Drug Delivery and Translational Research最新文献

{"title":"Oleogels for the ocular delivery of epalrestat: formulation, in vitro, in ovo, ex vivo and in vivo evaluation.","authors":"Axel Kattar, Maria Vivero-Lopez, Angel Concheiro, Rajeev Mudakavi, Anuj Chauhan, Carmen Alvarez-Lorenzo","doi":"10.1007/s13346-024-01560-7","DOIUrl":"10.1007/s13346-024-01560-7","url":null,"abstract":"<p><p>The ocular administration of lipophilic and labile drugs such as epalrestat, an aldose reductase inhibitor with potential for diabetic retinopathy treatment, demands the development of topical delivery systems capable of providing sufficient ocular bioavailability. The aim of this work was to develop non-aqueous oleogels based on soybean oil and gelators from natural and sustainable sources (ethyl cellulose, beeswax and cocoa butter) and to assess their reproducibility, safety and efficiency in epalrestat release and permeation both ex vivo and in vivo. Binary combinations of gelators at 10% w/w resulted in solid oleogels (oleorods), while single gelator oleogels at 5% w/w remained liquid at room temperature, with most of the oleogels displaying shear thinning behavior. The oleorods released up to 4 µg epalrestat per mg of oleorod in a sustained or burst pattern depending on the gelator (approx. 10% dose in 24 h). The HET-CAM assay indicated that oleogel formulations did not induce ocular irritation and were safe for topical ocular administration. Corneal and scleral ex vivo assays evidenced the permeation of epalrestat from the oleorods up to 4 and 2.5 µg/cm² after six hours, respectively. Finally, the capacity of the developed oleogels to sustain release and provide significant amounts of epalrestat to the ocular tissues was demonstrated in vivo against aqueous-based niosomes and micelles formulations loaded with the same drug concentration. Overall, the gathered information provides valuable insights into the development of oleogels for ocular drug delivery, emphasizing their safety and controlled release capabilities, which have implications for the treatment of diabetic neuropathy and other ocular conditions.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3291-3308"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitosan nanoparticles laden contact lenses for enzyme-triggered controlled delivery of timolol maleate: A promising strategy for managing glaucoma.","authors":"Furqan A Maulvi, Ashmi R Patel, Kiran H Shetty, Ditixa T Desai, Dinesh O Shah, Mark D P Willcox","doi":"10.1007/s13346-024-01543-8","DOIUrl":"10.1007/s13346-024-01543-8","url":null,"abstract":"<p><p>To improve drug bioavailability, eye drops can be replaced by drug-eluting contact lenses. However, issues of drug leaching from lenses during manufacture and storage, and sterilization, currently limit their commercial application. To address the issues, stimuli-(lysozyme)-sensitive chitosan nanoparticles were developed to provide controlled ocular drug delivery. Nanoparticles were prepared by ionic gelation and characterized by TEM, X-ray diffraction, DSC, and FTIR. In the flux study, conventional-soaked contact lenses (SM-TM-CL) showed high-burst release, while with direct drug-only laden contact lenses (DL-TM-CL) the drug was lost during extraction and sterilization, as well as having poor swelling and optical properties. The nanoparticle-laden contact lenses (TM-Cht-NPs) showed controlled release of timolol for 120 h in the presence of lysozyme, with acceptable opto-physical properties. In the shelf-life study, the TM-Cht-NPs contact lenses showed no leaching or alteration in the drug release pattern. In animal studies, the TM-NPs-CL lenses gave a high drug concentration in rabbit tear fluid (mean = 11.01 µg/mL for 56 h) and helped maintain a low intraocular pressure for 120 h. In conclusion, the chitosan nanoparticle-laden contact lenses demonstrated the potential application to treat glaucoma with acceptable opto-physical properties and addressed the issues of drug-leaching during sterilization and storage.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3212-3224"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971396","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":"Precise control of microfluidic flow conditions is critical for harnessing the in vitro transfection capability of pDNA-loaded lipid-Eudragit nanoparticles.","authors":"Diviya Santhanes, Huiming Zhang, Alex Wilkins, Robert John Aitken, Anne-Louise Gannon, Mingtao Liang","doi":"10.1007/s13346-024-01523-y","DOIUrl":"10.1007/s13346-024-01523-y","url":null,"abstract":"<p><p>Microfluidics is widely regarded as a leading technology for industrial-scale manufacture of multicomponent, gene-based nanomedicines in a reproducible manner. Yet, very few investigations detail the impact of flow conditions on the biological performance of the product, particularly biocompatibility and therapeutic efficiency. Herein, this study investigated the engineering of a novel lipid-Eudragit hybrid nanoparticle in a bifurcating microfluidics micromixer for plasmid DNA (pDNA) delivery. Nanoparticles of ~150 nm in size, with uniform polydispersity index (PDI = 0.2) and ξ-potential of 5-11 mV were formed across flow rate ratios (FRR, aqueous to organic phase) of 3:1 and 5:1, respectively. The hybrid nanoparticles maintained colloidal stability and structural integrity of loaded pDNA following recovery by ultracentrifugation. Importantly, in vitro testing in human embryonic kidney cell line (HEK293T) revealed significant differences in biocompatibility and transfection efficiency (TE). Lipid-Eudragit nanoparticles produced at FRR 3:1 displayed high cellular toxicity (0-30% viability), compared with nanoparticles prepared at FRR 5:1 (50-100% viability). Red fluorescent protein (RFP) expression was sustained for 24-72 h following exposure of cells to nanoparticles, indicating controlled release of pDNA and trafficking to the nucleus. Nanoparticles produced at FRR 5:1 resulted in markedly higher TE (12%) compared with those prepared at FRR 3:1 (2%). Notably, nanoparticles produced using the bench-scale nanoprecipitation method resulted in lower biocompatibility (30-90%) but higher RFP expression (25-38%). These findings emphasize the need for in-depth analysis of the effect of formulation and flow conditions on the physicochemical and biological performance of gene nanomedicines when transitioning from bench to clinic.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3055-3069"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of excipients on the interactions of self-emulsifying drug delivery systems with human blood plasma and plasma membranes.","authors":"Bao Le-Vinh, Nguyet-Minh Nguyen Le, Thi Nhu Quynh Phan, Hung Thanh Lam, Andreas Bernkop-Schnürch","doi":"10.1007/s13346-024-01541-w","DOIUrl":"10.1007/s13346-024-01541-w","url":null,"abstract":"<p><p>Due to its versatility in formulation and manufacturing, self-emulsifying drug delivery systems (SEDDS) can be used to design parenteral formulations. Therefore, it is necessary to understand the effects of excipients on the behavior of SEDDS formulations upon parenteral administration, particularly their interactions with blood plasma and cell membranes. In this study, we prepared three neutrally charged SEDDS formulations composed of medium-chain triglycerides as the oil phase, polyoxyl-35 castor oil (EL35) and polyethylene glycol (15)-hydroxystearate (HS15) as the nonionic surfactants, medium-chain mono- and diglycerides as the co-surfactant, and propylene glycol as the co-solvent. The cationic surfactant, didodecyldimethylammonium bromide (DDA), and the anionic surfactant, sodium deoxycholate (DEO), were added to the neutral SEDDS preconcentrates to obtain cationic and anionic SEDDS, respectively. SEDDS were incubated with human blood plasma and recovered by size exclusion chromatography. Data showed that SEDDS emulsion droplets can bind plasma protein to different extents depending on their surface charge and surfactant used. At pH 7.4, the least protein binding was observed with anionic SEDDS. Positive charges increased protein binding. SEDDS stabilized by HS15 can adsorb more plasma protein and induce more plasma membrane disruption activity than SEDDS stabilized by EL35. These effects were more pronounced with the HS15 + DDA combination. The addition of DDA and DEO to SEDDS increased plasma membrane disruption (PMD) activities, and DDA (1% w/w) was more active than DEO (2% w/w). PMD activities of SEDDS were concentration-dependent and vanished at appropriate dilution ratios.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3200-3211"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ti₃C₂ (MXene), an advanced carrier system: role in photothermal, photoacoustic, enhanced drugs delivery and biological activity in cancer therapy.","authors":"Vishal Kumar Deb, Utkarsh Jain","doi":"10.1007/s13346-024-01572-3","DOIUrl":"10.1007/s13346-024-01572-3","url":null,"abstract":"<p><p>In the realm of healthcare and the advancing field of medical sciences, the development of efficient drug delivery systems become an immense promise to cure several diseases. Despite considerable advancements in drug delivery systems, numerous challenges persist, necessitating further enhancements to optimize patient outcomes. Smart nano-carriers, for instance, 2D sheets nano-carriers are the recently emerging nanosheets that may garner attention for targeted delivery of bioactive compounds, drugs, and genes to kill cancer cells. Within these advancements, Ti₃C₂T_X-MXene, characterized as a two-dimensional transition metal carbide, has surfaced as a prominent intelligent nanocarrier within nanomedicine. Its noteworthy characteristics facilitated it as an ideal nanocarrier for cancer therapy. In recent advancements in drug delivery research, Ti₃C₂T_X-MXene 2D nanocarriers have been designed to release drugs in response to specific stimuli, guided by distinct physicochemical  parameters. This review emphasized the multifaceted role of Ti₃C₂T_X-MXene as a potential carrier for delivering poorly hydrophilic drugs to cancer cells, facilitated by various polymer coatings. Furthermore, beyond drug delivery, this smart nanocarrier demonstrates utility in photoacoustic imaging and photothermal therapy, further highlighting its significant role in cellular mechanisms.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3009-3031"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140858820","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":"Preparation and characterization of Sorafenib nano-emulsion: impact on pharmacokinetics and toxicity; an in vitro and in vivo study.","authors":"Dalia Zaafar, Heba M A Khalil, Gehad E Elkhouly, Abanoub Selim Sedeky, Yasmine H Ahmed, Mona G Khalil, Yasmin Abo-Zeid","doi":"10.1007/s13346-024-01530-z","DOIUrl":"10.1007/s13346-024-01530-z","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths worldwide. Current treatment strategies include surgical resection, liver transplantation, liver-directed therapy, and systemic therapy. Sorafenib (Sor) is the first systemic drug authorized by the US Food and Drug Administration (FDA) for HCC treatment. Nevertheless, the conventional oral administration of Sor presents several limitations: poor solubility, low bioavailability, drug resistance development, and off-target tissue accumulation, leading to numerous adverse effects. Nano-emulsion, a nano-delivery system, is a viable carrier for poorly water-soluble drugs. It aims to enhance drug bioavailability, target organ accumulation, and reduce off-target tissue exposure, thus improving therapeutic outcomes while minimizing side effects. This study formulated Sor nano-emulsion (Sor NanoEm) using the homogenization technique. The resultant nano-emulsion was characterized by particle size (121.75 ± 12 nm), polydispersity index (PDI; 0.310), zeta potential (-12.33 ± 1.34 mV), viscosity (34,776 ± 3276 CPs), and pH (4.38 ± 0.3). Transmission Electron Microscopy exhibited spherical nano-droplets with no aggregation signs indicating stability. Furthermore, the encapsulation of Sor within the nano-emulsion sustained its release, potentially reducing the frequency of therapeutic doses. Cytotoxicity assessments on the HepG2 cell line revealed that Sor NanoEm had a significantly (P < 0.05) more potent cytotoxic effect compared to Sor suspension. Subsequent tests highlighted superior pharmacokinetic parameters and reduced dosage requirements of Sor NanoEm in mice. It exhibited an enhanced safety profile, particularly in behavior, brain, and liver, compared to its suspended form. These findings underscore the enhanced pharmacological and toxicological attributes of Sor Nano-emulsion, suggesting its potential utility in HCC treatment.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3089-3111"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational development of fingolimod nano-embedded microparticles as nose-to-brain neuroprotective therapy for ischemic stroke.","authors":"Xinyue Zhang, Guangpu Su, Zitong Shao, Ho Wan Chan, Si Li, Stephanie Chow, Chi Kwan Tsang, Shing Fung Chow","doi":"10.1007/s13346-024-01721-8","DOIUrl":"https://doi.org/10.1007/s13346-024-01721-8","url":null,"abstract":"<p><p>Ischemic stroke is one of the major diseases causing varying degrees of dysfunction and disability worldwide. The current management of ischemic stroke poses significant challenges due to short therapeutic windows and limited efficacy, highlighting the pressing need for novel neuroprotective treatment strategies. Previous studies have shown that fingolimod (FIN) is a promising neuroprotective drug. Here, we report the rational development of FIN nano-embedded nasal powders using full factorial design experiments, aiming to provide rapid neuroprotection after ischemic stroke. Flash nanoprecipitation was employed to produce FIN nanosuspensions with the aid of polyvinylpyrrolidone and cholesterol as stabilizers. The optimized nanosuspension (particle size = 134.0 ± 0.6 nm, PDI = 0.179 ± 0.021, physical stability = 72 ± 0 h, and encapsulation efficiency of FIN = 90.67 ± 0.08%) was subsequently spray-dried into a dry powder, which exhibited excellent redispersibility (RdI = 1.09 ± 0.04) and satisfactory drug deposition in the olfactory region using a customized 3D-printed nasal cast (45.4%) and an Alberta Idealized Nasal Inlet model (8.6%) at 15 L/min. The safety of the optimized FIN nano-embedded dry powder was confirmed in cytotoxicity studies with nasal (RPMI 2650 and Calu-3 cells) and brain related cells (SH-SY5Y and PC 12 cells), while the neuroprotective effects were demonstrated by observed behavioral improvements and reduced cerebral infarct size in a middle cerebral artery occlusion mouse stroke model. The neuroprotective effect was further evidenced by increased expression of anti-apoptotic protein BCL-2 and decreased expression of pro-apoptotic proteins CC3 and BAX in brain peri-infarct tissues. Our findings highlight the potential of nasal delivery of FIN nano-embedded dry powder as a rapid neuroprotective treatment strategy for acute ischemic stroke.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562433","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 calcitriol and PGD₂-G-loaded lipid nanocapsules on oligodendrocyte progenitor cell differentiation and remyelination.","authors":"Ariane Mwema, Viridiane Gratpain, Bernard Ucakar, Kevin Vanvarenberg, Océane Perdaens, Vincent van Pesch, Giulio G Muccioli, Anne des Rieux","doi":"10.1007/s13346-024-01535-8","DOIUrl":"10.1007/s13346-024-01535-8","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS) in need of a curative treatment. MS research has recently focused on the development of pro-remyelinating treatments and neuroprotective therapies. Here, we aimed at favoring remyelination and reducing neuro-inflammation in a cuprizone mouse model of brain demyelination using nanomedicines. We have selected lipid nanocapsules (LNC) coated with the cell-penetrating peptide transactivator of translation (TAT), loaded with either a pro-remyelinating compound, calcitriol (Cal-LNC TAT), or an anti-inflammatory bioactive lipid, prostaglandin D₂-glycerol ester (PGD₂-G) (PGD₂-G-LNC TAT). Following the characterization of these formulations, we showed that Cal-LNC TAT in combination with PGD₂-G-LNC TAT increased the mRNA expression of oligodendrocyte differentiation markers both in the CG-4 cell line and in primary mixed glial cell (MGC) cultures. However, while the combination of Cal-LNC TAT and PGD₂-G-LNC TAT showed promising results in vitro, no significant impact, in terms of remyelination, astrogliosis, and microgliosis, was observed in vivo in the corpus callosum of cuprizone-treated mice following intranasal administration. Thus, although calcitriol's beneficial effects have been abundantly described in the literature in the context of MS, here, we show that the different doses of calcitriol tested had a negative impact on the mice well-being and showed no beneficial effect in the cuprizone model in terms of remyelination and neuro-inflammation, alone and when combined with PGD₂-G-LNC TAT.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3128-3146"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139746386","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":"Characterizing interregional differences in the rheological properties and composition of rat small intestinal mucus.","authors":"Mette Klitgaard, Jette Jacobsen, Maja Nørgaard Kristensen, Ragna Berthelsen, Anette Müllertz","doi":"10.1007/s13346-024-01574-1","DOIUrl":"10.1007/s13346-024-01574-1","url":null,"abstract":"<p><p>The mucus layer in the small intestine is generally regarded as a barrier to drug absorption. However, the mucus layer is a complex system, and presently, only a few studies have been conducted to elucidate its physicochemical properties. The current study hypothesizes that the mucus layer contains solubility-enhancing surfactants and thus might aid the oral absorption of poorly water-soluble drugs. Mucus was sampled from sections of the small intestine of fasted rats to analyze the rheological properties and determine the mucus pH and concentrations of proteins and endogenous surfactants, i.e., bile salts, polar lipids, and neutral lipids. The mucus layer in the two proximal sections of the small intestine exhibited different rheological properties such as higher zero-shear viscosity and lower loss tangent and higher protein concentrations compared to all subsequent sections of the small intestine. The pH of the mucus layer was stable at ~ 6.5 throughout most of the small intestine, but increased to 7.5 in the ileum. The bile salt concentrations increased from the duodenum (16.0 ± 2.2 mM) until the mid jejunum (55.1 ± 9.5 mM), whereas the concentrations of polar lipids and neutral lipids decreased from the duodenum (17.4 ± 2.2 mM and 37.8 ± 1.6 mM, respectively) until the ileum (4.8 ± 0.4 mM and 10.7 ± 1.1 mM, respectively). In conclusion, the mucus layer of the rat small intestine contains endogenous surfactants at levels that might benefit solubilization and absorption of orally administered poorly water-soluble drugs.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3309-3320"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local administration of irinotecan using an implantable drug delivery device stops high-grade glioma tumor recurrence in a glioblastoma tumor model.","authors":"Dina Abdelnabi, Sarah Lastakchi, Colin Watts, Hannah Atkins, Shawn Hingtgen, Alain Valdivia, Christopher McConville","doi":"10.1007/s13346-024-01524-x","DOIUrl":"10.1007/s13346-024-01524-x","url":null,"abstract":"<p><p>The treatment for Glioblastoma is limited due to the presence of the blood brain barrier, which restricts the entry of chemotherapeutic drugs into the brain. Local delivery into the tumor resection margin has the potential to improve efficacy of chemotherapy. We developed a safe and clinically translatable irinotecan implant for local delivery to increase its efficacy while minimizing systemic side effects. Irinotecan-loaded implants were manufactured using hot melt extrusion, gamma sterilized at 25 kGy, and characterized for their irinotecan content, release, and drug diffusion. Their therapeutic efficacy was evaluated in a patient-derived xenograft mouse resection model of glioblastoma. Their safety and translatability were evaluated using histological analysis of brain tissue and serum chemistry analysis. Implants containing 30% and 40% w/w irinotecan were manufactured without plasticizer. The 30% and 40% implants showed moderate local toxicity up to 2- and 6-day post-implantation. Histopathology of the implantation site showed signs of necrosis at days 45 and 14 for the 30% and 40% implants. Hematological analysis and clinical chemistry showed no signs of serious systemic toxicity for either implant. The 30% implants had an 80% survival at day 148, with no sign of tumor recurrence. Gamma sterilization and 12-month storage had no impact on the integrity of the 30% implants. This study demonstrates that the 30% implants are a promising novel treatment for glioblastoma that could be quickly translated into the clinic.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3070-3088"},"PeriodicalIF":5.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}