Cell-based Carriers Research Articles

Structurally Dynamic Monocyte-Liposome Hybrid Vesicles as an Anticancer Drug Delivery Vehicle: A Crucial Correlation of Microscopic Elasticity and Ultrafast Dynamics.

A biomimetic cell-based carrier system based on monocyte membranes and liposomes has been designed to create a hybrid "Monocyte-LP" which inherits the surface antigens of the monocytes along with the drug encapsulation property of the liposome. Förster resonance energy transfer (FRET) and polarization gated anisotropy measurements show the stiffness of the vesicles obtained from monocyte membranes (Mons), phosphatidylcholine membranes (LP), and Monocyte-LP to follow an increasing order of Mons > Monocyte-LP > LP. The dynamics of interface bound water molecules plays a key role in the elasticity of the vesicles, which in turn imparts higher delivery efficacy to the hybrid Monocyte-LP for a model anticancer drug doxorubicin than the other two vesicles, indicating a critical balance between flexibility and rigidity for an efficient cellular uptake. The present work provides insight on the influence of elasticity of delivery vehicles for enhanced drug delivery.

Near infrared-emitting persistent luminescence nanoparticles@macrophages as cell-based carriers for precise imaging-guided cancer cell ablation

Schematic diagrams illustrate the capability of the new ICG@mZGC@macrophage delivery system to achieve simultaneous intra-tumoral imaging and photothermal therapy.

Engineered platelet cell motors for boosted cancer radiosensitization

Design of engineered cells to target and deliver nanodrugs to the hard-to-reach regions has become an exciting research area. However, the limited penetration and retention of cell-based carriers in tumor tissue restricted their therapeutic efficiency. Inspired by the enhanced delivery behavior of mobile micro/nanomotors, herein, urease-powered platelet cell motors (PLT@Au@Urease) capable of active locomotion, tumor targeting, and radiosensitizers delivery were designed for boosting radiosensitization. The engineered platelet cell motors were constructed by in situ synthesis and loading of radiosensitizers gold nanoparticles in platelets, and then conjugation with urease as the engine. Under physiological concentration of urea, thrust around PLT@Au@Urease motors can be generated via the biocatalytic reactions of urease, leading to rapid tumor cell targeting and enhanced cellular uptake of radiosensitizers. Encouragingly, in comparison with engineered PLT without propulsion capability (PLT@Au), the self-propelled PLT@Au@Urease motors could significantly increase intracellular ROS level and exacerbate nuclear DNA damage induced by γ-radiation, resulting in a remarkably high sensitization enhancement rate (1.89) than that of PLT@Au (1.08). In vivo experiments with 4 T1-bearing mice demonstrated that PLT@Au@Urease in combination with radiation therapy possessed good antitumor performance. Such an intelligent cell motor would provide a promising approach to enhance radiosensitization and broaden the applications of cell motor-based delivery systems.

Synthesis of Bacteria-mimetic Gold Nanoparticles for Phagocytosis by Immune Cells.

Cell-based carrier exhibits inherent advantages as the next generation of drug delivery system, namely high biocompatibility and physiological function. Current cell-based carriers are constructed via direct payload internalization or conjugation between cell and payload. However, the cells involved in these strategies must be firstly extracted from the body and the cell-based carrier must be prepared in vitro. Herein, we synthesize bacteria-mimetic gold nanoparticles (GNPs) for the construction of cell-based carrier in mice. Both β-cyclodextrin (β-CD)-modified GNPs and adamantane (ADA)-modified GNPs are coated by E. coli outer membrane vesicles (OMVs). The E. coli OMVs induce the phagocytosis of GNPs by circulating immune cells, leading to intracellular degradation of OMVs and subsequent supramolecular self-assembly of GNPs driven by β-CD-ADA host-guest interactions. In vivo construction of cell-based carrier based on bacteria-mimetic GNPs avoids the immunogenicity induced by allogeneic cells and restriction by the number of separated cells. Due to the inflammatory tropism, endogenous immune cells carry the intracellular GNP aggregates to the tumor tissues in vivo. Graphical overview Collect the outer membrane vesicles (OMVs) of E. coli by gradient centrifugation (a) and coat on gold nanoparticles (GNP) surface (b) to prepare OMV-coated cyclodextrin (CD)-GNPs and OMV-coated adamantane (ADA)-GNPs (c) via ultrasonic method.

Chemical Approaches for the Preparation of Bacteria - Nano/Microparticle Hybrid Systems.

Bacteria represent a class of living cells that are very attractive carriers for the transport and delivery of nano- and microsized particles. The use of cell-based carriers, such as for example bacteria, may allow to precisely direct nano- or microsized cargo to a desired site, which would greatly enhance the selectivity of drug delivery and allow to mitigate side effects. One key step towards the use of such nano-/microparticle - bacteria hybrids is the immobilization of the cargo on the bacterial cell surface. To fabricate bacteria - nano-/microparticle biohybrid microsystems, a wide range of chemical approaches are available that can be used to immobilize the particle payload on the bacterial cell surface. This article presents an overview of the various covalent and noncovalent chemistries that are available for the preparation of bacteria - nano-/microparticle hybrids. For each of the different chemical approaches, an overview will be presented that lists the bacterial strains that have been modified, the type and size of nanoparticles that have been immobilized, as well as the methods that have been used to characterize the nanoparticle-modified bacteria.

Red Blood Cells as Drug Delivery and Imaging Agents: An Update

Red blood cells are essential physiologic cellular components that are produced constantly at abundant levels throughout life, making them an easily obtainable vehicle for both targeted cellular delivery of exogenous drugs as well as non-invasive in vivo imaging of the vasculature. As red blood cells are readily acquired in sufficient quantities and minimally immunogenic by nature, red blood cell-based agents may allow delivery of pharmaceuticals into the body under conditions of both reduced toxicity and increased physiologic half-life, when compared to the non-carrier-based drug equivalent. Research efforts in this area have recently seen major advances that are likely to accelerate the translation of red blood cell-based carrier methods into the clinical setting in the near future. This includes the coupling of therapeutic agents to the external surface of red blood cells, as well as more refined methods for internal encapsulation of drugs within red blood cells or cell-based derivatives. Here we review some of the more recent advances in the field regarding the loading of various therapeutic agents onto red blood cells as well as the use of red blood cell based imaging agents for in vivo vascularity imaging.

Lactic Acid Bacteria Simultaneously Encapsulate Diverse Bioactive Compounds from a Fruit Extract and Enhance Thermal Stability.

This study develops an innovative cell-based carrier to simultaneously encapsulate multiple phytochemicals from a complex plant source. Muscadine grapes (MG) juice prepared from fresh fruit was used as a model juice. After incubation with inactivated bacterial cells, 66.97% of the total anthocyanins, and 72.67% of the total antioxidant compounds were encapsulated in the cells from MG juice. Confocal images illustrated a uniform localization of the encapsulated material in the cells. The spectral emission scans indicated the presence of a diverse class of phenolic compounds, which was characterized using high-performance liquid chromatography (HPLC). Using HPLC, diverse phytochemical compound classes were analyzed, including flavanols, phenolic acid, hydroxycinnamic acid, flavonols, and polymeric polyphenols. The analysis validated that the cell carrier could encapsulate a complex profile of bioactive compounds from fruit juice, and the encapsulated content and efficiencies varied by the chemical class and compound. In addition, after the heat treatment at 90 °C for 60 min, >87% total antioxidant capacity and 90% anthocyanin content were recovered from the encapsulated MG. In summary, these results highlight the significant potential of a selected bacterial strain for simultaneous encapsulation of diverse phenolic compounds from fruit juice and improving their process stability.

Cell-based carrier for targeted hitchhiking delivery.

Drug delivery systems aim at improving drug transport efficiency and therapeutic efficacy by rational design, and current research on conventional delivery systems brings new developments for disease treatment. Recently, studies on cell-based drug delivery systems are rapidly emerging, which shows great advantages in comparison to conventional drug delivery system. The system uses cells as carriers to delivery conventional drugs or nanomedicines and shows good biocompatibility and enhanced targeting efficiency, beneficial from self component and its physiological function. The construction methodology of cell-based carrier determines the effect on the physiological functions of transporting cell and affects its clinical application. There are different strategies to prepare cell-based carrier, such as direct internalization or surface conjugation of drugs or drug loaded materials. Thus, it is necessary to fully understand the advantages and disadvantages of different strategies for constructing cell-based carrier and then to seek the appropriate construction methodology for achieving better therapeutic results based on disease characterization. We here summarize the application of different types of cell-based carriers reported in recent years and further discuss their applications in disease therapy and the dilemmas faced in clinical translation. We hope that this summary can accelerate the process of clinical translation by promoting the technology development of cell-based carrier.

Cell-based carriers incorporated antimicrobial coatings on diverse food contact surfaces for preventing cross-contamination of fresh produce

Cross-contamination is a key food safety risk during both harvesting and post-harvest processing of fresh produce. Very few effective intervention approaches are available for reducing cross-contamination risks from diverse food contact surfaces during harvesting and post-harvest processing. Therefore, developing an effective antimicrobial coating that can be simply applied on a diversity of food contact surfaces is highly desirable. This work demonstrates a cost-effective and one-step antimicrobial coating approach that can be applied on diverse food contact surfaces, such as plastic films, Sparta brushes, and polyfoam sponges. The incorporation of chlorine charged antimicrobial yeast cell wall particles (YCWPs) into chitosan-based coatings provides unique advantages in achieving a high concentration of chlorine on food contact surface and extending the stability of chlorine. Approximately 583 nmol/cm2 of active chlorine bound to the coated poly(vinyl alcohol-co-ethylene) (PVA-co-PE) film surface after 60 min of incubation with bleach at room temperature, which enabled a significant antimicrobial activity of this coating. An inactivation of approximately 3-log and 5-log units of Listeria innocua with organic load (COD = 500 mg/L) were achieved after treatment for 2 min and 5 min, respectively. This antimicrobial coating with chlorine charged YCWPs effectively reduce the cross-contamination between fresh produce and plastic films. Baby spinach leaves were selected as a model fresh produce. The results represent that chitosan-YCWPs coatings led to more than 3 log reduction in the bacterial population transferred to leaf surface upon 10 min of contact with contaminated plastic films, while native chitosan without chlorine charged YCWPs coating did not result in any significant reduction. The results in this study also demonstrate the feasibility of using this antimicrobial coating on contaminated sponges and brushes to reduce cross-contamination of fresh produce during washing steps. No bacterial cells were detected from the leaf surface after contact with contaminated sponges or brush samples coated with chitosan and chlorine-charged YCWPs. This cost-effective and one-step antimicrobial coating approach with a high potential of scale-up will significantly enhance the efficacy of surface sanitation and prevent the cross-contamination of fresh produce.

Yeast cell microcarriers for delivery of a model bioactive compound in skin

This study aimed at developing a cell-based encapsulation carrier for topical delivery of bioactives to the skin. The overall objectives were to evaluate affinity of the yeast-cell based carrier to bind to the skin surface following topical application and to quantify controlled release of curcumin as a model bioactive in ex-vivo skin models using a combination of imaging, modeling and analytical measurements. Both porcine skin tissue and clinically obtained human skin biopsies were studied. The results demonstrated that upon incubation with the ex-vivo skin tissues, the cell carriers rapidly bound to the skin surface following topical delivery and provided sustained release of encapsulated curcumin. The microcarrier binding and penetration of curcumin in the dermal compartment also showed to increase with incubation time. The average flux of curcumin in human skin biopsies Jp was 0.89 ± 0.02 μg/cm2/h. These results illustrated the potential of a novel cell-based carrier for high affinity binding to skin surface, efficient encapsulation of a model bioactive and controlled release from the cell carrier to the skin with enhanced permeation to the dermis section. Overall, this study demonstrated a new class of cost-effective carriers for improving delivery of bioactives to the skin and potentially other epithelial tissues.

Nucleic Acid Delivery with Red-Blood-Cell-Based Carriers.

Gene therapy has the potential to become a staple of 21st-century medicine. However, to overcome the limitations of existing gene-delivery therapies, that is, poor stability and inefficient and delivery and accumulation of nucleic acids (NAs), safe drug-delivery systems (DDSs) allowing the prolonged circulation and expression of the administered genes in vivo are needed. In this review article, the development of DDSs over the past 70 years is briefly described. Since synthetic DDSs can be recognized and eliminated as foreign substances by the immune system, new approaches must be found. Using the body’s own cells as DDSs is a unique and exciting strategy and can be used in a completely new way to overcome the critical limitations of existing drug-delivery approaches. Among the different circulatory cells, red blood cells (RBCs) are the most abundant and thus can be isolated in sufficiently large quantities to decrease the complexity and cost of the treatment compared to other cell-based carriers. Therefore, in the second part, this article describes 70 years of research on the development of RBCs as DDSs, covering the most important RBC properties and loading methods. In the third part, it focuses on RBCs as the NA delivery system with advantages and drawbacks discussed to decide whether they are suitable for NA delivery in vivo.

Eradication of large established tumors by drug-loaded bacterial particles via a neutrophil-mediated mechanism

The treatment of large established tumors remains a significant challenge and is generally hampered by poor drug penetration and intrinsic drug resistance of tumor cells in the central tumor region. In the present study, we developed bacterial particles (BactPs) to deliver chemotherapeutics into the tumor mass by hijacking neutrophils as natural cell-based carriers. BactPs loaded with doxorubicin, 5-fluorosuracil, or paclitaxel induced significantly greater tumor regression than unconjugated drugs. This effect was mediated by the ability of BactPs to incorporate chemotherapeutics and serve as vascular disrupting agents that trigger innate host responses and recruit phagocytic neutrophils. Vascular disruption resulted in extensive cell death in the central areas of the tumor mass. Recruited neutrophils acted as natural cellular carriers to deliver engulfed BactPs, which ensured drug delivery into the tumor mass and cytotoxic effects in areas that are normally inaccessible to traditional chemotherapy. Thus, BactPs eradicate large established tumors by functioning as vascular disrupters and natural drug carriers for neutrophil-mediated chemotherapy.

Efficient delivery of oncolytic enterovirus by carrier cell line NK-92

Many members of the enterovirus family are considered as promising oncolytic agents; however, their systemic administration is largely inefficient due to the rapid neutralization of the virus in the circulation and the barrier functions of the endothelium. We aimed to evaluate natural killer cells as carriers for the delivery of oncolytic enteroviruses, which would combine the effects of cell immunotherapy with virotherapy. We tested four strains of nonpathogenic enteroviruses against the glioblastoma cell line panel and evaluated the produced infectious titers. Next, we explored whether these virus strains could be delivered to the tumor by natural killer cell line NK-92, which is being actively evaluated as a clinically acceptable therapeutic. Several strains of enteroviruses demonstrated oncolytic properties, but only coxsackievirus A7 (CVA7) could replicate in NK-92 cells efficiently. We compared the delivery efficiency of CVA7 in vivo, using NK-92 cells and direct intravenous administration, and found significant advantages of cell delivery even after a single injection. This suggests that the NK-92 cell line can be utilized as a vehicle for the delivery of the oncolytic strain of CVA7, which would improve the clinical potential of this viral oncolytic for the treatment of glioblastoma multiforme and other forms of cancer.

Chemical Cell Surface Modification and Analysis of Nanoparticle-Modified Living Cells.

Cells are promising as carriers that can enhance the delivery of nanomedicines. Cells that carry nanomedicinal cargo, either immobilized on the cell surface or internalized, can allow for highly specific delivery and can enable the transport of nanomedicines across challenging physiological barriers. The effective use of cells as carriers for the transport and delivery of nanomedines requires a careful selection of the chemical strategies that are used to load the cell-based carriers with their cargo. To this end, an in-depth understanding of the impact of various cell-surface modification chemistries on the viability and functional properties of the cells is essential, and techniques are needed that allow characterization of nanoparticle-modified living cells. This article touches upon both of these aspects. The first part of this review will present an overview of contemporary strategies that are available for the cell surface immobilization of nanoparticle cargo. After that, the various techniques that are most frequently used for the characterization of nanoparticle-modified cells will be discussed.

Fluorescence-Based and Fluorescent Label-Free Characterization of Polymer Nanoparticle Decorated T Cells.

Cells are attractive carriers for the transport and delivery of nanoparticulate cargo. The use of cell-based carriers allows one to enhance control over the biodistribution of drug-loaded polymers and polymer nanoparticles. One key element in the development of cell-based delivery systems is the loading of the cell-based carrier with the nanoparticle cargo, which can be achieved either by internalization of the payload or by immobilization on the cell surface. The surface modification of cells with nanoparticles or the internalization of nanoparticles by cells is usually monitored with fluorescence-based techniques, such as flow cytometry and confocal microscopy. In spite of the widespread use of these techniques, the use of fluorescent labels also poses some risks and has several drawbacks. Fluorescent dyes may bleach, or leach from, the nanoparticles or alter the physicochemical properties of nanoparticles and their interactions with and uptake by cells. Using poly(d,l-lactic acid) nanoparticles that are loaded with Coumarin 6, BODIPY 493/503, or DiO dyes as a model system, this paper demonstrates that the use of physically entrapped fluorescent labels can lead to false negative or erroneous results. The use of nanoparticles that contain covalently tethered fluorescent dyes instead was found to provide a robust approach to monitor cell surface conjugation reactions and to quantitatively analyze nanoparticle-decorated cells. Finally, it is shown that optical diffraction tomography is an attractive, alternative technique for the characterization of nanoparticle-decorated cells, which obviates the need for fluorescent labels.

Extracellular Vesicles for Cancer Therapy: Impact of Host Immune Response.

In recent times, extracellular vesicles (EVs) have come under the spotlight as potential therapeutics for cancer, due to the relative ease of manipulation of contents and potential for tumor targeting. The use of EVs as delivery vehicles may bypass some of the negative effects associated with cell-based carriers, and there has been a major focus on defining EV subtypes, establishing transparent nomenclature, and isolation and characterization techniques. EVs are believed to be a fingerprint of the secreting cell and so researchers harness the positive aspects of a particular cell of origin, and can then further modify EV contents to improve therapeutic efficacy. In this review, we highlight studies employing EVs as cancer therapeutics that have reported on immune response. As we rapidly advance towards potential application in the clinical setting, the question of immune response to EV administration in the cancer setting has become critically important.

Bioaccessibility of curcumin encapsulated in yeast cells and yeast cell wall particles

This study evaluates the role of intracellular composition and integrity of cell walls in modulating the release and bioaccessibility of phytochemicals during simulated gastrointestinal digestion of cell-based carriers. Native yeast and yeast cell wall particles (YCWPs) were used as model cell-based carriers with distinct intracellular composition and curcumin was a model encapsulated bioactive. The results highlight the essential role of gastric treatments and the presence of bile salts in the release and bioaccessibility of encapsulated compound from cell-based carriers. YCWPs with significantly reduced intracellular contents have a significantly faster intestinal release after gastric digestion. Multimodal imaging approaches confirm the release of encapsulated curcumin in intestinal compartment without any significant changes in the cellular structure including cell walls. Based on these results, the study proposes a model that illustrate the significance of gastric digestion in influencing the release of curcumin during gastrointestinal digestion.

Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling.

The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein that is regarded as one of the markers for tumor initiating cells (TIC) in human hepatocellular carcinoma (HCC). Much work has been directed towards targeting these TICs as a mean of placing these master regulators of cell proliferation and drug resistance under control. Human bone marrow-derived mesenchymal stem cells are known to exhibit an innate property of tumor tropism. However, the possible relationship between MSC and TIC is not well understood. In this study, we show that MSC migration to HCC can be effectively inhibited by TACE and γ-secretase inhibitors that stop the activation of EpCAM signaling event. Silencing of EpCAM expression through siRNA and antibody approaches also resulted in impaired MSC migration. By contrast, increase levels of EpICD proteins in HCC cells and HCC mouse xenografts resulted in enhanced MSC migration. Taken together, these findings show that MSC is drawn to the more oncogenic population of HCC, and could potentially serve as a cell-based carrier of therapeutic genes to target EpICD-enriched hepatic tumor cells.

Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma.

SummaryThe challenges to effective drug delivery to brain tumors are twofold: (1) there is a lack of non-invasive methods of local delivery and (2) the blood-brain barrier limits systemic delivery. Intranasal delivery of therapeutics to the brain overcomes both challenges. In mouse model of malignant glioma, we observed that a small fraction of intranasally delivered neural stem cells (NSCs) can migrate to the brain tumor site. Here, we demonstrate that hypoxic preconditioning or overexpression of CXCR4 significantly enhances the tumor-targeting ability of NSCs, but without altering their phenotype only in genetically modified NSCs. Modified NSCs deliver oncolytic virus to glioma more efficiently and extend survival of experimental animals in the context of radiotherapy. Our findings indicate that intranasal delivery of stem cell-based therapeutics could be optimized for future clinical applications, and allow for safe and repeated administration of biological therapies to brain tumors and other CNS disorders.

Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions

Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis—all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.