Macrophages with cellular backpacks for targeted drug delivery to the brain

Klyachko, Natalia L.; Polak, Roberta; Haney, Matthew J.; Zhao, Yanxin; Neto, Reginaldo Jose Gomes; Hill, Michael C.; Kabanov, Alexander V.; Cohen, Robert E.; Rubner, Michael F.; Batrakova, Elena V.

doi:10.1016/j.biomaterials.2017.06.017

Cited by 129 publications

(94 citation statements)

References 55 publications

(57 reference statements)

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“…In 2015, Mitragotri and co‐workers advanced their earlier work by showing that monocytes can deliver backpacks to inflamed areas in the body as a step toward immunotherapeutic applications (see Figure f for more recent iterations of backpacks made from PLGA) . Batrakova and co‐workers later showed that catalase‐loaded backpacks bound to monocytes can penetrate the blood–brain barrier of mice with LPS‐induced encephalitis and reduce inflammation caused by ROS from M1 polarized microglia . Instead of using monocytes and macrophages, Irvine and co‐workers published a study in 2012 using a nanoparticle functionalized with maleimide to bind to T cells for cargo delivery to their synapses as a way to prevent autoimmunity, or conversely, to boost antitumor immunity .…”

Section: Microscale Materials For Immunotherapymentioning

confidence: 99%

Materials for Immunotherapy

et al. 2019

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Breakthroughs in materials engineering have accelerated the progress of immunotherapy in preclinical studies. The interplay of chemistry and materials has resulted in improved loading, targeting, and release of immunomodulatory agents. An overview of the materials that are used to enable or improve the success of immunotherapies in preclinical studies is presented, from immunosuppressive to proinflammatory strategies, with particular emphasis on technologies poised for clinical translation. The materials are organized based on their characteristic length scale, whereby the enabling feature of each technology is organized by the structure of that material. For example, the mechanisms by which i) nanoscale materials can improve targeting and infiltration of immunomodulatory payloads into tissues and cells, ii) microscale materials can facilitate cell‐mediated transport and serve as artificial antigen‐presenting cells, and iii) macroscale materials can form the basis of artificial microenvironments to promote cell infiltration and reprogramming are discussed. As a step toward establishing a set of design rules for future immunotherapies, materials that intrinsically activate or suppress the immune system are reviewed. Finally, a brief outlook on the trajectory of these systems and how they may be improved to address unsolved challenges in cancer, infectious diseases, and autoimmunity is presented.

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Section: Microscale Materials For Immunotherapymentioning

confidence: 99%

Materials for Immunotherapy

et al. 2019

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“…Wang et al, 2015). PD patients have reduced catalase activity in the substantia nigra (Ambani, Van Woert, & Murphy, 1975), and catalase containing nanoparticle delivery to brain has been explored as a therapeutic strategy in PD animal models (Klyachko et al, 2017).…”

mentioning

confidence: 99%

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

Olsen

Feany

2019

Glia

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α‐Synucleinopathies are neurodegenerative diseases that are characterized pathologically by α‐synuclein inclusions in neurons and glia. The pathologic contribution of glial α‐synuclein in these diseases is not well understood. Glial α‐synuclein may be of particular importance in multiple system atrophy (MSA), which is defined pathologically by glial cytoplasmic α‐synuclein inclusions. We have previously described Drosophila models of neuronal α‐synucleinopathy, which recapitulate key features of the human disorders. We have now expanded our model to express human α‐synuclein in glia. We demonstrate that expression of α‐synuclein in glia alone results in α‐synuclein aggregation, death of dopaminergic neurons, impaired locomotor function, and autonomic dysfunction. Furthermore, co‐expression of α‐synuclein in both neurons and glia worsens these phenotypes as compared to expression of α‐synuclein in neurons alone. We identify unique transcriptomic signatures induced by glial as opposed to neuronal α‐synuclein. These results suggest that glial α‐synuclein may contribute to the burden of pathology in the α‐synucleinopathies through a cell type‐specific transcriptional program. This new Drosophila model system enables further mechanistic studies dissecting the contribution of glial and neuronal α‐synuclein in vivo, potentially shedding light on mechanisms of disease that are especially relevant in MSA but also the α‐synucleinopathies more broadly.

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“…There are several sources from which primary macrophages can be isolated from mice. We selected BMDMs for several reasons, including i) their reported use as drug carriers in other studies, and ii) their higher cell isolation yield and superior capacity for phagocytosis in comparison to macrophages isolated from the spleen or peritoneal cavity . Unfortunately, macrophages were unable to efficiently phagocytose these particles within 24 h, as determined by fluorescence microscopy ( Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

Evans

Shields

Krishnan

et al. 2019

Advanced Therapeutics

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Hypoxia‐activated prodrugs (HAPs) have tremendous clinical potential due to their selective toxicity toward poorly oxygenated tissues, which is a hallmark of solid tumors. Despite their promising results in vitro, HAPs have failed to make a clinical impact. This is largely because tumor hypoxia is located far from blood vessels, making it difficult for HAPs to accumulate in therapeutically sufficient concentrations. Here, a generalized strategy to overcome this barrier by employing macrophages as drug carriers to enhance the penetration and accumulation of HAPs deep in solid tumors is reported. The system leverages the chemotactic and phagocytic abilities of macrophages to improve delivery of nanoparticles encapsulating a model HAP, tirapazamine (TPZ), to the hypoxic regions of solid tumors. A sequence of in vitro assays is used to refine the properties of the system by minimizing carrier cell toxicity while maximizing therapeutic efficacy. It is demonstrated in vivo that the system improves drug accumulation in hypoxic areas of 4T1 breast tumors and slows their growth by itself and in combination with irinotecan. The results provide early evidence that macrophages can significantly improve the transport and efficacy of HAPs by improving their tumor penetration, highlighting a potential strategy to advance them into the clinic.

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Macrophages with cellular backpacks for targeted drug delivery to the brain

Cited by 129 publications

References 55 publications

Materials for Immunotherapy

Materials for Immunotherapy

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

Macrophage‐Mediated Delivery of Hypoxia‐Activated Prodrug Nanoparticles

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