with pulmonary fibrosis were treated with MM@TPGS/F127@RAPA through intratracheal instillation. The results showed that compared with TPGS/F127@RAPA, MM@TPGS/F127@RAPA could better reduce the area of pulmonary fibrosis and collagen deposition, inhibit tumor cell proliferation and improve lung function, exhibited longer retention time in lung and better lung distribution and deposition.
Conclusion: Our results revealed that the biomimetic strategy of MM@TPGS/F127@RAPA may be a good choice for the treatment of lung cancer patients with pulmonary fibrosis.
{"title":"Macrophage membrane entraped rapamycin-loaded TPGS/F127 micelles through intratracheal instillation for enhanced drug delivery and therapy to lung cancer with pulmonary fibrosis.","authors":"Hongting Liu, Shihao Cai, Yao Sun, Conglu Zhao, Xiang Xu, Songtao Gu, Shouchun Peng, Qingguo Di, Honggang Zhou, Xiaoting Gu, Xiaoyu Ai, Cheng Yang","doi":"10.1016/j.ijpharm.2025.125429","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125429","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with pulmonary fibrosis are prone to developing lung cancer. Pulmonary fibrosis and lung cancer have many common pathogenic factors and similar pathological features. For patients with IPF combined with lung cancer, there is currently no better treatment method available now. The purpose of this study is to develop a rapamycin pulmonary administration preparation that can treat lung cancer with pulmonary fibrosis, thereby overcoming the limitations of rapamycin treatment.</p><p><strong>Methods: </strong>In this study, rapamycin-loaded mixed micelle nanoparticles (TPGS/F127@RAPA) were first prepared by the film dispersion method. Then biomimetic nanoparticles (MM@TPGS/F127@RAPA) were obtained by coating the surface of TPGS/F127@RAPA with macrophage membranes (MM) using a co-incubation method.</p><p><strong>Results: </strong>TPGS/F127@RAPA and MM@TPGS/F127@RAPA showed particle sizes of about 15 nm and 260 nm respectively. Transmission electron microscope results showed that TPGS/F127@RAPA and MM@TPGS/F127@RAPA had homogeneous spherical shape morphologies and that the TPGS/F127@RAPA core was successfully covered with the macrophage membrane. In vitro studies demonstrated that MM@TPGS/F127@RAPA could effectively inhibit the excessive proliferation and migration of A549 cells and activated-Mlg cells. Moreover, MM@TPGS/F127@RAPA could increase the uptake of rapamycin by cells. By inhibiting the TGF-β1/Smad3 and PI3K/AKT/mTOR signaling pathways, TPGS/F127@RAPA and MM@TPGS/F127@RAPA could further reduce collagen deposition, inhibit tumor cell proliferation and improve lung function. Mice suffering from lung cancer with pulmonary fibrosis were treated with MM@TPGS/F127@RAPA through intratracheal instillation. The results showed that compared with TPGS/F127@RAPA, MM@TPGS/F127@RAPA could better reduce the area of pulmonary fibrosis and collagen deposition, inhibit tumor cell proliferation and improve lung function, exhibited longer retention time in lung and better lung distribution and deposition.</p><p><strong>Conclusion: </strong>Our results revealed that the biomimetic strategy of MM@TPGS/F127@RAPA may be a good choice for the treatment of lung cancer patients with pulmonary fibrosis.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125429"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572822","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}
Pub Date : 2025-03-04DOI: 10.1016/j.ijpharm.2025.125431
Sushesh Srivatsa Palakurthi , Nitin Bharat Charbe , Sumedha Kapre , Wei Zheng , Maharshi Thalla , D. Palaniappan , Dai Lu , Srinath Palakurthi
Ophthalmic emulsions are considered complex drug products due to their unique product characteristics, presence of multiple phases as aqueous, swollen micellar and oil phases resulting in a complex drug release pattern. FDA recommends in vivo pharmacokinetic or clinical end point study; or in vitro comparative physicochemical characterization study to demonstrate similarity between the reference and generic products. Purpose of the current investigation is to develop a comprehensive biowaiver approach to assess performance of the nanoemullsions of difluprednate through testing their critical quality attributes (CQA). CQA of the Q1/Q2 formulations such as viscosity, pH, globule size distribution, drug distribution in different phases of emulsion, and in vitro release were tested. Drug and surfactant distribution in various phases was analyzed using UPLC following phase separation by ultracentrifugation. In vitro drug release testing (IVRT) was performed using Franz diffusion and microdialysis methods. Microdialysis method was developed and validated by studying the drug release from Q1/Q2 formulations compared to that of the reference product. Of the two IVRT methods used in the current study, the conventional Franz diffusion cell method served as quality control dissolution method with about 80 % drug release in ≅ 2.5 h, differentiating the drug release profiles between the micelle, emulsions of different globule size distribution. In contrast, microdialysis served as a biorelevant method that can be used to test the drug release as early as 2 min with reproducibility and discriminatory ability. It is likely that the above biowaiver approach using a series of product characterization tests and microdialysis as a bio-relevant IVRT method support the industry in generic product development and in establishing in vitro bioequivalence of complex ophthalmic products.
{"title":"Evaluating critical quality attributes and novel drug release testing of difluprednate nanoemulsions","authors":"Sushesh Srivatsa Palakurthi , Nitin Bharat Charbe , Sumedha Kapre , Wei Zheng , Maharshi Thalla , D. Palaniappan , Dai Lu , Srinath Palakurthi","doi":"10.1016/j.ijpharm.2025.125431","DOIUrl":"10.1016/j.ijpharm.2025.125431","url":null,"abstract":"<div><div>Ophthalmic emulsions are considered complex drug products due to their unique product characteristics, presence of multiple phases as aqueous, swollen micellar and oil phases resulting in a complex drug release pattern. FDA recommends <em>in vivo</em> pharmacokinetic or clinical end point study; or <em>in vitro</em> comparative physicochemical characterization study to demonstrate similarity between the reference and generic products. Purpose of the current investigation is to develop a comprehensive biowaiver approach to assess performance of the nanoemullsions of difluprednate through testing their critical quality attributes (CQA). CQA of the Q1/Q2 formulations such as viscosity, pH, globule size distribution, drug distribution in different phases of emulsion, and <em>in vitro</em> release were tested. Drug and surfactant distribution in various phases was analyzed using UPLC following phase separation by ultracentrifugation. In vitro drug release testing (IVRT) was performed using Franz diffusion and microdialysis methods. Microdialysis method was developed and validated by studying the drug release from Q1/Q2 formulations compared to that of the reference product. Of the two IVRT methods used in the current study, the conventional Franz diffusion cell method served as quality control dissolution method with about 80 % drug release in ≅ 2.5 h, differentiating the drug release profiles between the micelle, emulsions of different globule size distribution. In contrast, microdialysis served as a biorelevant method that can be used to test the drug release as early as 2 min with reproducibility and discriminatory ability. It is likely that the above biowaiver approach using a series of product characterization tests and microdialysis as a bio-relevant IVRT method support the industry in generic product development and in establishing <em>in vitro</em> bioequivalence of complex ophthalmic products.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125431"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566471","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}
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