Real-time release testing (RTRt) of tablet dissolution can significantly improve manufacturing efficiency along with the adoption of continuous manufacturing in the pharmaceutical industry. To assure product quality without destructive testing, models for RTRt should be sufficiently reliable and robust. Whereas mechanistic models have merits of broader applicability and interpretability, data-driven models have been common approaches due to computational speed. This paper discusses challenges and opportunities in the application of mechanistic models for dissolution testing to enable RTRt of solid dosage. After a comprehensive literature review on mechanistic dissolution models and RTRt, the potential benefits and challenges of mechanistic models are presented. Compared to data-driven models, mechanistic models require less experimental data that can reduce time and cost for RTRt development. However, to enable the implementation of mechanistic models in RTRt, computational time should be short either by using a simple mechanistic model or by applying surrogate models.
{"title":"Mathematical models of dissolution testing: Challenges and opportunities toward real-time release testing","authors":"Kensaku Matsunami , Alexander Ryckaert , Valérie Vanhoorne , Ashish Kumar","doi":"10.1016/j.ijpharm.2024.125002","DOIUrl":"10.1016/j.ijpharm.2024.125002","url":null,"abstract":"<div><div>Real-time release testing (RTRt) of tablet dissolution can significantly improve manufacturing efficiency along with the adoption of continuous manufacturing in the pharmaceutical industry. To assure product quality without destructive testing, models for RTRt should be sufficiently reliable and robust. Whereas mechanistic models have merits of broader applicability and interpretability, data-driven models have been common approaches due to computational speed. This paper discusses challenges and opportunities in the application of mechanistic models for dissolution testing to enable RTRt of solid dosage. After a comprehensive literature review on mechanistic dissolution models and RTRt, the potential benefits and challenges of mechanistic models are presented. Compared to data-driven models, mechanistic models require less experimental data that can reduce time and cost for RTRt development. However, to enable the implementation of mechanistic models in RTRt, computational time should be short either by using a simple mechanistic model or by applying surrogate models.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125002"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768705","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 : 2025-01-25DOI: 10.1016/j.ijpharm.2024.125009
Gisele Rodrigues da Silva , Euisun Song , Karen M. Chen , Fang Chen , Li Jiang , Hyeonji Kim , Nae-Won Kang , Won-Gun Koh , David Myung
Electrospun gelatin nanofibers coated with hyaluronic acid (GelNF-HA) were synthesized as a scaffold for delivering human corneal mesenchymal stromal cells (C-MSCs) directly to deep corneal injuries. Aligned GelNFs were produced by electrospinning, crosslinked using vapor of glutaraldehyde, coated with HA, and crosslinked with EDC/NHS. The GelNF-HA was characterized by SEM, mechanical, and optical properties. It was then investigated as a substrate for C-MSC proliferation and migration in vitro and in a rabbit cornea culture model. The expression of α-smooth muscle actin (α-SMA) was determined in the ex vivo model. SEM showed that the GelNF-HA scaffold was composed of aligned GelNFs with 75 % of the fibers oriented against the same angle. It exhibited a Young’s modulus of 1.66 ± 0.59 MPa and approximately 93 % transmittance of visible light. The GelNF-HA membranes supported C-MSC proliferation in vitro. In a scratch migration assay, it facilitated complete wound closure after 48 h in culture. C-MSC-laden GelNF-HA scaffolds supported corneal wound healing in an ex vivo model as well, expressing a lower percentage of stromal α-SMA compared to both the no-treatment keratectomy-only and C-MSC groups (p < 0.05). The C-MSC-supportive GelNF-HA scaffolds hold therapeutic potential for stromal regeneration in the treatment of deep corneal defects.
{"title":"Gelatin nanofibers coated with hyaluronic acid as a mesenchymal stromal cell scaffold for corneal regeneration","authors":"Gisele Rodrigues da Silva , Euisun Song , Karen M. Chen , Fang Chen , Li Jiang , Hyeonji Kim , Nae-Won Kang , Won-Gun Koh , David Myung","doi":"10.1016/j.ijpharm.2024.125009","DOIUrl":"10.1016/j.ijpharm.2024.125009","url":null,"abstract":"<div><div>Electrospun gelatin nanofibers coated with hyaluronic acid (GelNF-HA) were synthesized as a scaffold for delivering human corneal mesenchymal stromal cells (C-MSCs) directly to deep corneal injuries. Aligned GelNFs were produced by electrospinning, crosslinked using vapor of glutaraldehyde, coated with HA, and crosslinked with EDC/NHS. The GelNF-HA was characterized by SEM, mechanical, and optical properties. It was then investigated as a substrate for C-MSC proliferation and migration <em>in vitro</em> and in a rabbit cornea culture model. The expression of α-smooth muscle actin (α-SMA) was determined in the <em>ex vivo</em> model. SEM showed that the GelNF-HA scaffold was composed of aligned GelNFs with 75 % of the fibers oriented against the same angle. It exhibited a Young’s modulus of 1.66 ± 0.59 MPa and approximately 93 % transmittance of visible light. The GelNF-HA membranes supported C-MSC proliferation <em>in vitro</em>. In a scratch migration assay, it facilitated complete wound closure after 48 h in culture. C-MSC-laden GelNF-HA scaffolds supported corneal wound healing in an <em>ex vivo</em> model as well, expressing a lower percentage of stromal α-SMA compared to both the no-treatment keratectomy-only and C-MSC groups (p < 0.05). The C-MSC-supportive GelNF-HA scaffolds hold therapeutic potential for stromal regeneration in the treatment of deep corneal defects.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125009"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754985","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 : 2025-01-25DOI: 10.1016/j.ijpharm.2024.125047
Sadia Tabassam Arif , Muhammad Ayub Khan , Patrick Frøslev , Shahiq uz Zaman , Danai Anastasia Panou , Hanne Mørck Nielsen , Joanne Heade
Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP in vitro and ex vivo as well as effects on the epithelium and mucosa was monitored. In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the Papp of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [14C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [3H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization.
{"title":"Nanostructured lipid carriers as a strategy to enhance oral levosulpiride delivery: An in vitro and ex vivo assessment","authors":"Sadia Tabassam Arif , Muhammad Ayub Khan , Patrick Frøslev , Shahiq uz Zaman , Danai Anastasia Panou , Hanne Mørck Nielsen , Joanne Heade","doi":"10.1016/j.ijpharm.2024.125047","DOIUrl":"10.1016/j.ijpharm.2024.125047","url":null,"abstract":"<div><div>Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP <em>in vitro</em> and <em>ex vivo</em> as well as effects on the epithelium and mucosa was monitored. <em>In vitro</em> and <em>ex vivo</em> permeation studies exhibited an 8-fold and 1.6-fold increase in the P<sub>app</sub> of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [<sup>14</sup>C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [<sup>3</sup>H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125047"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800755","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}
Expanding devices designed to physically facilitate the permeation of drugs across the gastrointestinal mucosa are gaining attention for the oral delivery of therapeutic macromolecules. The ideal system should be biodegradable with latex-like properties, allowing it to withstand gut movement without breaking prematurely and preventing intestinal obstruction or damage. A highly foldable and elastic device is desirable because it can fit into commercial capsules by being compressed into confined spaces. However, this compression has limits due to the device’s tendency to spring back to its original shape driven by stored elastic energy after deformation. This challenge can be addressed by using shape-memory polymers. In this work, we report a photo-crosslinkable resin suitable for 3D printing by digital light processing that yields an elastomer with latex-like properties, shape-recovery at body temperature, and degradation within 6 h under simulated intestinal conditions. Thermal shape-memory was conferred by adding stearyl(acrylate) to poly(β-aminoester)-based inks, achieving high elasticity (>700 %) and strength (>7.5 MPa), along with strain-hardening properties.
{"title":"4D printing of biodegradable intestinal drug delivery devices with shape-memory effect","authors":"Yulia Yuts , Reece McCabe , Maya Krell , Marilena Bohley , Jean-Christophe Leroux","doi":"10.1016/j.ijpharm.2024.125051","DOIUrl":"10.1016/j.ijpharm.2024.125051","url":null,"abstract":"<div><div>Expanding devices designed to physically facilitate the permeation of drugs across the gastrointestinal mucosa are gaining attention for the oral delivery of therapeutic macromolecules. The ideal system should be biodegradable with latex-like properties, allowing it to withstand gut movement without breaking prematurely and preventing intestinal obstruction or damage. A highly foldable and elastic device is desirable because it can fit into commercial capsules by being compressed into confined spaces. However, this compression has limits due to the device’s tendency to spring back to its original shape driven by stored elastic energy after deformation. This challenge can be addressed by using shape-memory polymers. In this work, we report a photo-crosslinkable resin suitable for 3D printing by digital light processing that yields an elastomer with latex-like properties, shape-recovery at body temperature, and degradation within 6 h under simulated intestinal conditions. Thermal shape-memory was conferred by adding stearyl(acrylate) to poly(β-aminoester)-based inks, achieving high elasticity (>700 %) and strength (>7.5 MPa), along with strain-hardening properties.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125051"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791359","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 : 2025-01-25DOI: 10.1016/j.ijpharm.2024.125064
Juan L. Paris , Lalitkumar K. Vora , Ana M. Pérez-Moreno , María del Carmen Martín-Astorga , Yara A. Naser , Qonita Kurnia Anjani , José Antonio Cañas , María José Torres , Cristobalina Mayorga , Ryan F. Donnelly
Dissolving microneedle array patches (DMAP) enable efficient and painless delivery of therapeutic molecules across the stratum corneum and into the upper layers of the skin. Furthermore, this delivery strategy can be combined with the sustained release of nanoparticles to enhance the therapeutic potential in a wide variety of pathological scenarios. Among the different types of nanoparticles that can be included in microneedle formulations, mesoporous silica nanoparticles (MSN) of tunable pore sizes constitute a promising tool as drug delivery systems for cargos of a wide range of molecular weights. In this work, a new preparation method was developed to produce DMAP containing ca. 2.3 mg of MSN of different pore sizes located mainly in the microneedle tips. The successful insertion of these DMAPs was confirmed in vitro (using Parafilm), ex vivo (using excised neonatal porcine skin) and in vivo (in the back of mice). The dissolution of the microneedles and deposition of the nanoparticles inside the skin were also confirmed both ex vivo and in vivo using fluorescent nanoparticles (with an intradermal deposition of 20.9 ± 7.26 % of the MSN in each DMAP in neonatal porcine skin). Finally, the in vivo release of the cargo from nanoparticles deposited inside mouse skin after microneedle insertion was confirmed through in vivo fluorescence measurements.
{"title":"Dissolving microneedle array patches containing mesoporous silica nanoparticles of different pore sizes as a tunable sustained release platform","authors":"Juan L. Paris , Lalitkumar K. Vora , Ana M. Pérez-Moreno , María del Carmen Martín-Astorga , Yara A. Naser , Qonita Kurnia Anjani , José Antonio Cañas , María José Torres , Cristobalina Mayorga , Ryan F. Donnelly","doi":"10.1016/j.ijpharm.2024.125064","DOIUrl":"10.1016/j.ijpharm.2024.125064","url":null,"abstract":"<div><div>Dissolving microneedle array patches (DMAP) enable efficient and painless delivery of therapeutic molecules across the <em>stratum corneum</em> and into the upper layers of the skin. Furthermore, this delivery strategy can be combined with the sustained release of nanoparticles to enhance the therapeutic potential in a wide variety of pathological scenarios. Among the different types of nanoparticles that can be included in microneedle formulations, mesoporous silica nanoparticles (MSN) of tunable pore sizes constitute a promising tool as drug delivery systems for cargos of a wide range of molecular weights. In this work, a new preparation method was developed to produce DMAP containing <em>ca</em>. 2.3 mg of MSN of different pore sizes located mainly in the microneedle tips. The successful insertion of these DMAPs was confirmed <em>in vitro</em> (using Parafilm), <em>ex vivo</em> (using excised neonatal porcine skin) and <em>in vivo</em> (in the back of mice). The dissolution of the microneedles and deposition of the nanoparticles inside the skin were also confirmed both <em>ex vivo</em> and <em>in vivo</em> using fluorescent nanoparticles (with an intradermal deposition of 20.9 ± 7.26 % of the MSN in each DMAP in neonatal porcine skin). Finally, the <em>in vivo</em> release of the cargo from nanoparticles deposited inside mouse skin after microneedle insertion was confirmed through <em>in vivo</em> fluorescence measurements.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125064"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812503","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}
Herpes simplex virus-1 (HSV-1) is the primary cause of infectious blindness. Despite impressive therapeutic outcomes of conventional treatments, HSV-1 drug resistance can be easily developed. Thus, more constructive strategies should be implemented. Led by this inspiration, this work describes the potential utility of a biodegradable silk fibroin/collagen (SF/Col) film combined with GI-20-loaded poly lactic-co-glycolic acid (PLGA) nanoparticle to provide efficient and sustained delivery platform for synthetic GI-20 peptide against HSV-1. A non-irritant film containing 90 % SF and 10 % Col incorporated with mentioned nanodrug showed some optimum physicochemical properties including loading efficiency (74.15 % ± 1.12), tensile strength (3.16 ± 0.67 MPa), water uptake ability (∼73 %), cytocompatibility (viable up to 35 µg/mL of GI-20), and sustained release paradigm (∼90 % within 14 days). Also, GI-20 peptide at concentration of 35 µg/mL could prophylactically attenuate viral titration by 5 log10 units. In addition, the corneal uptake was improved without vascular irritation. In accordance with in vitro results, no hallmarks of keratitis and significant neovascularization along with ignorable inflammatory responses were obtained. Taken together, these results could guarantee the potential of mentioned multifunctional biomaterial in the healing of infected corneal tissue.
{"title":"Development of silk fibroin/collagen film containing GI-20 peptide-loaded PLGA nanoparticles against corneal herpes simplex virus-1","authors":"Razieh Sohrabi , Amir Hossein Miri , Mazda Rad-Malekshahi , Fatemeh Saadatpour , Bahareh Pourjabbar , Saeed Heidari Keshel , Ehsan Arefian , Saeed Balalaei , Ahmad Masoumi , Fereshte Khalili , Ismaeil Haririan , Mohammad Akrami , Mohammad Hassan Shahriari","doi":"10.1016/j.ijpharm.2024.125022","DOIUrl":"10.1016/j.ijpharm.2024.125022","url":null,"abstract":"<div><div>Herpes simplex virus-1 (HSV-1) is the primary cause of infectious blindness. Despite impressive therapeutic outcomes of conventional treatments, HSV-1 drug resistance can be easily developed. Thus, more constructive strategies should be implemented. Led by this inspiration, this work describes the potential utility of a biodegradable silk fibroin/collagen (SF/Col) film combined with GI-20-loaded poly lactic-co-glycolic acid (PLGA) nanoparticle to provide efficient and sustained delivery platform for synthetic GI-20 peptide against HSV-1. A non-irritant film containing 90 % SF and 10 % Col incorporated with mentioned nanodrug showed some optimum physicochemical properties including loading efficiency (74.15 % ± 1.12), tensile strength (3.16 ± 0.67 MPa), water uptake ability (∼73 %), cytocompatibility (viable up to 35 µg/mL of GI-20), and sustained release paradigm (∼90 % within 14 days). Also, GI-20 peptide at concentration of 35 µg/mL could prophylactically attenuate viral titration by 5 log<sub>10</sub> units. In addition, the corneal uptake was improved without vascular irritation. In accordance with <em>in vitro</em> results, no hallmarks of keratitis and significant neovascularization along with ignorable inflammatory responses were obtained. Taken together, these results could guarantee the potential of mentioned multifunctional biomaterial in the healing of infected corneal tissue.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125022"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823965","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}
Developing nanocarriers that can carry medications directly to tumors is an exciting development in cancer nanomedicine. The efficacy of this intriguing therapeutic approach is, however, compromised by intricate and immunosuppressive circumstances that arise concurrently with the onset of cancer. The artificial antigen presenting cell (aAPC), a micro or nanoparticle based device that mimics an antigen presenting cell by providing crucial signal proteins to T lymphocytes to activate them against cancer, is one cutting-edge method for cancer immunotherapy. This review delves into the critical design considerations for aAPCs, particularly focusing on particle size, shape, and the non-uniform distribution of T cell activating proteins on their surfaces. Adequate surface contact between T cells and aAPCs is essential for activation, prompting engineers to develop nano-aAPCs with microscale contact areas through techniques such as shape modification and nanoparticle clustering. Additionally, we explore recommendations for future advancements in this field.
{"title":"A review of innovative design strategies: Artificial antigen presenting cells in cancer immunotherapy","authors":"Rabiya Riffath Syed Altaf , Agilandeswari Mohan , Naveen Palani , Keren Celestina Mendonce , P. Monisha , Suriyaprakash Rajadesingu","doi":"10.1016/j.ijpharm.2024.125053","DOIUrl":"10.1016/j.ijpharm.2024.125053","url":null,"abstract":"<div><div>Developing nanocarriers that can carry medications directly to tumors is an exciting development in cancer nanomedicine. The efficacy of this intriguing therapeutic approach is, however, compromised by intricate and immunosuppressive circumstances that arise concurrently with the onset of cancer. The artificial antigen presenting cell (aAPC), a micro or nanoparticle based device that mimics an antigen presenting cell by providing crucial signal proteins to T lymphocytes to activate them against cancer, is one cutting-edge method for cancer immunotherapy. This review delves into the critical design considerations for aAPCs, particularly focusing on particle size, shape, and the non-uniform distribution of T cell activating proteins on their surfaces. Adequate surface contact between T cells and aAPCs is essential for activation, prompting engineers to develop nano-aAPCs with microscale contact areas through techniques such as shape modification and nanoparticle clustering. Additionally, we explore recommendations for future advancements in this field.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125053"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817554","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}
Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery.
In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake.
Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions.
In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.
{"title":"Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos","authors":"Beatrice Ruzzante , Flaminia Fruzzetti , Marco Cattaneo , Giuseppe Lauria Pinter , Stefania Marcuzzo , Gabriele Candiani , Nina Bono","doi":"10.1016/j.ijpharm.2024.125008","DOIUrl":"10.1016/j.ijpharm.2024.125008","url":null,"abstract":"<div><div>Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery.</div><div>In this study, we utilized osmotic shock to enhance (nano)cargos internalization. We examined the effects of hypotonic/hypertonic shock on both primary and cell lines, assessing parameters such as cell viability, cell volume, membrane tension changes, and particle uptake. Our results indicate that short-lived osmotic shock does not harm cells. Hypotonic shock induced temporary shape changes lasting up to 5 min, followed by a 15-minute recovery period. Importantly, hypotonic shock increased the uptake of 100-nm and 500-nm particles by ∼ 3- and ∼ 5-fold, respectively, compared to isotonic conditions. In contrast, the hypertonic shock did not impact cell behavior or particle uptake.</div><div>Notably, the internalization mechanisms triggered by osmotic shock operate independently of active endocytic pathways, making hypotonic stimulation particularly beneficial for hard-to-treat cells. When primary fibroblasts derived from amyotrophic lateral sclerosis (ALS)-patients were exposed to hypotonic shock in the presence of the therapeutic cargo icerguastat, there was an increased expression of miR-106b-5p compared to isotonic conditions.</div><div>In conclusion, osmotic shock presents a promising strategy for improving drug delivery within cells and, potentially, in tissues such as muscles or skin, where localized drug administration is preferred.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125008"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785634","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 : 2025-01-25DOI: 10.1016/j.ijpharm.2024.125097
Friederike L. Jayes , Ria D. Corder , Robert B. Vachieri , Saad A. Khan , Darlene K. Taylor
Injectable drug delivery for uterine fibroid therapy is an ambitious, possibly fertility-preserving concept, that could meet the challenges associated with the structure of these tumors and their location in the uterus. This study was conducted to advance a thermosensitive injectable quadpolymer for effective sustained release of anti-fibrotic drug formulations and to evaluate the feasibility of its use for delivery of the anti-fibrotic drug pirfenidone as a therapy to reduce fibroid cell proliferation.
A series of quadpolymers were prepared by free radical polymerization of N-isopropylacrylamide (NIPAM) with different amounts of polylactic acid functionalized hydroxyethyl methacrylate (HEMA-PLA), acrylic acid (AAc), and methacrylate functionalized hyperbranched polyglycerol (HPG-MA) to optimize the sol–gel phase transition temperature and mechanical stiffness. Poly(NIPAM-co-HEMA-PLA-co-AAc-co-HPG-MA) with feed ratio (83–7–1–9), at 17% w/v, readily formed an aqueous solution that could be manipulated by syringe at room temperature. The quadpolymer also rapidly formed a stable gel at physiological body temperature, and partially biodegraded over time as confirmed by several spectroscopic characterization techniques. To evaluate the potential range of utility, quadpolymer 83–7–1–9 was loaded in-vitro with caffeine (a prototype hydrophilic drug) or the hydrophobic drug pirfenidone. Pirfenidone-loaded quadpolymer 83–7–1–9 formulations released 50% of drug loaded in double the time as compared to other reported liposome and nanoparticle injectable pirfenidone formulations. Furthermore, treatment of cultured fibroid cells with pirfenidone-loaded quadpolymer 83–7–1–9 formulations confirmed that activity of pirfenidone was preserved and proliferation of fibroid cells was inhibited. These results support that quadpolymer 83–7–1–9 is a promising candidate to be further developed for localized delivery of drugs for uterine fibroid therapy.
{"title":"Multiple hour antifibrotic drug release enabled by a thermosensitive quadpolymer","authors":"Friederike L. Jayes , Ria D. Corder , Robert B. Vachieri , Saad A. Khan , Darlene K. Taylor","doi":"10.1016/j.ijpharm.2024.125097","DOIUrl":"10.1016/j.ijpharm.2024.125097","url":null,"abstract":"<div><div>Injectable drug delivery for uterine fibroid therapy is an ambitious, possibly fertility-preserving concept, that could meet the challenges associated with the structure of these tumors and their location in the uterus. This study was conducted to advance a thermosensitive injectable quadpolymer for effective sustained release of anti-fibrotic drug formulations and to evaluate the feasibility of its use for delivery of the anti-fibrotic drug pirfenidone as a therapy to reduce fibroid cell proliferation.</div><div>A series of quadpolymers were prepared by free radical polymerization of N-isopropylacrylamide (NIPAM) with different amounts of polylactic acid functionalized hydroxyethyl methacrylate (HEMA-PLA), acrylic acid (AAc), and methacrylate functionalized hyperbranched polyglycerol (HPG-MA) to optimize the sol–gel phase transition temperature and mechanical stiffness. Poly(NIPAM-co-HEMA-PLA-co-AAc-co-HPG-MA) with feed ratio (83–7–1–9), at 17% w/v, readily formed an aqueous solution that could be manipulated by syringe at room temperature. The quadpolymer also rapidly formed a stable gel at physiological body temperature, and partially biodegraded over time as confirmed by several spectroscopic characterization techniques. To evaluate the potential range of utility, quadpolymer 83–7–1–9 was loaded in-vitro with caffeine (a prototype hydrophilic drug) or the hydrophobic drug pirfenidone. Pirfenidone-loaded quadpolymer 83–7–1–9 formulations released 50% of drug loaded in double the time as compared to other reported liposome and nanoparticle injectable pirfenidone formulations. Furthermore, treatment of cultured fibroid cells with pirfenidone-loaded quadpolymer 83–7–1–9 formulations confirmed that activity of pirfenidone was preserved and proliferation of fibroid cells was inhibited. These results support that quadpolymer 83–7–1–9 is a promising candidate to be further developed for localized delivery of drugs for uterine fibroid therapy.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125097"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854137","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}
Intracorneal delivery of ten amino acid (alanine, arginine, asparagine, glutamine, glycine, histidine, isoleucine, lysine, methionine and valine) ester prodrugs of triamcinolone acetonide (TA-AA) was investigated in vitro, using a corneal iontophoresis device (IONTOFOR-CXL; SOOFT Italia S.p.A.) approved for clinical use in the treatment of keratoconus. Short duration iontophoresis (1 mA for 5 min) was performed and intracorneal deposition of TA was quantified by HPLC-UV and UHPLC-MS/MS. The data evidenced the clear advantage of TA-AA prodrug iontophoresis compared to passive delivery and revealed unexpected and prodrug dependent deposition profiles. Despite their superior electrical mobility, intracorneal delivery of dications, TA-Arg and TA-Lys, did not outperform that of TA-Ala and TA-Gly. In silico investigations to relate the TA-AA prodrugs’ physicochemical properties to their electrotransport confirmed that increased lipophilicity potential did not favour iontophoretic transport. For TA-Ala and TA-Gly, it was hypothesized that the greater charge distribution and decreased tendency to interact with the corneal tissue via electrostatic and H-bonds contributed to their successful iontophoretic delivery. Intracorneal biodistribution of TA confirmed that TA-Gly iontophoresis resulted in supratherapeutic concentrations in deep corneal stroma, exceeding TA IC50 by ∼ 104-fold. The results clearly demonstrated the successful combination of the clinically approved SOOFT iontophoretic device and the TA-AA prodrugs for targeted corneal iontophoretic delivery.
{"title":"Intracorneal iontophoretic delivery of triamcinolone acetonide prodrugs: Physicochemical parameters guiding electrotransport","authors":"Verena Santer , Deborah Chiara Minzaghi , César Eulogio Serna-Jiménez , Yogeshvar N. Kalia","doi":"10.1016/j.ijpharm.2024.125096","DOIUrl":"10.1016/j.ijpharm.2024.125096","url":null,"abstract":"<div><div>Intracorneal delivery of ten amino acid (alanine, arginine, asparagine, glutamine, glycine, histidine, isoleucine, lysine, methionine and valine) ester prodrugs of triamcinolone acetonide (TA-AA) was investigated <em>in vitro</em>, using a corneal iontophoresis device (IONTOFOR-CXL; SOOFT Italia S.p.A.) approved for clinical use in the treatment of keratoconus. Short duration iontophoresis (1 mA for 5 min) was performed and intracorneal deposition of TA was quantified by HPLC-UV and UHPLC-MS/MS. The data evidenced the clear advantage of TA-AA prodrug iontophoresis compared to passive delivery and revealed unexpected and prodrug dependent deposition profiles. Despite their superior electrical mobility, intracorneal delivery of dications, TA-Arg and TA-Lys, did not outperform that of TA-Ala and TA-Gly. <em>In silico</em> investigations to relate the TA-AA prodrugs’ physicochemical properties to their electrotransport confirmed that increased lipophilicity potential did not favour iontophoretic transport. For TA-Ala and TA-Gly, it was hypothesized that the greater charge distribution and decreased tendency to interact with the corneal tissue via electrostatic and H-bonds contributed to their successful iontophoretic delivery. Intracorneal biodistribution of TA confirmed that TA-Gly iontophoresis resulted in supratherapeutic concentrations in deep corneal stroma, exceeding TA IC<sub>50</sub> by ∼ 10<sup>4</sup>-fold. The results clearly demonstrated the successful combination of the clinically approved SOOFT iontophoretic device and the TA-AA prodrugs for targeted corneal iontophoretic delivery.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"669 ","pages":"Article 125096"},"PeriodicalIF":5.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854127","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}
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