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Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases. Unwanted uptake in the liver and limited accumulation in target organs is a major obstacle to targeted drug delivery. Here, the authors report on the hitchhiking of nanocarriers on red blood cells and the targeted upstream delivery to different target organs in mice, pigs and ex vivo human lungs.

In many countries around the globe, private freehold lands cover large areas. Conservation on these private lands, next to statutory protected areas, promises to play a critical role in efforts for reaching internationally agreed environmental protection targets. Lying at the heart of an emerging land system science, in which ecology, economics, geography, psychology, and other social sciences interact, private land conservation is reflecting the intertwined and multiscalar processes of our rapidly transforming world. Situated at this disciplinary meeting point, private land conservation invites a great breadth of approaches and cross-disciplinary work that offer deep insights into social and environmental change, often from surprising angles. Although many questions remain in private land conservation, we can now build on a large body of recent high-quality studies as we push this field forward in both research and practice. The Special Feature “Private Land Conservation - Landowner Motives, Policies, and Outcomes of Conservation Measures in Unprotected Landscapes” brings together contributions that explore the diversity of recent advances in private land conservation science. As an introduction to this Special Feature, first we are reviewing recent dynamics in important social-ecological drivers with bearing on private land conservation science. We go on to introduce the individual contributions to this Special Feature and then examine common themes as they are emerging from these papers, including the need for flexibility in conservation approaches, pursuit of community cobenefits of conservation, increasing consideration of environmental justice questions, and acknowledgment of the importance of social psychology in shaping private land conservation. We conclude with identification of knowledge gaps and recommendations for future research, as we advance from diagnostics to normative work in private land conservation science.

Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood–brain barrier, thus benefiting numerous brain pathologies.

Cannabis agriculture is a multi-billion dollar industry in the United States that is changing rapidly with policy liberalization. Anecdotal observations fuel speculation about associated environmental impacts, and there is an urgent need for systematic empirical research. An example from Humboldt County California, a principal cannabis-producing region, involved digitizing 4428 grow sites in 60 watersheds with Google Earth imagery. Grows were clustered, suggesting disproportionate impacts in ecologically important locales. Sixty-eight percent of grows were >500 m from developed roads, suggesting risk of landscape fragmentation. Twenty-two percent were on steep slopes, suggesting risk of erosion, sedimentation, and landslides. Five percent were <100 m from threatened fish habitat, and the estimated 297 954 plants would consume an estimated 700 000 m3 of water, suggesting risk of stream impacts. The extent and magnitude of cannabis agriculture documented in our study demands that it be regulated and researched on par with conventional agriculture.

Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs to the brain. However, there is a potential solution in targeted drug delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following a TBI, the blood-brain barrier (BBB) becomes permeable, which can last for years and allow the leakage of harmful plasma proteins. Consequently, an appealing approach for TBI treatment involves using drug delivery systems that utilize targeting antibodies and nanocarriers to help restore BBB integrity. In our investigation of this strategy, we examined the efficacy of free antibodies and nanocarriers targeting a specific endothelial surface marker called vascular cell adhesion molecule-1 (VCAM-1), which is known to be upregulated during inflammation. In a mouse model of TBI utilizing central fluid percussion injury, free VCAM-1 antibody did not demonstrate superior targeting when comparing sham vs. TBI brain. However, the administration of VCAM-1-targeted nanocarriers (liposomes) exhibited a 10-fold higher targeting specificity in TBI brain than in sham control. Flow cytometry and confocal microscopy analysis confirmed that VCAM-1 liposomes were primarily taken up by brain endothelial cells post-TBI. Consequently, VCAM-1 liposomes represent a promising platform for the targeted delivery of therapeutics to the brain following traumatic brain injury.

Attachment 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.

After dozens of clinical trials, there are still no Food and Drug Administration–approved drugs that improve mortality in acute respiratory distress syndrome (ARDS). These poor results may be caused in part by three unique pharmacological challenges presented by ARDS: (1) Patients with ARDS are fragile because of concomitant multiple organ dysfunction, so they do not tolerate off-target side effects of drugs; (2) inhaled drug delivery is impeded by the column of proteinaceous fluid covering the injured alveoli; and (3) ARDS is heterogeneous in its underlying pathophysiology, so targeting one pathway is unlikely to improve most patients. To address these three pharmacological problems, I present the development of pulmonary endothelium–targeted liposomes (PELs). PELs are approximately 100-nm drug carriers coated with antibodies that bind to the pulmonary capillary endothelium. In model organisms, intravenously injected PELs strongly concentrate drugs in alveoli, even in animal models displaying severe, spatially heterogeneous pathology similar to severe ARDS. By concentrating drugs in inflamed alveoli, PELs solve pharmacological challenge (1) above. By being obligate intravenous medications, they solve challenge (2). Finally, because PELs can be loaded with at least three drugs, they can solve challenge (3) with combination drug therapy. My colleagues and I are currently testing PELs loaded with numerous candidate drugs in mouse models of ARDS, and we are testing drug distribution in live pigs and ex vivo human lungs. We aim to use such preclinical validation to move PELs into a partnership with industry, and then to patients.

Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways—either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo—depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.

On agricultural frontiers, minimal regulation and potential windfall profits drive opportunistic land use that often results in environmental damage. Cannabis, an increasingly decriminalized agricultural commodity in many places throughout the world, may now be creating new agricultural frontiers. We examined how cannabis frontiers have boomed in northern California, one of the United States' leading production areas. From 2012-2016 cannabis farms increased in number by 58%, cannabis plants increased by 183%, and the total area under cultivation increased by 91%. Growth in number of sites (80%), as well as in site size (56% per site) contributed to the observed expansion. Cannabis expansion took place in areas of high environmental sensitivity, including 80%-116% increases in cultivation sites near high-quality habitat for threatened and endangered salmonid fish species. Production increased by 40% on steep slopes, sites more than doubled near public lands, and increased by 44% in remote locations far from paved roads. Cannabis farm abandonment was modest, and driven primarily by farm size, not location within sensitive environments. To address policy and institutions for environmental protection, we examined state budget allocations for cannabis regulatory programs. These increased six-fold between 2012-2016 but remained very low relative to other regulatory programs. Production may expand on frontiers elsewhere in the world, and our results warn that without careful policy and institutional development these frontiers may pose environmental threats, even in locations with otherwise robust environmental laws and regulatory institutions.

Despite current resuscitation strategies, circulatory shock and organ injury after cardiac surgery occur in 25-40% of patients. Goal-directed resuscitation after cardiac surgery has generated significant interest, but clinical practice to normalize hemodynamic variables including mean arterial pressure, cardiac filling pressures, and cardiac output may not reverse microcirculation abnormalities and do not address cellular dysoxia. Recent advances in technology have made it possible to measure critical components of oxygen delivery and oxygen utilization systems in live human tissues and blood cells. The MicroRESUS study will be the first study to measure microcirculatory and mitochondrial function in patients with circulatory shock and link these findings with clinical outcomes. This will be a prospective, observational study that includes patients undergoing elective cardiovascular surgery with cardiopulmonary bypass (CPB). Microcirculation will be quantified with sublingual incident dark field videomicroscopy. Mitochondrial respiration will be measured by performing a substrate-uncoupler-inhibitor titration protocol with high resolution respirometry on peripheral blood mononuclear cells at baseline and serial timepoints during resuscitation and at recovery as a possible liquid biomarker. Plasma samples will be preserved for future analysis to examine endothelial injury and other mechanisms of microcirculatory dysfunction. Thirty-day ventilator and vasopressor-free days (VVFDs) will be measured as a primary outcome, along with sequential organ failure assessment scores, and other clinical parameters to determine if changes in microcirculation and mitochondrial respiration are more strongly associated with clinical outcomes compared to traditional resuscitation targets. This will be the first prospective study to examine both microcirculatory and mitochondrial function in human patients with circulatory shock undergoing cardiac bypass and address a key mechanistic knowledge gap in the cardiovascular literature. The results of this study will direct future research efforts and therapeutic development for patients with shock.