Person: Mitragotri, Samir
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Mitragotri
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Samir
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Mitragotri, Samir
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Publication Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro‐in vivo correlation(John Wiley and Sons Inc., 2018) Vogus, Douglas; Pusuluri, Anusha; Chen, Renwei; Mitragotri, SamirAbstract Combination chemotherapy is commonly used to treat late stage cancer; however, treatment is often limited by systemic toxicity. Optimizing drug ratio and schedule can improve drug combination activity and reduce dose to lower toxicity. Here, we identify gemcitabine (GEM) and doxorubicin (DOX) as a synergistic drug pair in vitro for the triple negative breast cancer cell line MDA‐MB‐231. Drug synergy and caspase activity were increased the most by exposing cells to GEM prior to DOX in vitro. While the combination was more effective than the single drugs at inhibiting MDA‐MB‐231 growth in vivo, the clear schedule dependence observed in vitro was not observed in vivo. Differences in drug exposure and cellular behavior in vivo compared to in vitro are likely responsible. This study emphasizes the importance in understanding how schedule impacts drug synergy and the need to develop more advanced strategies to translate synergy to the clinic.Publication Ionic liquids for addressing unmet needs in healthcare(John Wiley and Sons Inc., 2018) Agatemor, Christian; Ibsen, Kelly; Tanner, Eden; Mitragotri, SamirAbstract Advances in the field of ionic liquids have opened new applications beyond their traditional use as solvents into other fields especially healthcare. The broad chemical space, rich with structurally diverse ions, and coupled with the flexibility to form complementary ion pairs enables task‐specific optimization at the molecular level to design ionic liquids for envisioned functions. Consequently, ionic liquids now are tailored as innovative solutions to address many problems in medicine. To date, ionic liquids have been designed to promote dissolution of poorly soluble drugs and disrupt physiological barriers to transport drugs to targeted sites. Also, their antimicrobial activity has been demonstrated and could be exploited to prevent and treat infectious diseases. Metal‐containing ionic liquids have also been designed and offer unique features due to incorporation of metals. Here, we review application‐driven investigations of ionic liquids in medicine with respect to current status and future potential.Publication Introduction to Special Issue: 2016 Translational Medicine and Bioengineering Conference(John Wiley and Sons Inc., 2017) Rege, Kaushal; Mitragotri, SamirPublication Microfluidic co‐culture devices to assess penetration of nanoparticles into cancer cell mass(John Wiley and Sons Inc., 2017) Jarvis, Maria; Arnold, Michael; Ott, Jenna; Pant, Kapil; Prabhakarpandian, Balabhaskar; Mitragotri, SamirAbstract In vitro and in vivo assessment of safety and efficacy are the essential first steps in developing nanoparticle‐based therapeutic systems. However, it is often challenging to use the knowledge gained from in vitro studies to predict the outcome of in vivo studies since the complexity of the in vivo environment, including the existence of flow and a multicellular environment, is often lacking in traditional in vitro models. Here, we describe a microfluidic co‐culture model comprising 4T1 breast cancer cells and EA.hy926 endothelial cells under physiological flow conditions and its utilization to assess the penetration of therapeutic nanoparticles from the vascular compartment into a cancerous cell mass. Camptothecin nanocrystals (∼310 nm in length), surface‐functionalized with PEG or folic acid, were used as a test nanocarrier. Camptothecin nanocrystals exhibited only superficial penetration into the cancerous cell mass under fluidic conditions, but exhibited cytotoxicity throughout the cancerous cell mass. This likely suggests that superficially penetrated nanocrystals dissolve at the periphery and lead to diffusion of molecular camptothecin deep into the cancerous cell mass. The results indicate the potential of microfluidic co‐culture devices to assess nanoparticle‐cancerous cell interactions, which are otherwise difficult to study using standard in vitro cultures.Publication Nanoparticle Properties Modulate Their Attachment and Effect on Carrier Red Blood Cells(Nature Publishing Group UK, 2018) Pan, Daniel C.; Myerson, Jacob W.; Brenner, Jacob S.; Patel, Priyal N.; Anselmo, Aaron C.; Mitragotri, Samir; Muzykantov, VladimirAttachment of nanoparticles (NPs) to the surface of carrier red blood cells (RBCs) profoundly alters their interactions with the host organism, decelerating NP clearance from the bloodstream while enabling NP transfer from the RBC surface to the vascular cells. These changes in pharmacokinetics of NPs imposed by carrier RBCs are favorable for many drug delivery purposes. On the other hand, understanding effects of NPs on the carrier RBCs is vital for successful translation of this novel drug delivery paradigm. Here, using two types of distinct nanoparticles (polystyrene (PSNP) and lysozyme-dextran nanogels (LDNG)) we assessed potential adverse and sensitizing effects of surface adsorption of NPs on mouse and human RBCs. At similar NP loadings (approx. 50 particles per RBC), adsorption of PSNPs, but not LDNGs, induces RBCs agglutination and sensitizes RBCs to damage by osmotic, mechanical and oxidative stress. PSNPs, but not LDNGs, increase RBC stiffening and surface exposure of phosphatidylserine, both known to accelerate RBC clearance in vivo. Therefore, NP properties and loading amounts have a profound impact on RBCs. Furthermore, LDNGs appear conducive to nanoparticle drug delivery using carrier RBCs.Publication Supramolecular Arrangement of Protein in Nanoparticle Structures Predicts Nanoparticle Tropism for Neutrophils in Acute Lung Inflammation(Springer Science and Business Media LLC, 2021-11-18) Myerson, Jacob W.; Patel, Priyal; Rubey, Kathryn M.; Zamora, Marco E.; Rubey, Kathryn; Zaleski, Michael H.; Habibi, Nahal; Walsh, Landis; Lee, Yi-Wei; Luther, David; Ferguson, Laura T.; Marcos-Contreras, Oscar A.; Glassman, Patrick M.; Mazaleuskaya, Liudmila L.; Johnston, Ian; Hood, Elizabeth D.; Shuvaeva, Tea; Wu, Jichuan; Zhang, Hong-Ying; Gregory, Jason V.; Kiseleva, Raisa Y.; Nong, Jia; Grosser, Tilo; Greineder, Colin F.; Mitragotri, Samir; Worthen, George S.; Rotello, Vincent M.; Lahann, Joerg; Muzykantov, Vladimir R.; Brenner, Jacob S.Publication Shape-based separation of synthetic microparticles(Springer Nature, 2018-12-10) Mage, Peter L.; Csordas, Andrew T.; Brown, Tyler; Klinger, Daniel; Eisenstein, Michael; Mitragotri, Samir; Soh, H. TomThe functional properties of colloidal materials can be tailored by tuning the shape of their constituent particles. Unfortunately, a reliable, general methodology for purifying colloidal materials solely based on shape is still missing. Here we exploit the single-particle analysis and sorting capabilities of the fluorescence-activated cell sorter (FACS), a commonly-used tool in biomedical research, and demonstrate the capability to separate mixtures of synthetic microparticles based solely on their shape with high purity. We achieve this by simultaneously obtaining four independent optical scattering signals from the FACS instrument to create shape-specific “scattering signatures” that can be used for particle classification and sorting. We demonstrate that these four-dimensional signatures can overcome the confounding effects of particle orientation on shape-based characterization. Using this strategy, robust discrimination of particles differing only slightly in shape and an efficient selection of desired shapes from mixtures comprising particles of diverse sizes and materials is demonstrated.Publication Systemic Tumour Suppression via the Preferential Accumulation of Erythrocyte-Anchored Chemokine-Encapsulating Nanoparticles in Lung Metastases(Springer Science and Business Media LLC, 2020-11-16) Zhao, Zongmin; Ukidve, Anvay; Krishnan, Vinu; Fehnel, Alexandra; Pan, Daniel; Gao, Yongsheng; Kim, Jayoung; Evans, Michael; Mandal, Abhirup; Guo, Junling; Muzykantov, Vladimir R.; Mitragotri, SamirEliciting immune responses against primary tumours is hampered by their immunosuppressive microenvironment and by the greater inaccessibility of deeper intratumoural cells. Metastatic tumour cells are however exposed to highly perfused and immunoactive organs, such as the lungs. Here, by taking advantage of the preferential co-localization of intravenously administered erythrocytes with metastases in the lung, we show that chemokine-encapsulating nanoparticles non-covalently anchored on the surface of injected erythrocytes result in local and systemic tumour suppression in mouse models of lung metastasis. Such ‘erythrocyte-anchored’ systemic immunotherapy led to the infiltration of effector immune cells into the lungs, to in situ immunization without the need of exogenous antigens, to the inhibition of the progression of lung metastasis, to significantly extended animal survival, and to systemic immunity that suppressed the growth of distant tumours after rechallenge. Erythrocyte-mediated systemic immunotherapy may represent a general and potent strategy for cancer vaccination.Publication Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control† †Electronic supplementary information (ESI) available: Includes detailed experimental details plus 10 additional figures. See DOI: 10.1039/c8sc00015h(Royal Society of Chemistry, 2018) Evans, Michael; Huang, Po-Ju; Iwamoto, Yuji; Ibsen, Kelly N.; Chan, Emory M.; Hitomi, Yutaka; Ford, Peter C.; Mitragotri, SamirNitric oxide (NO) holds great promise as a treatment for cancer hypoxia, if its concentration and localization can be precisely controlled. Here, we report a “Trojan Horse” strategy to provide the necessary spatial, temporal, and dosage control of such drug-delivery therapies at targeted tissues. Described is a unique package consisting of (1) a manganese–nitrosyl complex, which is a photoactivated NO-releasing moiety (photoNORM), plus Nd3+-doped upconverting nanoparticles (Nd-UCNPs) incorporated into (2) biodegradable polymer microparticles that are taken up by (3) bone-marrow derived murine macrophages. Both the photoNORM [Mn(NO)dpaqNO2]BPh4(dpaqNO2 = 2-[N,N-bis(pyridin-2-yl-methyl)]-amino-N′-5-nitro-quinolin-8-yl-acetamido) and the Nd-UCNPs are activated by tissue-penetrating near-infrared (NIR) light at ∼800 nm. Thus, simultaneous therapeutic NO delivery and photoluminescence (PL) imaging can be achieved with a NIR diode laser source. The loaded microparticles are non-toxic to their macrophage hosts in the absence of light. The microparticle-carrying macrophages deeply penetrate into NIH-3T3/4T1 tumor spheroid models, and when the infiltrated spheroids are irradiated with NIR light, NO is released in quantifiable amounts while emission from the Nd-UCNPs provides images of microparticle location. Furthermore, varying the intensity of the NIR excitation allows photochemical control over NO release. Low doses reduce levels of hypoxia inducible factor 1 alpha (HIF-1α) in the tumor cells, while high doses are cytotoxic. The use of macrophages to carry microparticles with a NIR photo-activated theranostic payload into a tumor overcomes challenges often faced with therapeutic administration of NO and offers the potential of multiple treatment strategies with a single system.