Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions

Brenner, J.; Bhamidipati, Kartik; Glassman, Patrick M.; Ramakrishnan, N.; Jiang, Depeng; Myerson, Jacob W.; Pan, Dongli; Shuvaev, Vladimir V.; Villa, Carlos H.; Hood, Elizabeth D.; Kiseleva, Raisa; Greineder, Colin F.; Radhakrishnan, Ravi; Muzykantov, Vladimir R.

doi:10.1016/j.nano.2016.12.019

Cited by 42 publications

(58 citation statements)

References 33 publications

(28 reference statements)

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“…A recent study in a spatially heterogeneous mouse model of acute respiratory distress syndrome found a similar enhancement of nontargeted carriers in regions of organ damage (39). Thus, our findings would seem to corroborate in human organs this previous observation in animal models.…”

Section: Discussionmentioning

confidence: 87%

Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys

et al. 2017

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Ex vivo normothermic machine perfusion (NMP) is a new clinical strategy to assess and resuscitate organs likely to be declined for transplantation, thereby increasing the number of viable organs available. Short periods of NMP provide a window of opportunity to deliver therapeutics directly to the organ and, in particular, to the vascular endothelial cells (ECs) that constitute the first point of contact with the recipient’s immune system. ECs are the primary targets of both ischemia-reperfusion injury and damage from preformed antidonor antibodies, and reduction of perioperative EC injury could have long-term benefits by reducing the intensity of the host’s alloimmune response. Using NMP to administer therapeutics directly to the graft avoids many of the limitations associated with systemic drug delivery. We have previously shown that polymeric nanoparticles (NPs) can serve as depots for long-term drug release, but ensuring robust NP accumulation within a target cell type (graft ECs in this case) remains a fundamental challenge of nanomedicine. We show that surface conjugation of an anti-CD31 antibody enhances targeting of NPs to graft ECs of human kidneys undergoing NMP. Using a two-color quantitative microscopy approach, we demonstrate that targeting can enhance EC accumulation by about 5-to 10-fold or higher in discrete regions of the renal vasculature. In addition, our studies reveal that NPs can also non-specifically accumulate within obstructed regions of the vasculature that are poorly perfused. These quantitative preclinical human studies demonstrate the therapeutic potential for targeted nanomedicines delivered during ex vivo NMP.

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Section: Discussionmentioning

confidence: 87%

Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys

et al. 2017

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“…Developing and testing new therapeutics for lung diseases starts with using outstanding preclinical models that recapitulate key aspects of human lung disease [15,18]. Intratracheal administration of injurious agents or inducing non-specific systemic inflammation either create bland injury that falls short of the severe injury that often produces the greatest mortality or it creates such a severe injury that studying long-term regeneration is not possible.…”

Section: Discussionmentioning

confidence: 99%

“…Radiolabeling nanoparticles Rat IgG (ThermoFisher catalog #31933) was labeled with I-125 via Pierce Iodination Beads (ThermoFisher catalog # 28665). We then conjugated the IgG to nanoparticles using our published protocol [15]. In brief, 100 L of polystyrene NPs were buffer exchanged Zeba™ Spin Desalting Columns, 7K MWCO, 0.5 mL (ThermoFisher catalog # 89882), exchanging for 50 mM MES buffer at pH 5.2, finally putting the buffer-exchanged beads into 1.5 mL Eppendorf tubes.…”

Section: Nanoparticle-based Tracking Of the Location Of Instillate Inmentioning

confidence: 99%

“…These diffuse ALI models are particularly problematic for the primary two translational medicine fields aiming to ameliorate ARDS: development of therapeutics and regenerative medicine [10][11][12][13][14][15]. In the therapeutics space, the problem is that investigators must show that potential therapeutics for ARDS reach the patches of inflamed tissue (not just healthy lung regions), but diffuse ALI models do not allow such analyses because of their diffuse nature [15].…”

Section: Introductionmentioning

confidence: 99%

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Using selective lung injury to improve murine models of spatially heterogeneous lung diseases

Paris

Guo

Dai

et al. 2018

Preprint

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Many lung diseases, such as acute respiratory distress syndrome (ARDS), display significant regional heterogeneity, with patches of severely injured tissue adjacent to apparently healthy tissue. Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDS's regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions, and precludes many regenerative medicine studies, since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies of current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used to track the location and extent of where the initial injury was, days later. Further, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves undamaged lung regions. Collectively, these attributes of CICSLI will allow better study of how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other lung diseases.

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“…I have recently shown that PECAM-targeted PELs accumulate in the lungs of mice at greater than 300-fold higher levels than typical small-molecule drugs (Figure 2A) (7). Further, those PELs appear to concentrate in the alveoli ( Figure 2B).…”

Section: Opinions and Ideasmentioning

confidence: 95%

Nanomedicine for the Treatment of Acute Respiratory Distress Syndrome. The 2016 ATS Bear Cage Award–winning Proposal

Brenner

2017

Annals ATS

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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.

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Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions

Cited by 42 publications

References 33 publications

Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys

Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys

Using selective lung injury to improve murine models of spatially heterogeneous lung diseases

Nanomedicine for the Treatment of Acute Respiratory Distress Syndrome. The 2016 ATS Bear Cage Award–winning Proposal

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