scholarly journals Optimising Hydrogel Release Profiles for Viro-Immunotherapy Using Oncolytic Adenovirus Expressing IL-12 and GM-CSF with Immature Dendritic Cells

2020 ◽  
Vol 10 (8) ◽  
pp. 2872 ◽  
Author(s):  
Adrianne L. Jenner ◽  
Federico Frascoli ◽  
Chae-Ok Yun ◽  
Peter S. Kim
Keyword(s):  
Dendritic Cells ◽  
Sustained Release ◽  
Immune Cells ◽  
Fundamental Problem ◽  
Release Kinetics ◽  
Delivery Systems ◽  
Release Profile ◽  
Oncolytic Viruses ◽  
Immature Dendritic Cells ◽  
Release Profiles

Sustained-release delivery systems, such as hydrogels, significantly improve cancer therapies by extending the treatment efficacy and avoiding excess wash-out. Combined virotherapy and immunotherapy (viro-immunotherapy) is naturally improved by these sustained-release systems, as it relies on the continual stimulation of the antitumour immune response. In this article, we consider a previously developed viro-immunotherapy treatment where oncolytic viruses that are genetically engineered to infect and lyse cancer cells are loaded onto hydrogels with immature dendritic cells (DCs). The time-dependent release of virus and immune cells results in a prolonged cancer cell killing from both the virus and activated immune cells. Although effective, a major challenge is optimising the release profile of the virus and immature DCs from the gel so as to obtain a minimum tumour size. Using a system of ordinary differential equations calibrated to experimental results, we undertake a novel numerical investigation of different gel-release profiles to determine the optimal release profile for this viro-immunotherapy. Using a data-calibrated mathematical model, we show that if the virus is released rapidly within the first few days and the DCs are released for two weeks, the tumour burden can be significantly decreased. We then find the true optimal gel-release kinetics using a genetic algorithm and suggest that complex profiles present unnecessary risk and that a simple linear-release model is optimal. In this work, insight is provided into a fundamental problem in the growing field of sustained-delivery systems using mathematical modelling and analysis.

scholarly journals Sustained Release of Linezolid from Prepared Hydrogels with Polyvinyl Alcohol and Aliphatic Dicarboxylic Acids of Variable Chain Lengths

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 982
Author(s):  
Gustavo Carreño ◽  
Adolfo Marican ◽  
Sekar Vijayakumar ◽  
Oscar Valdés ◽  
Gustavo Cabrera-Barjas ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Polyvinyl Alcohol ◽  
Sustained Release ◽  
Release Kinetics ◽  
Dicarboxylic Acids ◽  
Release Profile ◽  
Significant Activity ◽  
Crosslinking Degree ◽  
Aliphatic Dicarboxylic Acids

A series of hydrogels with a specific release profile of linezolid was successfully synthesized. The hydrogels were synthesized by cross-linking polyvinyl alcohol (PVA) and aliphatic dicarboxylic acids, which include succinic acid (SA), glutaric acid (GA), and adipic acid (AA). The three crosslinked hydrogels were prepared by esterification and characterized by equilibrium swelling ratio, infrared spectroscopy, thermogravimetric analysis, mechanical properties, and scanning electron microscopy. The release kinetics studies of the linezolid from prepared hydrogels were investigated by cumulative drug release and quantified by chromatographic techniques. Mathematical models were carried out to understand the behavior of the linezolid release. These data revealed that the sustained release of linezolid depends on the aliphatic dicarboxylic acid chain length, their polarity, as well as the hydrogel crosslinking degree and mechanical properties. The in vitro antibacterial assay of hydrogel formulations was assessed in an Enterococcus faecium bacterial strain, showing a significant activity over time. The antibacterial results were consistent with cumulative release assays. Thus, these results demonstrated that the aliphatic dicarboxylic acids used as crosslinkers in the PVA hydrogels were a determining factor in the antibiotic release profile.

Optimization Study to Develop Once-a-day Controlled Release Formulation of Metoclopramide with Predictable Design Space

1970 ◽  
Vol 1 (1) ◽  
pp. 71-76
Author(s):  
Rajesh Dubey ◽  
Udaya K. Chowdary ◽  
Venkateswarlu V.
Keyword(s):  
Controlled Release ◽  
Drug Release ◽  
Design Space ◽  
Release Kinetics ◽  
Release Profile ◽  
Release Formulation ◽  
Linear Effect ◽  
Controlled Release Formulation ◽  
The Difference ◽  
Face Centered

A controlled release formulation of metoclopramide was developed using a combination of hypromellose (HPMC) and hydrogenated castor oil (HCO). Developed formulations released the drug over 20 hr with release kinetics following Higuchi model. Compared to HCO, HPMC showed significantly higher influence in controlling the drug release at initial as well as later phase. The difference in the influence can be explained by the different swelling and erosion behaviour of the polymers. Effect of the polymers on release was optimized using a face-centered central composite design to generate a predictable design space. Statistical analysis of the drug release at various levels indicated a linear effect of the polymers’ levels on the drug release. The release profile of formulations containing the polymer levels at extremes of their ranges in design space was found to be similar to the predicted release profile

Development and Evaluation of Sustained Release Lipid Nanocarriers for Curcumin

2020 ◽  
Vol 5 (3) ◽  
pp. 224-235
Author(s):  
Harshal A. Pawar ◽  
Bhagyashree D. Bhangale
Keyword(s):  
Drug Delivery ◽  
Sustained Release ◽  
Drug Delivery Systems ◽  
Biological Activities ◽  
Curcuma Longa ◽  
Research Work ◽  
Elimination Rate ◽  
Delivery Systems ◽  
Physicochemical Stability ◽  
Wide Range

Background: Lipid based excipients have increased acceptance nowadays in the development of novel drug delivery systems in order to improve their pharmacokinetic profiles. Drugs encapsulated in lipids have enhanced stability due to the protection they experience in the lipid core of these nano-formulations. Phytosomes are newly discovered drug delivery systems and novel botanical formulation to produce lipophilic molecular complex which imparts stability, increases absorption and bioavailability of phytoconstituent. Curcumin, obtained from turmeric (Curcuma longa), has a wide range of biological activities. The poor solubility and wettability of curcumin are responsible for poor dissolution and this, in turn, results in poor bioavailability. To overcome these limitations, the curcumin-loaded nano phytosomes were developed to improve its physicochemical stability and bioavailability. Objective: The objective of the present research work was to develop nano-phytosomes of curcumin to improve its physicochemical stability and bioavailability. Methods: Curcumin-loaded nano phytosomes were prepared by using phospholipid Phospholipon 90 H using a modified solvent evaporation method. The developed curcumin nano phytosomes were evaluated by particle size analyzer and differential scanning calorimetry (DSC). Results: Results indicated that phytosomes prepared using curcumin and lipid in the ratio of 1:2 show good entrapment efficiency. The obtained curcumin phytosomes were spherical in shape with a size less than 100 nm. The prepared nano phytosomal formulation of curcumin showed promising potential as an antioxidant. Conclusion: The phytosomal complex showed sustained release of curcumin from vesicles. The sustained release of curcumin from phytosome may improve its absorption and lowers the elimination rate with an increase in bioavailability.

Higher CD1a Levels Correlate with PD-L1 Expression and Predict Worse Overall Survival in Triple-Negative Breast Carcinoma

Breast Care ◽  
2021 ◽  
pp. 1-9
Author(s):  
Jian Zheng ◽  
Yuntao Wei ◽  
Xiaoxi Li ◽  
Zhan Shen ◽  
Yong Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Breast Carcinoma ◽  
Triple Negative ◽  
Carcinoma Tissue ◽  
Kaplan Meier ◽  
Immature Dendritic Cells ◽  
Triple Negative Breast Carcinoma ◽  
High Median

Objective: The aim of this study was to measure the expression of PD-L1, CD1a (a marker for immature dendritic cells), and CD83 (a marker for mature dendritic cells) and further examine the associations of PD-L1, CD83, and CD1a with overall survival (OS) in triple-negative breast carcinoma patients. Methods: PD-L1, CD1a, and CD83 expression in breast carcinoma tissues and CD83 expression in lymph node tissues were examined by immunohistochemistry and tissue microarray in 159 patients. Patients were classified into the low, medium, and high PD-L1, CD1a, and CD83 levels. Pearson χ2 test was used to analyze the correlations between PD-L1, CD1a, and CD83. The Kaplan-Meier method was used to calculate the OS. Multivariate analysis was used to identify determinants of 3- and 5-year OS. Results: 25.1, 25.8, and 49.1% of the patients had low, medium, and high PD-L1 levels, respectively. PD-L1 levels significantly correlated with CD1a (r = 0.30409, p < 0.001) and CD83 levels (r = 0.6146, p < 0.001) in breast carcinoma tissue, as well as CD83 levels (r = 0.17508, p = 0.027) in lymph node. The median OS was 83 months (range 12–106), and the 3- and 5-year OS rates were 94.97% (95% CI 91.57–98.37) and 86.79% (95% CI 81.53–92.06), respectively. Moreover, patients with high median CD1a levels had a significantly lower 5-year OS rate (75.6%) than those with low median CD1a levels (93.5%, p = 0.038). Conclusion: PD-L1, CD1a, and CD83 are variably expressed in triple-negative breast carcinoma tissues, and PD-L1 expression correlates with CD1a and CD83. Higher CD1a levels correlate with PD-L1 expression and predict worse OS in triple-negative breast carcinoma.

scholarly journals Cell subtypes and immune dysfunction in peritoneal fluid of endometriosis revealed by single-cell RNA-sequencing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gen Zou ◽  
Jianzhang Wang ◽  
Xinxin Xu ◽  
Ping Xu ◽  
Libo Zhu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Single Cell ◽  
Natural Killer ◽  
Rna Sequencing ◽  
Peritoneal Cavity ◽  
Immune Cells ◽  
Peritoneal Fluid ◽  
Control Sample ◽  
Immune Dysfunction ◽  
Single Cell Rna Sequencing

Abstract Background Endometriosis is a refractory and recurrent disease and it affects nearly 10% of reproductive-aged women and 40% of infertile patients. The commonly accepted theory for endometriosis is retrograde menstruation where endometrial tissues invade into peritoneal cavity and fail to be cleared due to immune dysfunction. Therefore, the comprehensive understanding of immunologic microenvironment of peritoneal cavity deserves further investigation for the previous studies mainly focus on one or several immune cells. Results High-quality transcriptomes were from peritoneal fluid samples of patients with endometriosis and control, and firstly subjected to 10 × genomics single-cell RNA-sequencing. We acquired the single-cell transcriptomes of 10,280 cells from endometriosis sample and 7250 cells from control sample with an average of approximately 63,000 reads per cell. A comprehensive map of overall cells in peritoneal fluid was first exhibited. We unveiled the heterogeneity of immune cells and discovered new cell subtypes including T cell receptor positive (TCR+) macrophages, proliferating macrophages and natural killer dendritic cells in peritoneal fluid, which was further verified by double immunofluorescence staining and flow cytometry. Pseudo-time analysis showed that the response of macrophages to the menstrual debris might follow the certain differentiation trajectory after endometrial tissues invaded into the peritoneal cavity, that is, from antigen presentation to pro-inflammation, then to chemotaxis and phagocytosis. Our analyses also mirrored the dysfunctions of immune cells including decreased phagocytosis and cytotoxic activity and elevated pro-inflammatory and chemotactic effects in endometriosis. Conclusion TCR+ macrophages, proliferating macrophages and natural killer dendritic cells are firstly reported in human peritoneal fluid. Our results also revealed that immune dysfunction happens in peritoneal fluid of endometriosis, which may be responsible for the residues of invaded menstrual debris. It provided a large-scale and high-dimensional characterization of peritoneal microenvironment and offered a useful resource for future development of immunotherapy.

scholarly journals A Novel Design of Tri-Layer Membrane with Controlled Delivery of Paclitaxel and Anti-Biofilm Effect for Biliary Stent Applications

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 486
Author(s):  
Abdelrahman I. Rezk ◽  
Jeesoo Park ◽  
Joon Yeon Moon ◽  
Sunny Lee ◽  
Chan Hee Park ◽  
...  
Keyword(s):  
Sustained Release ◽  
Antibacterial Effect ◽  
Release Profile ◽  
Biliary Stent ◽  
Fickian Diffusion ◽  
Release Mechanism ◽  
Dual Function ◽  
Electrospinning Technique ◽  
Layer Membrane

Here, we developed a novel biliary stent coating material that is composed of tri-layer membrane with dual function of sustained release of paclitaxel (PTX) anticancer drug and antibacterial effect. The advantages of using electrospinning technique were considered for the even distribution of PTX and controlled release profile from the nanofiber mat. Furthermore, film cast method was utilized to fabricate AgNPs-immobilized PU film to direct the release towards the tumor site and suppress the biofilm formation. The in vitro antibacterial test conducted against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria species showed excellent antibacterial effect. The in vitro drug release study confirmed the sustained release of PTX from the tri-layer membrane and the release profile fitted first order with correlation coefficient of R2 = 0.98. Furthermore, the release mechanism was studied using Korsmeyer–Peppas model, revealing that the release mechanism follows Fickian diffusion. Based on the results, this novel tri-layer membrane shows curative potential in clinical development.

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