scholarly journals Genetically engineered cell membrane–coated nanoparticles for targeted delivery of dexamethasone to inflamed lungs

2021 ◽  
Vol 7 (25) ◽  
pp. eabf7820
Author(s):  
Joon Ho Park ◽  
Yao Jiang ◽  
Jiarong Zhou ◽  
Hua Gong ◽  
Animesh Mohapatra ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Targeted Delivery ◽  
Biological Membrane ◽  
Genetically Engineered ◽  
Target Cells ◽  
Coated Nanoparticles ◽  
Ligand Interactions ◽  
Late Antigen

As numerous diseases are associated with increased local inflammation, directing drugs to the inflamed sites can be a powerful therapeutic strategy. One of the common characteristics of inflamed endothelial cells is the up-regulation of vascular cell adhesion molecule–1 (VCAM-1). Here, the specific affinity between very late antigen–4 (VLA-4) and VCAM-1 is exploited to produce a biomimetic nanoparticle formulation capable of targeting inflammation. The plasma membrane from cells genetically modified to constitutively express VLA-4 is coated onto polymeric nanoparticle cores, and the resulting cell membrane–coated nanoparticles exhibit enhanced affinity to target cells that overexpress VCAM-1 in vitro. A model anti-inflammatory drug, dexamethasone, is encapsulated into the nanoformulation, enabling improved delivery of the payload to inflamed lungs and significant therapeutic efficacy in vivo. Overall, this work leverages the unique advantages of biological membrane coatings to engineer additional targeting specificities using naturally occurring target-ligand interactions.

scholarly journals The Delivery of Biologically Active Agents into the Nuclei of Target Cells for the Purposes of Translational Medicine

Acta Naturae ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 47-56
Author(s):  
A. S. Sobolev
Keyword(s):  
Targeted Delivery ◽  
Translational Medicine ◽  
Intracellular Transport ◽  
Biologically Active ◽  
Target Cells ◽  
Subcellular Compartment ◽  
Core Technology ◽  
Dividing Cells

Development of vehicles for the subcellular targeted delivery of biologically active agents is very promising for the purposes of translational medicine. This review summarizes the results obtained by researchers from the Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology RAS, which allowed them to design the core technology: modular nanotransporters. This approach ensures high efficacy and cell specificity for different anti-cancer agents, as they are delivered into the most vulnerable subcellular compartment within the cells of interest and makes it possible for antibody mimetics to penetrate into a compartment of interest within the target cells (diving antibodies). Furthermore, polyplexes, complexes of polycationic block copolymers of DNA, have been developed and characterized. These complexes are efficient both in vitro and in vivo and demonstrate predominant transfection of actively dividing cells.

scholarly journals Non-cationic RGD-containing protein carrier for tumor-targeted siRNA delivery

2021 ◽  
Author(s):  
Xiaolin Yu ◽  
Lu Xue ◽  
Jingjing Zhao ◽  
Shuhua Zhao ◽  
Daqing Wu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Sirna Delivery ◽  
Integrin Αvβ3 ◽  
Cationic Liposome ◽  
Genetically Engineered ◽  
Endosomal Escape ◽  
Widespread Application ◽  
Rgd Peptides

Abstract Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effect, poor clearance, low serum stability, and high toxicity. In this study, we have genetically engineered a non-cationic tumor-targeted universal siRNA nanocarrier. This protein nanocarrier consists of three function domains: dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidines for endosome escape, and two RGD peptides at N-and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specific targets on integrin αvβ3 expressing cells in vitro, and homes siRNA to tumor in vivo. The delivered siRNA leads target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional, biomimetic, charge-neutral siRNA carrier is biodegradable, low toxic, suitable for mass production by fermentation, and serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.

scholarly journals Cabozantinib unlocks efficient in vivo targeted delivery of neutrophil-loaded nanoparticles into murine prostate tumors

2020 ◽  
Author(s):  
Kiranj Chaudagar ◽  
Natalie Landon-Brace ◽  
Aniruddh Solanki ◽  
Hanna M. Hieromnimon ◽  
Emma Hegermiller ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Kinase Inhibitor ◽  
Tumor Regression ◽  
Flow Cytometric Analysis ◽  
Fold Increase ◽  
Genetically Engineered ◽  
Prostate Tumors ◽  
Major Barrier

AbstractA major barrier to the successful application of nanotechnology for cancer treatment is the efficient delivery of therapeutic payloads to metastatic tumor deposits. We have previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anti-cancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of bovine serum albumin (BSA)-coated polymeric nanoparticles (NPs) into murine PTEN/p53-deficient prostate tumors. Based on the observation that BSA-coating of NPs enhanced association and internalization by activated neutrophils in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pre-treated with cabozantinib. Flow cytometric analysis revealed a 4-fold increase of neutrophil-associated NPs within the tumor microenvironment (TME) of mice pre-treated with cabozantinib relative to untreated controls. At steady-state, following 3 days of cabozantinib/NP administration, 1% of systemically injected dye-loaded NPs selectively accumulated within the TME of mice that were pre-treated with cabozantinib, compared to 0.11% uptake for mice that did not receive cabozantinib pre-treatment. Strikingly, neutrophil depletion with Ly6G antibody abolished NP accumulation in tumors to baseline levels, demonstrating targeted neutrophil-mediated NP delivery to the prostate TME. In summary, we have discovered a novel nano-immunotherapeutic strategy for enhanced intratumoral delivery of injected NPs, which results in significantly higher NP accumulation than reported strategies in the nanotechnology literature to-date.

scholarly journals Non-Cationic RGD-Containing Protein Nanocarrier for Tumor-Targeted siRNA Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2182
Author(s):  
Xiaolin Yu ◽  
Lu Xue ◽  
Jing Zhao ◽  
Shuhua Zhao ◽  
Daqing Wu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Sirna Delivery ◽  
Integrin Αvβ3 ◽  
Genetically Engineered ◽  
Endosomal Escape ◽  
Widespread Application ◽  
Rgd Peptides ◽  
Low Toxicity

Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvβ3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.

scholarly journals Engineering human megakaryocytic microparticles for targeted delivery of nucleic acids to hematopoietic stem and progenitor cells

2018 ◽  
Vol 4 (11) ◽  
pp. eaau6762 ◽  
Author(s):  
Chen-Yuan Kao ◽  
Eleftherios T. Papoutsakis
Keyword(s):  
Progenitor Cells ◽  
Targeted Delivery ◽  
Fluorescent Protein ◽  
Ex Vivo ◽  
Patient Specific ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Hematopoietic stem and progenitor cells (HSPCs) are important target cells for gene therapy applications. Current genetic modifications of HSPCs rely on viral vectors in vivo or electroporation ex vivo. Here, we developed a nonviral system based on megakaryocytic microparticles (MPs) for targeted delivery of plasmid DNA (pDNA) and small RNAs to HSPCs. We have previously shown that megakaryocytic MPs, the most abundant MPs in blood circulation, target specifically and deliver cargo to HSPCs both in vitro and in vivo. With an optimized electroporation protocol, an average of 4200 plasmid copies per MP were loaded into MP, thus enabling effective delivery of green fluorescent protein (GFP)–encoding pDNA to HSPCs and HSPC nuclei, with up to 81% nuclei containing pDNA. Effective functional small interfering RNA (siRNA) and microRNA (miRNA) delivery were also demonstrated. As patient-specific or generic megakaryocytic MPs can be readily generated and stored frozen, our data suggest that this system has great potential for therapeutic applications targeting HSPCs.

scholarly journals Biomimetic Upconversion Nanoparticles and Gold Nanoparticles for Novel Simultaneous Dual-Modal Imaging-Guided Photothermal Therapy of Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3136 ◽  
Author(s):  
Ruliang Wang ◽  
Han Yang ◽  
Rongxin Fu ◽  
Ya Su ◽  
Xue Lin ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cancer Cell ◽  
Photothermal Therapy ◽  
Tumor Targeting ◽  
Imaging System ◽  
Imaging Systems ◽  
Coated Nanoparticles ◽  
Cancer Theranostics

Multimodal imaging-guided near-infrared (NIR) photothermal therapy (PTT) is an interesting and promising cancer theranostic method. However, most of the multimodal imaging systems provide structural and functional information used for imaging guidance separately by directly combining independent imaging systems with different detectors, and many problems arise when trying to fuse different modal images that are serially taken by inviting extra markers or image fusion algorithms. Further, most imaging and therapeutic agents passively target tumors through the enhanced permeability and retention (EPR) effect, which leads to low utilization efficiency. To address these problems and systematically improve the performance of the imaging-guided PTT methodology, we report a novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as a platform for PTT-based cancer theranostics. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. In vitro and in vivo evaluation of macrophage escape and active homologous tumor targeting were performed. Cancer cell membrane-coated nanoparticles (CC-NPs) displayed excellent immune evasion ability, longer blood circulation time, and higher tumor targeting specificity compared to normal PEGylated nanoparticles, which led to highly specific upconversion luminescence (UCL) imaging and PTT-based anti-tumor efficacy. The anti-cancer efficacy of the dual-modal imaging-guided PTT was also evaluated both in vitro and in vivo. Dual-modal imaging yielded precise anatomical and functional information for the PTT process, and complete tumor ablation was achieved with CC-AuNPs. Our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics.

scholarly journals 202 In vivo and in vitro characterization of AIM ACT, a novel nanoparticle-based technology, expanded MART-1 specific T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A213-A213
Author(s):  
Ruipeng Wang ◽  
Lauren Suarez ◽  
Emily Lu ◽  
Pratima Kunwar ◽  
Daniel Dembrow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Manufacturing Process ◽  
Genetically Engineered ◽  
Target Cells ◽  
Clinical Scale

BackgroundNexImmune is developing highly differentiated immunotherapies to target, activate and expand tumor antigen-specific T cells using the proprietary Artificial Immune Modulation (AIM™) nanotechnology platform. The AIM nanoparticle (AIM-np) technology functions as synthetic dendritic cells capable of directing a specific T cell-mediated immune response. By mimicking natural T cell biology, NexImmune’s non-genetically engineered cellular therapy product candidates (AIM ACT) are designed to combine the attributes of cellular precision, potency, and persistence with reduced potential for undesired toxicities.MethodsHere we present an example of AIM ACT expanded MART-1 specific T cells and their phenotypic and functional characterization in vitro and in vivo. Leukopaks from healthy donors were used to produce AIM ACT T cell products with our proprietary AIM ACT enrichment and expansion (E+E) manufacturing process and antigen peptide-loaded AIM-nanoparticles.ResultsThe final MART1 T cell products include up to 62.8% (20.8% in average) MART-1-specific CD8+ T cells as determined by MART1 peptide (ELAGIGILTV)-loaded multimer staining. MART1-specific T cells were tested in flow cytometry-based and live cell imaging-based cytotoxicity assays using HLA-A2 positive MART1 peptide-loaded target cells. The AIM ACT-generated T cells showed potent cytotoxicity to MART1 peptide-loaded target cells in vitro, while unloaded control cells were not killed. In over 30 independent AIM ACT E+E clinical scale runs, the expanded T cells consisted of a combined average of 91.7% T stem cell like, central and effector memory T cells, as determined by CD62L, CD45RA and CD95 staining. These phenotypes have been associated with long term in vivo persistence and anti-tumor efficacy. In a human melanoma PDX model, we confirmed that transfusion of AIM ACT T cells resulted in long term survival in vivo and significant reduction of tumor growth with complete tumor clearance in 6 out of 15 animals.ConclusionsThe results demonstrate that AIM ACT MART1 T cells have long term persistence and anti-tumor activity in solid tumors such as melanoma, and that the AIM ACT E+E approach is a reproducible clinical scale manufacturing process for non-genetically engineered antigen-specific T cells. The AIM ACT platform is currently being used for generating T cell products for our current clinical trials, NEXI-001 (NCT04284228) and NEXI-002 (NCT04505813), and our pre-clinical development for HPV-associated malignancies. The findings support initiating Phase I trials of adoptive T cell therapy in solid tumors.Ethics ApprovalThe study was approved by the Institutional Animal Care and Use Committee (IACUC).

scholarly journals Cell membrane coating integrity affects the internalization mechanism of biomimetic nanoparticles

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lizhi Liu ◽  
Xuan Bai ◽  
Maria-Viola Martikainen ◽  
Anna Kårlund ◽  
Marjut Roponen ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Immune Escape ◽  
Target Cells ◽  
Coated Nanoparticles ◽  
Internalization Mechanism ◽  
Cancer Nanomedicine ◽  
Biomimetic Nanoparticles ◽  
Membrane Coating ◽  
Time Specific

AbstractCell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. However, the integrity of the cell membrane coating on NPs, a key metrics related to the quality of these biomimetic-systems and their resulting biomedical function, has remained largely unexplored. Here, we report a fluorescence quenching assay to probe the integrity of cell membrane coating. In contradiction to the common assumption of perfect coating, we uncover that up to 90% of the biomimetic NPs are only partially coated. Using in vitro homologous targeting studies, we demonstrate that partially coated NPs could still be internalized by the target cells. By combining molecular simulations with experimental analysis, we further identify an endocytic entry mechanism for these NPs. We unravel that NPs with a high coating degree (≥50%) enter the cells individually, whereas the NPs with a low coating degree (<50%) need to aggregate together before internalization. This quantitative method and the fundamental understanding of how cell membrane coated NPs enter the cells will enhance the rational designing of biomimetic nanosystems and pave the way for more effective cancer nanomedicine.

Internal and External Triggering Mechanism of “Smart” Nanoparticle-Based DDSs in Targeted Tumor Therapy

2018 ◽  
Vol 24 (15) ◽  
pp. 1639-1651 ◽  
Author(s):  
Xian-ling Qian ◽  
Jun Li ◽  
Ran Wei ◽  
Hui Lin ◽  
Li-xia Xiong
Keyword(s):  
Targeted Delivery ◽  
Tumor Therapy ◽  
Burst Release ◽  
Tumor Site ◽  
Chemotherapeutic Drugs ◽  
Triggering Mechanism ◽  
Triggering Factors ◽  
Or Genes

Background: Anticancer chemotherapeutics have a lot of problems via conventional Drug Delivery Systems (DDSs), including non-specificity, burst release, severe side-effects, and damage to normal cells. Owing to its potential to circumventing these problems, nanotechnology has gained increasing attention in targeted tumor therapy. Chemotherapeutic drugs or genes encapsulated in nanoparticles could be used to target therapies to the tumor site in three ways: “passive”, “active”, and “smart” targeting. Objective: To summarize the mechanisms of various internal and external “smart” stimulating factors on the basis of findings from in vivo and in vitro studies. Method: A thorough search of PubMed was conducted in order to identify the majority of trials, studies and novel articles related to the subject. Results: Activated by internal triggering factors (pH, redox, enzyme, hypoxia, etc.) or external triggering factors (temperature, light of different wavelengths, ultrasound, magnetic fields, etc.), “smart” DDSs exhibit targeted delivery to the tumor site, and controlled release of chemotherapeutic drugs or genes. Conclusion: In this review article, we summarize and classify the internal and external triggering mechanism of “smart” nanoparticle-based DDSs in targeted tumor therapy, and the most recent research advances are illustrated for better understanding.

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