Journal of pharmaceutical sciences最新文献_第9页

Assessment of immunogenicity and protective efficiency of multi-epitope antigen-loaded in mannan decorated PLGA nanoparticles against tuberculosis.

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-02 DOI: 10.1016/j.xphs.2024.11.025

Yousef Amini, Mona Kabiri, Saeid Amel Jamehdar, Mojtaba Sankian, Zahra Meshkat, Sirwan Zare, Saman Soleimanpour, Hadi Farsiani, Bagher Moradi, Mohsen Tafaghodi

{"title":"Assessment of immunogenicity and protective efficiency of multi-epitope antigen-loaded in mannan decorated PLGA nanoparticles against tuberculosis.","authors":"Yousef Amini, Mona Kabiri, Saeid Amel Jamehdar, Mojtaba Sankian, Zahra Meshkat, Sirwan Zare, Saman Soleimanpour, Hadi Farsiani, Bagher Moradi, Mohsen Tafaghodi","doi":"10.1016/j.xphs.2024.11.025","DOIUrl":"10.1016/j.xphs.2024.11.025","url":null,"abstract":"The antigen-targeting to dendritic cells (DCs) has gained increasing attention as the potential approach for immunotherapy in recent years due to the ability of DCs to regulate innate and adaptive immunity. In the present study, the immunogenicity and protective efficiency of mannan-decorated PLGA nanoparticles (NPs) loaded with multi-epitopes mycobacterium tuberculosis antigen (HspX-Ppe44-EsxV) were evaluated as a targeted delivery system to DCs. For this purpose, PLGA nanoparticle formulations were prepared and subsequently decorated by mannan. The physicochemical properties and level of mannan incorporation, as well as encapsulation efficiency and antigen release, were assessed. The potential of formulated NPs for antigen targeting to DCs, and immunogenicity against tuberculosis (TB) were investigated using immunofluorescence assay and in-vivo experiments. Mannan incorporation enhanced the uptake of fusion-loaded PLGA by DCs. The cytokine and antibody assays demonstrated that mannosylation of NPs and BCG-primed mice boosted by mannan-PLGA could significantly elevate Th1-biased immune responses relative to the BCG and non-modified PLGA NPs. Our findings also proved that the mannosylated vaccine in the presence of CpG could evoke Th1 and Th17 responses with appropriate protective efficiency against TB in mice. This result illustrated that the active targeting of DCs by mannan-PLGA NPs could induce a proper anti-tuberculosis response, which is essential for protection against tuberculosis.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780484","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}

引用次数: 0

Storage stability and solution binding affinity of an Fc-fusion mimetic.

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-02 DOI: 10.1016/j.xphs.2024.11.016

Sama Prikalkhoran, David Guiliano, Hanieh Khalili

引用次数: 0

Visualisation and quantification of subcutaneous injections of different volumes, viscosities and injection rates: An ex-vivo micro-CT study. 不同体积、粘度和注射速度的皮下注射的可视化和量化：体外显微 CT 研究。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-09-19 DOI: 10.1016/j.xphs.2024.08.019

Joel Gresham, Gerard Bruin, Marie Picci, Karoline Bechtold-Peters, Thomas Dimke, Evan Davies, Kasia Błażejczyk, Wouter Willekens, Heleen Fehervary, Greetje Vande Velde

{"title":"Visualisation and quantification of subcutaneous injections of different volumes, viscosities and injection rates: An ex-vivo micro-CT study.","authors":"Joel Gresham, Gerard Bruin, Marie Picci, Karoline Bechtold-Peters, Thomas Dimke, Evan Davies, Kasia Błażejczyk, Wouter Willekens, Heleen Fehervary, Greetje Vande Velde","doi":"10.1016/j.xphs.2024.08.019","DOIUrl":"10.1016/j.xphs.2024.08.019","url":null,"abstract":"The effects of subcutaneous (SC) injection parameters such as drug formulation volume, viscosity and injection rate on therapeutic performance and tolerability have not been established for any drug product. In this study four groups of SC injections were performed on fresh ex vivo minipig abdominal tissue samples, varying volume (0.5-1 mL), viscosity (1-11 cP) and rate (0.02-0.1 mL/s). Micro-CT provided high resolution (50 micron) imaging of the SC tissues before and after injection, enabling a detailed 3D visualisation and analysis of how both injection parameters and tissue microstructure influence spatial distribution of injectables. We found that volume was the only significant factor for spatial distribution of injectate within our design space, and there were no significant factors for tissue backpressure. Variability within test groups was typically greater than differences between group means. Accordingly, whilst the higher viscosity formulations consistently exhibited reduced spatial distribution, the sample size was not large enough to establish confidence in this result. Comparing our findings to clinical evidence, we conclude that injection site and depth are more likely to influence PK and bioavailability than volume, viscosity and rate within our experimental space.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3447-3456"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289721","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}

引用次数: 0

Determination of solid-state acidity of lyophilized trehalose containing citrate, phosphate, and histidine buffers using UV/VIS diffuse reflectance and solid-state NMR spectroscopy. 利用 UV/VIS 漫反射和固态 NMR 光谱测定含柠檬酸盐、磷酸盐和组氨酸缓冲液的冻干海藻糖的固态酸度。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-09-21 DOI: 10.1016/j.xphs.2024.09.019

Ashley Lay-Fortenbery, Xiaoda Yuan, Lukáš Veselý, Dominik Heger, Evgenyi Shalaev, Yongchao Su, Eric Munson

{"title":"Determination of solid-state acidity of lyophilized trehalose containing citrate, phosphate, and histidine buffers using UV/VIS diffuse reflectance and solid-state NMR spectroscopy.","authors":"Ashley Lay-Fortenbery, Xiaoda Yuan, Lukáš Veselý, Dominik Heger, Evgenyi Shalaev, Yongchao Su, Eric Munson","doi":"10.1016/j.xphs.2024.09.019","DOIUrl":"10.1016/j.xphs.2024.09.019","url":null,"abstract":"Changes in the protonation state of lyophilized proteins can impact structural integrity, chemical stability, and propensity to aggregate upon reconstitution. When a buffer is chosen, the freezing/drying process may result in dramatic changes in the protonation state of the protein due to ionization shift of the buffer. In order to determine whether protonation shifts are occurring, ionizable probes can be added to the formulation. Optical probes (dyes) have shown dramatic ionization changes in lyophilized products, but it is unclear whether the pH indicator is uniform throughout the matrix and whether the change in the pH indicator actually mirrors drug ionization changes. In solid-state NMR (SSNMR) spectroscopy, the chemical shift of the carbonyl carbon in carboxylic acids is very sensitive to the ionization state of the acid. Therefore, SSNMR can be used to measure ionization changes in a lyophilized matrix by employing a small quantity of an isotopically-labeled carboxylic acid species in the formulation. This paper compares the apparent pH of six trehalose-containing lyophilized buffer systems using SSNMR and UV-Vis diffuse reflectance spectroscopy (UVDRS). Both SSNMR and UVDRS results using two different ionization probes (butyric acid and bromocresol purple, respectively) showed little change in apparent acidity compared to the pre-lyophilized solution in a sodium citrate buffer, but a greater change was observed in potassium phosphate, sodium phosphate, and histidine buffers. While the trends between the two methods were similar, there were differences in the numerical values of equivalent pH (pHeq) observed between the two methods. The potential causes contributing to the differences are discussed.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3479-3488"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307976","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}

引用次数: 0

Optimization and characterization of a dose-controllable orodispersible dexamethasone film for personalized medicine. 用于个性化医疗的可控制剂量的口服地塞米松薄膜的优化和表征。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-10-01 DOI: 10.1016/j.xphs.2024.09.023

Motoki Inoue, Moyumi Odate, Toshiro Fukami

{"title":"Optimization and characterization of a dose-controllable orodispersible dexamethasone film for personalized medicine.","authors":"Motoki Inoue, Moyumi Odate, Toshiro Fukami","doi":"10.1016/j.xphs.2024.09.023","DOIUrl":"10.1016/j.xphs.2024.09.023","url":null,"abstract":"Decadron® tablets are commercially available in 0.5 and 4 mg formulations, often requiring the use of multiple tablets or fractional doses when the required dosage is unavailable. This practice can lead to inaccuracies and handling difficulties associated with tablet splitting and crushing tablets into powder. This study aimed to develop an orodispersible dexamethasone film that would allow precise dose control and overcome these challenges. The film formulation was optimized by dissolving varying amounts of hypromellose, glycerol, and dexamethasone in ethanolic solutions. These solutions were cast and dried at different thicknesses. Statistical optimization using the design of experiments was used to determine the ideal film composition. The optimized films met pharmaceutical standards, with a mass variation ≦ 2 %, thickness variation ≦ 2.5 %, and disintegration time ≦ 20 s. The uniform distribution of dexamethasone within the film enabled easy content control based on the film area. Dissolution testing indicated that the dissolution behavior of the film formulation behaved similarly to commercial tablets for up to 90 min. In conclusion, the developed orodispersible film offers precise dexamethasone dose control and addresses the limitations of tablet splitting, positioning it as a promising candidate for personalized medicine applications.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3518-3524"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372108","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}

引用次数: 0

Physical compatibility and chemical stability of bupivacaine, epinephrine, and nalbuphine in 0.45 % sodium chloride, 0.9 % sodium chloride, or plasma-lyte A. 布比卡因、肾上腺素和纳布啡在 0.45%氯化钠、0.9%氯化钠或血浆-Lyte A 中的物理兼容性和化学稳定性。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-10-18 DOI: 10.1016/j.xphs.2024.10.003

Zachary Senger, Gladys Uwera Mihigo, Mitchell S Howard, Gabriella Baki, Mariann D Churchwell, Virender Kumar, Justin P Reinert

{"title":"Physical compatibility and chemical stability of bupivacaine, epinephrine, and nalbuphine in 0.45 % sodium chloride, 0.9 % sodium chloride, or plasma-lyte A.","authors":"Zachary Senger, Gladys Uwera Mihigo, Mitchell S Howard, Gabriella Baki, Mariann D Churchwell, Virender Kumar, Justin P Reinert","doi":"10.1016/j.xphs.2024.10.003","DOIUrl":"10.1016/j.xphs.2024.10.003","url":null,"abstract":"Purpose: To evaluate the physical compatibility and chemical stability of the combination of bupivacaine, epinephrine, and nalbuphine when in mixed in 0.45 % sodium chloride, 0.9 % sodium chloride, or Plasma-Lyte A.Methods: Bupivacaine 0.5 % (15 mL), epinephrine 1 mg/mL (0.15 mL), and nalbuphine 10 mg/mL (0.5 mL) were combined to prepare three distinct admixtures with 0.45 % sodium chloride, 0.9 % sodium chloride, or Plasma-Lyte A. Visual inspection, spectrophotometric analysis, pH evaluation, and high-performance liquid chromatography tests were conducted at hours 0, 1, 5, 8, and 24. Samples were stored in ambient room light at room temperature.Results: There were no demonstrable changes identified in any of the samples with regards to visual changes, spectrophotometric absorbance, or pH. In each studied fluid, the remaining drug concentrations were an average of 100.92 % bupivacaine, 95.8 % epinephrine, and 100.02 % nalbuphine.Conclusions: The combination of bupivacaine, epinephrine, and nalbuphine was found to be physically compatibility and chemically stable for a period of 24 h at room temperature.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3538-3542"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468296","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}

引用次数: 0

Using the refined Developability Classification System (rDCS) to guide the design of oral formulations. 使用改良的显影性分类系统 (rDCS) 指导口服制剂的设计。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-10-05 DOI: 10.1016/j.xphs.2024.09.022

Kristian Beran, Eline Hermans, René Holm, Kia Sepassi, Jennifer Dressman

{"title":"Using the refined Developability Classification System (rDCS) to guide the design of oral formulations.","authors":"Kristian Beran, Eline Hermans, René Holm, Kia Sepassi, Jennifer Dressman","doi":"10.1016/j.xphs.2024.09.022","DOIUrl":"10.1016/j.xphs.2024.09.022","url":null,"abstract":"The refined Developability Classification System (rDCS) provides a comprehensive animal-free approach for assessing biopharmaceutical risks associated with developing oral formulations. This work demonstrates practical application of a recently advanced rDCS framework guiding formulation design for six diverse active pharmaceutical ingredients (APIs) and compares rDCS classifications with those of the Biopharmaceutics Classification System (BCS). While the BCS assigns five of the APIs to class II/IV, indicating potentially unfavorable biopharmaceutical attributes, the rDCS provides a more nuanced risk assessment. Both BCS and rDCS assign acetaminophen to class I at therapeutic doses. Voriconazole and lemborexant (both BCS II) are classified in rDCS class I at therapeutic doses, indicating suitability for development as conventional oral formulations. Fedratinib is classified as BCS IV but the rDCS indicates a stratified risk (class I, IIa or IIb), depending on the relevance of supersaturation/precipitation in vivo. Voxelotor and istradefylline (both BCS II) belong to rDCS class IIb, requiring solubility enhancement to achieve adequate oral bioavailability. Comparing the rDCS analysis with literature on development and pharmacokinetics demonstrates that the rDCS reliably supports oral formulation design over a wide range of API characteristics, thus providing a strong foundation for guiding development.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3497-3517"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391358","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}

引用次数: 0

A novel cocrystal approach celecoxib with piperine: Simultaneously enhance dissolution rate and compressibility. 塞来昔布与胡椒碱的新型共晶体方法：同时提高溶出率和可压缩性

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-10-15 DOI: 10.1016/j.xphs.2024.10.011

Lili Fitriani, Fauziyyah Dirfedli, Yori Yuliandra, Dwi Setyawan, Masaki Uchida, Hironaga Oyama, Hidehiro Uekusa, Erizal Zaini

{"title":"A novel cocrystal approach celecoxib with piperine: Simultaneously enhance dissolution rate and compressibility.","authors":"Lili Fitriani, Fauziyyah Dirfedli, Yori Yuliandra, Dwi Setyawan, Masaki Uchida, Hironaga Oyama, Hidehiro Uekusa, Erizal Zaini","doi":"10.1016/j.xphs.2024.10.011","DOIUrl":"10.1016/j.xphs.2024.10.011","url":null,"abstract":"Celecoxib, a selective COX-2 inhibitor non-steroidal anti-inflammatory drug (NSAID), exhibits analgesic and anti-inflammatory properties similar to piperine, the secondary metabolite of Piper nigrum L. Unfortunately, celecoxib has a low compressibility and low dissolution rate in aqueous medium. This study aimed to prepare a cocrystal of celecoxib and piperine to enhance the dissolution rate and compressibility properties of celecoxib. The cocrystal was synthesized using the seeding method and thoroughly characterized using Powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectrophotometry, and single-crystal X-ray diffraction techniques. The complete change in PXRD, decrease in melting point in DSC measurements, and shift in the NH stretching band in the FT-IR spectrum suggested the formation of cocrystals phase. Single-crystal XRD confirmed the formation of an equimolar ratio of cocrystals of celecoxib and piperine. The intrinsic dissolution test was conducted to confirm the impact on the cocrystal to dissolution, and it showed a slight increase compared to intact celecoxib. To assess the physico-mechanical properties, the cocrystal powders were compressed into tablets with varying forces. The results demonstrated a significant improvement in compressibility compared with intact celecoxib owing to the slip plane in the crystal lattice of the cocrystal. In conclusion, our novel celecoxib-piperine cocrystal exhibited distinct physicochemical characteristics compared to intact celecoxib, showing enhanced dissolution rate and compressibility.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3565-3573"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468266","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}

引用次数: 0

Injectability of high concentrated suspensions using model microparticles. 使用模型微粒研究高浓度悬浮液的可注射性。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-10-05 DOI: 10.1016/j.xphs.2024.09.026

Kavin Kowsari, Lynn Lu, Steven C Persak, Guangli Hu, William Forrest, Robert Berger, Jeffrey C Givand, Sahab Babaee

{"title":"Injectability of high concentrated suspensions using model microparticles.","authors":"Kavin Kowsari, Lynn Lu, Steven C Persak, Guangli Hu, William Forrest, Robert Berger, Jeffrey C Givand, Sahab Babaee","doi":"10.1016/j.xphs.2024.09.026","DOIUrl":"10.1016/j.xphs.2024.09.026","url":null,"abstract":"Administration of high-concentrated suspension formulations (i.e., solid particles dispersed in a liquid vehicle) can be limited due to their greater propensity for needle occlusion. The physical interaction between the solid phase (i.e., particles), the vehicle (i.e., flow field), and injection devices could result in the formation of particle bridging or filtering, posing a major risk in dose delivery accuracy and injectability. Here, given the limited understanding on how clogging initiates in syringe and needle delivery systems, we report an experimental approach to fully characterize the transient injection behavior of suspensions. In particular, we first established a custom fluorescence tagging and imaging technique with integrated force sensor to enable visual observation of local particle concentrations and plunger force monitoring throughout injection. Then, we investigated the effects of key formulation properties and device parameters including particle concentration and morphology, carrier viscosity, injection rate, needle and syringe sizes, and tissue backpressure on the incidence of suspension particle jamming and needle clogging. We performed systematic benchmark studies demonstrating that increasing needle inner diameter (ID) and particle density considerably reduced clogging risk, while increasing vehicle viscosity, particle size, and tissue backpressure significantly increased clogging. The experimental framework presented is amenable to quantifying clogging risk in drug-loaded particle suspensions and provides a guideline to make informed decisions on the tradeoffs between creating particles for pharmaceutical impact and feasibility of injection delivery.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3525-3537"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381146","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}

引用次数: 0

Immunogenicity risk assessment of empty capsids present in adeno-associated viral vectors using predictive innate immune responses. 利用预测性先天性免疫反应评估腺相关病毒载体空壳的免疫原性风险。

IF 3.7 3区医学

Journal of pharmaceutical sciences Pub Date : 2024-12-01 Epub Date: 2024-09-24 DOI: 10.1016/j.xphs.2024.09.006

Nicole Jarvi, Kirk Hofman, Aditi Venkatesh, Emily Gorecki, Sathy V Balu-Iyer

{"title":"Immunogenicity risk assessment of empty capsids present in adeno-associated viral vectors using predictive innate immune responses.","authors":"Nicole Jarvi, Kirk Hofman, Aditi Venkatesh, Emily Gorecki, Sathy V Balu-Iyer","doi":"10.1016/j.xphs.2024.09.006","DOIUrl":"10.1016/j.xphs.2024.09.006","url":null,"abstract":"Immunogenicity of gene therapy and the impacts on safety and efficacy are of increasing interest in the pharmaceutical industry. Unique structural aspects of gene therapy delivery vectors, such as adeno-associated viral (AAV) vectors, are expected to activate the innate immune system. The risk of innate immune activation is critical to understand due to the potential impacts on safety and on subsequent adaptive immune responses. In this study, we investigated the responses of key innate immune players-dendritic cells, natural killer (NK) cells, and the complement system-to AAV8 capsids. Immunogenicity risk was also predicted in the presence empty AAV capsids for AAV gene therapy. Compared to genome-containing \"full\" AAV8 capsids, empty AAV8 capsids more strongly induced proinflammatory cytokine production and migration by human and mouse dendritic cells, but the \"full\" capsid increased expression of co-stimulatory markers. Furthermore, in an NK cell degranulation assay, we found mixtures of empty and full AAV8 capsids to activate expression of TNF-α, IFN-γ, and CD107a more strongly in multiple NK cell populations compared to either capsid type alone. Serum complement C3a was also induced more strongly in the presence of mixed empty and full AAV8 capsid formulations. Risk for innate immune activation suggests the importance to determine acceptable limits of empty capsids. Immunogenicity risk assessment of novel biological modalities will benefit from the aforementioned in vitro innate immune activation assays providing valuable mechanistic information.","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"3457-3469"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348825","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}

引用次数: 0