@article{fromen_rahhal_robbins_kai_shen_luft_desimone_2016, title={Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells}, volume={12}, ISSN={["1549-9642"]}, DOI={10.1016/j.nano.2015.11.002}, abstractNote={Engineered nanoparticles have the potential to expand the breadth of pulmonary therapeutics, especially as respiratory vaccines. Notably, cationic nanoparticles have been demonstrated to produce superior local immune responses following pulmonary delivery; however, the cellular mechanisms of this increased response remain unknown. To this end, we investigated the cellular response of lung APCs following pulmonary instillation of anionic and cationic charged nanoparticles. While nanoparticles of both surface charges were capable of trafficking to the draining lymph node and were readily internalized by alveolar macrophages, both CD11b and CD103 lung dendritic cell (DC) subtypes preferentially associated with cationic nanoparticles. Instillation of cationic nanoparticles resulted in the upregulation of Ccl2 and Cxc10, which likely contributes to the recruitment of CD11b DCs to the lung. In total, these cellular mechanisms explain the increased efficacy of cationic formulations as a pulmonary vaccine carrier and provide critical benchmarks in the design of pulmonary vaccine nanoparticles.Advance in nanotechnology has allowed the production of precise nanoparticles as vaccines. In this regard, pulmonary delivery has the most potential. In this article, the authors investigated the interaction of nanoparticles with various types of lung antigen presenting cells in an attempt to understand the cellular mechanisms. The findings would further help the future design of much improved vaccines for clinical use.}, number={3}, journal={NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE}, author={Fromen, Catherine A. and Rahhal, Tojan B. and Robbins, Gregory R. and Kai, Marc P. and Shen, Tammy W. and Luft, J. Christopher and DeSimone, Joseph M.}, year={2016}, month={Apr}, pages={677–687} }
 @article{kai_brighton_fromen_shen_luft_luft_keeler_robbins_ting_zamboni_et al._2016, title={Tumor Presence Induces Global Immune Changes and Enhances Nanoparticle Clearance}, volume={10}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.5b05999}, abstractNote={Long-circulating nanoparticles are essential for increasing tumor accumulation to provide therapeutic efficacy. While it is known that tumor presence can alter the immune system, very few studies have explored this impact on nanoparticle circulation. In this report, we demonstrate how the presence of a tumor can change the local and global immune system, which dramatically increases particle clearance. We found that tumor presence significantly increased clearance of PRINT hydrogel nanoparticles from the circulation, resulting in increased accumulation in the liver and spleen, due to an increase in M2-like macrophages. Our findings highlight the need to better understand interactions between immune status and nanoparticle clearance, and suggest that further consideration of immune function is required for success in preclinical and clinical nanoparticle studies.}, number={1}, journal={ACS NANO}, author={Kai, Marc P. and Brighton, Hailey E. and Fromen, Catherine A. and Shen, Tammy W. and Luft, J. Christopher and Luft, Yancey E. and Keeler, Amanda W. and Robbins, Gregory R. and Ting, Jenny P. Y. and Zamboni, William C. and et al.}, year={2016}, month={Jan}, pages={861–870} }
 @article{fromen_robbins_shen_kai_ting_desimone_2015, title={Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization}, volume={112}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.1422923112}, abstractNote={Significance To our knowledge, no other nano-based vaccine delivery platform has directly assessed the effects of nanoparticle charge on pulmonary vaccination without affecting other physio/chemical particle characteristics and/or antigen loading. The Particle Replication in Non-Wetting Templates nanoparticle fabrication process is unique in that it allows for isolation of charge as the sole variable in these studies while maintaining all other physical and chemical parameters constant. We find that positively charged nanoparticles induce robust mucosal and systemic antibody responses following pulmonary administration, whereas negatively charged nanoparticles fail to do so. Therefore, our studies underscore the importance of considering nanoparticle charge as a critical design parameter when generating pulmonary-based vaccines and may have implications for particulate vaccination through other routes of administration. Pulmonary immunization enhances local humoral and cell-mediated mucosal protection, which are critical for vaccination against lung-specific pathogens such as influenza or tuberculosis. A variety of nanoparticle (NP) formulations have been tested preclinically for pulmonary vaccine development, yet the role of NP surface charge on downstream immune responses remains poorly understood. We used the Particle Replication in Non-Wetting Templates (PRINT) process to synthesize hydrogel NPs that varied only in surface charge and otherwise maintained constant size, shape, and antigen loading. Pulmonary immunization with ovalbumin (OVA)-conjugated cationic NPs led to enhanced systemic and lung antibody titers compared with anionic NPs. Increased antibody production correlated with robust germinal center B-cell expansion and increased activated CD4+ T-cell populations in lung draining lymph nodes. Ex vivo treatment of dendritic cells (DCs) with OVA-conjugated cationic NPs induced robust antigen-specific T-cell proliferation with ∼100-fold more potency than soluble OVA alone. Enhanced T-cell expansion correlated with increased expression of surface MHCII, T-cell coactivating receptors, and key cytokines/chemokine expression by DCs treated with cationic NPs, which were not observed with anionic NPs or soluble OVA. Together, these studies highlight the importance of NP surface charge when designing pulmonary vaccines, and our findings support the notion that cationic NP platforms engender potent humoral and mucosal immune responses.}, number={2}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Fromen, Catherine A. and Robbins, Gregory R. and Shen, Tammy W. and Kai, Marc P. and Ting, Jenny P. Y. and DeSimone, Joseph M.}, year={2015}, month={Jan}, pages={488–493} }
 @article{shen_fromen_kai_luft_rahhal_robbins_desimone_2015, title={Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery}, volume={32}, ISSN={0724-8741 1573-904X}, url={http://dx.doi.org/10.1007/s11095-015-1701-7}, DOI={10.1007/s11095-015-1701-7}, abstractNote={We evaluated the role of a poly(ethylene glycol) (PEG) surface coating to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung.Three sizes of PRINT hydrogel particles (80 × 320 nm, 1.5 and 6 μm donuts) with and without a surface PEG coating were instilled in the airways of C57/b6 mice. At time points of 1, 7, and 28 days, BALF and whole lungs were evaluated for the inflammatory cytokine Il-6 and chemokine MIP-2, histopathology, cellular populations of macrophages, dendritic cells (DCs), and granulocytes, and particulate uptake within these cells through flow cytometry, ELISAs, and fluorescent imaging.Particles of all sizes and surface chemistries were readily observed in the lung with minimal inflammatory response at all time points. Surface modification with PEGylation was found to significantly increase lung residence times and homogeneous lung distribution, delaying macrophage clearance of all sizes, with the largest increase in residence time observed for 80 × 320 nm particles. Additionally, it was observed that DCs were recruited to the airway following administration of unPEGylated particles and preferentially associated with these particles.Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics.}, number={10}, journal={Pharmaceutical Research}, publisher={Springer Science and Business Media LLC}, author={Shen, Tammy W. and Fromen, Catherine A. and Kai, Marc P. and Luft, J. Christopher and Rahhal, Tojan B. and Robbins, Gregory R. and DeSimone, Joseph M.}, year={2015}, month={May}, pages={3248–3260} }
 @article{jones_roberts_robbins_perry_kai_chen_bo_napier_ting_desimone_et al._2013, title={Nanoparticle clearance is governed by Th1/Th2 immunity and strain background}, volume={123}, ISSN={["1558-8238"]}, DOI={10.1172/jci66895}, abstractNote={Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopy-based assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte-derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans.}, number={7}, journal={JOURNAL OF CLINICAL INVESTIGATION}, author={Jones, Stephen W. and Roberts, Reid A. and Robbins, Gregory R. and Perry, Jillian L. and Kai, Marc P. and Chen, Kai and Bo, Tao and Napier, Mary E. and Ting, Jenny P. Y. and DeSimone, Joseph M. and et al.}, year={2013}, month={Jul}, pages={3061–3073} }
 @article{perry_reuter_kai_herlihy_jones_luft_napier_bear_desimone_2012, title={PEGylated PRINT Nanoparticles: The Impact of PEG Density on Protein Binding, Macrophage Association, Biodistribution, and Pharmacokinetics}, volume={12}, ISSN={["1530-6992"]}, DOI={10.1021/nl302638g}, abstractNote={In this account, we varied PEGylation density on the surface of hydrogel PRINT nanoparticles and systematically observed the effects on protein adsorption, macrophage uptake, and circulation time. Interestingly, the density of PEGylation necessary to promote a long-circulating particle was dramatically less than what has been previously reported. Overall, our methodology provides a rapid screening technique to predict particle behavior in vivo and our results deliver further insight to what PEG density is necessary to facilitate long-circulation.}, number={10}, journal={NANO LETTERS}, author={Perry, Jillian L. and Reuter, Kevin G. and Kai, Marc P. and Herlihy, Kevin P. and Jones, Stephen W. and Luft, J. Chris and Napier, Mary and Bear, James E. and DeSimone, Joseph M.}, year={2012}, month={Oct}, pages={5304–5310} }