Tomato Bushy Stunt Virus nanoparticles as a Platform for Drug Delivery to Shh-dependent Medulloblastoma

2021 ◽  
Author(s):  
Chiara Lico ◽  
Barbara Tanno ◽  
Luca Marchetti ◽  
Flavia Novelli ◽  
Paola Giardullo ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Large Scale ◽  
Primary Cultures ◽  
Late Toxicity ◽  
Tomato Bushy Stunt Virus ◽  
Central Nervous System Tumor ◽  
Innovative Solution ◽  
Dynamics Simulations

Abstract Background: Medulloblastoma (MB) is a primary central nervous system tumor that affects mainly young children. New strategies of drug delivery are urgent to treat this cancer and, in particular, the SHH-dependent subtype - the most common subgroup in infants - in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles represent an innovative solution to approach this challenge.Methods: Tomato Bushy Stunt virus (TBSV) was functionally characterized using a murine model as carrier for targeted delivery to Shh-MB. The TBSV nanoparticles surface was engineered with peptides described as enabling targeting to brain cancer cells and the modified particles were then produced on large scale using Nicotiana benthamiana plants. Results: Tests on primary cultures of Shh-MB cells and on their cerebellar precursors allowed to define the most efficient peptides able to induce specific uptake of the viral NPs. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association to the viral particle. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV particles allowed to reduce the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV nanoparticles in MB symptomatic mice confirmed the ability of the virus particles to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide.Conclusion: Overall, these results open new perspectives for the use of TBSV particles as vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.

scholarly journals Tomato Bushy Stunt Virus Nanoparticles as a Platform for Drug Delivery to Shh-Dependent Medulloblastoma

2021 ◽  
Vol 22 (19) ◽  
pp. 10523
Author(s):  
Chiara Lico ◽  
Barbara Tanno ◽  
Luca Marchetti ◽  
Flavia Novelli ◽  
Paola Giardullo ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Large Scale ◽  
Primary Cultures ◽  
Late Toxicity ◽  
Tomato Bushy Stunt Virus ◽  
Genetically Engineered ◽  
Central Nervous System Tumor ◽  
Dynamics Simulations

Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype—the most common in infants—in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using Nicotiana benthamiana plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.

scholarly journals Tumor-microenvironment Responsive Targeted Exosome-like Nanovesicles From Dunaliella Salina for Enhancing Gene/immune Combination Therapy

2021 ◽  
Author(s):  
Mengxi Zhu ◽  
Shan Li ◽  
Shuying Feng ◽  
Haojie Wang ◽  
Lina Hu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Delivery System ◽  
Targeted Delivery ◽  
Large Scale ◽  
Dunaliella Salina ◽  
High Efficiency ◽  
Particle Diameter ◽  
Matrix Metalloproteinase 2 ◽  
Scale Production

Abstract BackgroundAs an endogenous extracellular vesicle, exosome is increasingly presenting its great potential in the field of drug delivery. However, it is the bottleneck to obtain a large number of uniform, stable and multi-component controllable exosomes with low cost and time. ResultsIn this study, we develop a novel targeted drug delivery system based on exosome-like nanovesicle by use of natural marine single-celled Dunaliella salina (DENV), the c(RGDyK) peptide has been conjugated to DENV surface to achieve the targeted delivery to esophageal cancer cells. Furthermore, miR-375 has been loaded into the cRGD-DENV through electroporation, and aPD-L1 has been conjugated onto its surface via Gly-PLGLAG-Cys peptide, a matrix metalloproteinase-2 (MMP-2)-cleavable peptide, which facilitates the release of aPD-L1 in tumor environment to achieve the high-efficiency combination of gene therapy and immunotherapy. Firstly, the engineered DENV delivery system was prepared and characterized. It exhibited a proper particle diameter (approximately 150 nm) with in vitro sustained release features in the presence of MMP-2/9. More importantly, the cRGD-DENV was effective, promoted selective delivery of cargo to the target site, and reduced nonspecific uptake, consequently, significantly inhibit tumor growth in vitro and in vivo. ConclusionThe specific nanocarrier delivery system provide a promising strategy for the rapid and large-scale production of functionalized exosome-like nanovesicle by adapting multifunctional peptides specifically targeted tumor.

Development and Characterization Colchicine-Loaded PEGylated Gelatin Nanoparticles for Targeted Delivery to Tumor

2013 ◽  
Vol 6 (2) ◽  
pp. 2058-2063
Author(s):  
G D Chandrethiya ◽  
P K Shelat ◽  
M N Zaveri
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
High Performance ◽  
Entrapment Efficiency ◽  
Stability Study ◽  
Spherical Particles ◽  
Precipitation Method ◽  
Antitumoral Activity ◽  
Gelatin Nanoparticles

PEGylated gelatin nanoparticles loaded with colchicine were prepared by ethanol precipitation method. Poly-(ethylene glycol)-5000-monomethylether (MPEG 5000), a hydrophilic polymer, was used to pegylate gelatin.  Gluteraldehyde was used as cross-linking agent. To obtain a high quality product, major formulation parameters were optimized.  Spherical particles with mean particles of 193 nm were measured by a Malvern particle size analyzer. Entrapment efficiency was found to be 71.7 ± 1.4% and determined with reverse phase high performance liquid charomatography (RP-HPLC). The in vitro drug release study was performed by dialysis bag method for a period of 168 hours. Lyophilizaton study showed sucrose at lower concentrations proved the best cryoprotectant for this formulation.  Stability study revealed that lyophilized nanoparticles were equally effective (p < 0.05) after one year of storage at 2-8°C with ambient humidity. In vitro antitumoral activity was accessed using the MCF-7 cell line by MTT assay.  The IC50 value was found to be 0.034 μg/ml for the prepared formulation. The results indicate that PEGylated gelatin nanoparticles could be utilized as a potential drug delivery for targeted drug delivery of tumors.  

scholarly journals Mechanisms and Pharmaceutical Action of Lipid Nanoformulation of Natural Bioactive Compounds as Efficient Delivery Systems in the Therapy of Osteoarthritis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1108
Author(s):  
Oana Craciunescu ◽  
Madalina Icriverzi ◽  
Paula Ecaterina Florian ◽  
Anca Roseanu ◽  
Mihaela Trif
Keyword(s):  
Drug Delivery ◽  
Bioactive Compounds ◽  
Targeted Delivery ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Joint Disease ◽  
Duration Of Action ◽  
Immune System Activation

Osteoarthritis (OA) is a degenerative joint disease. An objective of the nanomedicine and drug delivery systems field is to design suitable pharmaceutical nanocarriers with controllable properties for drug delivery and site-specific targeting, in order to achieve greater efficacy and minimal toxicity, compared to the conventional drugs. The aim of this review is to present recent data on natural bioactive compounds with anti-inflammatory properties and efficacy in the treatment of OA, their formulation in lipid nanostructured carriers, mainly liposomes, as controlled release systems and the possibility to be intra-articularly (IA) administered. The literature regarding glycosaminoglycans, proteins, polyphenols and their ability to modify the cell response and mechanisms of action in different models of inflammation are reviewed. The advantages and limits of using lipid nanoformulations as drug delivery systems in OA treatment and the suitable route of administration are also discussed. Liposomes containing glycosaminoglycans presented good biocompatibility, lack of immune system activation, targeted delivery of bioactive compounds to the site of action, protection and efficiency of the encapsulated material, and prolonged duration of action, being highly recommended as controlled delivery systems in OA therapy through IA administration. Lipid nanoformulations of polyphenols were tested both in vivo and in vitro models that mimic OA conditions after IA or other routes of administration, recommending their clinical application.

scholarly journals Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 927
Author(s):  
Sebas D. Pronk ◽  
Erik Schooten ◽  
Jurgen Heinen ◽  
Esra Helfrich ◽  
Sabrina Oliveira ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Single Domain ◽  
Drug Conjugates ◽  
Intracellular Drug Delivery ◽  
Internalization Rate ◽  
Single Domain Antibodies ◽  
Different Characteristics

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.

Abstract WP313: Liposomes With Anti-Fibrin Protein Binders to Target Clot in Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Robert Mikulik ◽  
Hana Petroková ◽  
Josef Mašek ◽  
Milan Kuchar ◽  
Andrea Vítecková Wünschová ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Targeted Delivery ◽  
Animal Studies ◽  
Large Scale ◽  
Small Diameter ◽  
Titration Calorimetry ◽  
Ribosome Display ◽  
Main Challenge ◽  
Protein Binders

Introduction: Direct clot targeting represents attractive concept for clot imaging as well as targeted delivery of drugs, e.g. thrombolytics. Small protein binders attached to nanoliposomes may target thrombi and deliver drugs although selective affinity to fibrin and not fibrinogen is the main challenge. Methods: For identification and preparation of fibrin-specific artificial protein binders derived from scaffolds of albumin-binding domain (ABD) of streptococcal protein G, a highly complex ABD-derived combinatorial library in combination with ribosome display selection was used. In vitro models were used to document delivery of nanoliposomes to human thrombi. Results: A recombinant target as a stretch of three identical fibrin fragments of 16 amino acid peptides of the Bβ chain fused to TolA protein carrying polyhistidylated tag and Avitag was constructed. Ribosome display was followed by large-scale ELISA screening of protein binders. Only four protein variants had selective affinity to human fibrin - see figure 1A. The most selective, variant D7, was modified by C-terminal FLAG/His 6 or His 6 /His 6 tag in order to be attached onto the surface of nanoliposomes. The electron microscopy then confirmed the structure of nanoliposome-binder particles. Isothermal titration calorimetry provided dissociation constant for liposome-binder metallochelating bond in the range 10 -7 to 10 -9 for mono- and double-HisTag forms. In vitro, in silicone replica of small diameter artery, the confocal and scanning electron microscopy confirmed a successful binding of D7-attached- to-nanoliposomes to fibrin fibres, see figure 1B. Conclusions: We developed binders relatively selective to fibrin, attached them to nanoliposomes, and documented targeting of fibrin in vitro. As the next step, selectivity needs to be now documented in animal studies.

scholarly journals FORMULATION OF NANOPARTICLES OF TELMISARTAN INCORPORATED IN CARBOXYMETHYLCHITOSAN FOR THE BETTER DRUG DELIVERY AND ENHANCED BIOAVAILABILITY

2017 ◽  
Vol 10 (9) ◽  
pp. 236
Author(s):  
Upasana Yadav ◽  
Angshuman Ray Chowdhuri ◽  
Sumanta Kumar Sahu ◽  
Nuzhat Husain ◽  
Qamar Rehman
Keyword(s):  
Electron Microscopy ◽  
Drug Delivery ◽  
Targeted Delivery ◽  
Drug Loading ◽  
Water Soluble ◽  
Bioavailability Enhancement ◽  
Water Soluble Drug ◽  
Efficient Option

  Objective: In this study, we have made an attempt to the developed formulation of nanoparticles (NPs) of telmisartan (TLM) incorporated in carboxymethyl chitosan (CMCS) for the better drug delivery and enhanced bioavailability.Materials and Methods: The NPs size and morphology were investigated by high-resolution transmission electron microscopy and field emission scanning electron microscopy, respectively. The crystal structures and surface functional groups were analyzed using X-ray diffraction pattern, and Fourier transform infrared spectroscopy, respectively.Results: To increase the solubility of TLM by targeted delivery of the drug through polymeric NPs is an alternative efficient, option for increasing the solubility. TLM nanosuspension powders were successfully formulated for dissolution and bioavailability enhancement of the drug. We focused on evaluating the influence of particle size and crystalline state on the in vitro and in vivo performance of TLM.Conclusion: In summary, we have developed a new approach toward the delivery of poorly water-soluble drug TLM by CMCS NPs. The particles having a good drug loading content and drug encapsulation efficiency. The cytotoxicity of the synthesized NPs is also very less.

scholarly journals Reassessing the Role of Intra-Arterial Drug Delivery for Glioblastoma Multiforme Treatment

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Jason A. Ellis ◽  
Matei Banu ◽  
Shaolie S. Hossain ◽  
Rajinder Singh-Moon ◽  
Sean D. Lavine ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Optical Measurements ◽  
Pharmacological Agents ◽  
Cellular Targets ◽  
Therapeutic Landscape ◽  
Rational Drug

Effective treatment for glioblastoma (GBM) will likely require targeted delivery of several specific pharmacological agents simultaneously. Intra-arterial (IA) delivery is one technique for targeting the tumor site with multiple agents. Although IA chemotherapy for glioblastoma (GBM) has been attempted since the 1950s, the predicted benefits remain unproven in clinical practice. This review focuses on innovative approaches to IA drug delivery in treating GBM. Guided by novel in vitro and in vivo optical measurements, newer pharmacokinetic models promise to better define the complex relationship between background cerebral blood flow and drug injection parameters. Advanced optical technologies and tracers, unique nanoparticles designs, new cellular targets, and rational drug formulations are continuously modifying the therapeutic landscape for GBM. Personalized treatment approaches are emerging; however, such tailored approaches will largely depend on effective drug delivery techniques and on the ability to simultaneously deliver multidrug regimens. These new paradigms for tumor-selective drug delivery herald dramatic improvements in the effectiveness of IA chemotherapy for GBM. Therefore, within this context of so-called “precision medicine,” the role of IA delivery for GBM is thoroughly reassessed.

Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes

2008 ◽  
Vol 294 (3) ◽  
pp. F554-F561 ◽  
Author(s):  
Sigrídur A. Ásgeirsdóttir ◽  
Peter J. Zwiers ◽  
Henriëtte W. Morselt ◽  
Hendrik E. Moorlag ◽  
Hester I. Bakker ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Targeted Delivery ◽  
Therapeutic Strategy ◽  
Disease Onset ◽  
Endothelial Activation ◽  
Pcr Analysis ◽  
Endothelial Cell Marker ◽  
Cell Adhesion Molecule 1

E-selectin-directed targeted drug delivery was analyzed in anti-glomerular basement membrane glomerulonephritis. Liposomes conjugated with anti-E-selectin antibodies (AbEsel liposomes) were internalized by activated endothelial cells in vitro through E-selectin-mediated endocytosis. At the onset of glomerulonephritis in mice, E-selectin was expressed on glomerular endothelial cells, which resulted in homing of AbEsel liposomes to glomeruli after intravenous administration. Accumulation of AbEsel liposomes in the kidney was 3.6 times higher than nontargeted IgG liposomes, whereas the accumulation of both liposomes in the clearance organs liver and spleen and in heart and lungs was comparable. In glomeruli, the AbEsel liposomes colocalized with the endothelial cell marker CD31. Quantitative RT-PCR analysis of laser-microdissected arterioles, glomeruli, and postcapillary venules demonstrated that targeted delivery of dexamethasone by AbEsel liposomes reduced glomerular endothelial expression of P-selectin, E-selectin, and vascular cell adhesion molecule-1 by 60–70%. The expression of these genes was not modulated in endothelial cells in nontargeted renal microvasculatures. Decrease of glomerular endothelial activation at disease onset was followed by reduced albuminuria at day 7. This study demonstrates the potential of vascular bed-specific drug delivery aimed at disease-induced epitopes on the microvascular endothelial cells as a therapeutic strategy for glomerulonephritis.

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