Engineering PEGylated Polyester Nanoparticles to Reduce Complement-Mediated Infusion Reaction

Maisha, Nuzhat; Naik, N. R.; Okesola, Mawuyon; Coombs, Tobias; Zilberberg, Rose; Pandala, Narendra; Lavik, Erin B.

doi:10.1021/acs.bioconjchem.1c00339

Cited by 11 publications

(15 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…How can we begin to develop screening systems to look at the safety of nanoparticles for translation based on these findings? We have previously seen that incubation of polyester nanoparticles with endothelial cells leads to a decrease in IL-6 28 similar to what is seen in the nai ̈ve arm of the study. In vitro screens like this play an important role in understanding how nanoparticles impact outcomes.…”

Section: Resultssupporting

confidence: 84%

“…20,26,55,56 In this work, we looked at nanoparticles that do not activate complement. 28 While these particles did not activate complement in vitro or in vivo, their administration unmasked other challenges that must be addressed.…”

Section: Resultsmentioning

confidence: 99%

“…This motivated us to develop a screening assay for complement activation with nanoparticles that was more sensitive than the ones most commonly described in the field . Using this assay, we identified a hemostatic nanoparticle formulation with two molecular weights of poly(ethylene oxide) (PEG) that led to no measurable complement activation in vitro . On this basis, we sought to determine the safety and efficacy of these hemostatic nanoparticles in a large animal model of trauma, a critical step in translating nanoparticles for trauma applications.…”

mentioning

confidence: 99%

See 2 more Smart Citations

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events

et al. 2022

Self Cite

View full text Add to dashboard Cite

Intravenously infusible nanoparticles to control bleeding have shown promise in rodents, but translation into preclinical models has been challenging as many of these nanoparticle approaches have resulted in infusion responses and adverse outcomes in large animal trauma models. We developed a hemostatic nanoparticle technology that was screened to avoid one component of the infusion response: complement activation. We administered these hemostatic nanoparticles, control nanoparticles, or saline volume controls in a porcine polytrauma model. While the hemostatic nanoparticles promoted clotting as marked by a decrease in prothrombin time and both the hemostatic nanoparticles and controls did not active complement, in a subset of the animals, hard thrombi were found in uninjured tissues in both the hemostatic and control nanoparticle groups. Using data science methods that allow one to work across heterogeneous data sets, we found that the presence of these thrombi correlated with changes in IL-6, INF-alpha, lymphocytes, and neutrophils. While these findings might suggest that this formulation would not be a safe one for translation for trauma, they provide guidance for developing screening tools to make nanoparticle formulations in the complex milieux of trauma as well as for therapeutic interventions more broadly. This is important as we look to translate intravenously administered nanoparticle formulations for therapies, particularly considering the vascular changes seen in a subset of patients following COVID-19. We need to understand adverse events like thrombi more completely and screen for these events early to make nanomaterials as safe and effective as possible.

show abstract

Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The PLA−PEG nanoparticles described here are a formulation that has been optimized to avoid complement activation in our previous work. 31 Creating a hydrated corona around nanoparticles using PEG 32−34 or other molecules has been shown to reduce complement activation significantly, but even when the hydrated corona is optimized the core can still impact the response. It is telling that the unfunctionalized polyurethane nanocapsules are as quiet as they are regarding complement activation.…”

mentioning

confidence: 99%

“…It is striking that changing the core from polyester to polyurethane can impact complement activation and cytokine concentrations. The PLA–PEG nanoparticles described here are a formulation that has been optimized to avoid complement activation in our previous work . Creating a hydrated corona around nanoparticles using PEG − or other molecules has been shown to reduce complement activation significantly, but even when the hydrated corona is optimized the core can still impact the response.…”

mentioning

confidence: 99%

Getting to the Core of It All: Nanocapsules to Mitigate Infusion Reactions Can Promote Hemostasis and Be a Platform for Intravenous Therapies

et al. 2021

Self Cite

View full text Add to dashboard Cite

Hemostatic nanomaterials can increase survival after traumatic injuries, which is a leading cause of death for people under 46. However, like many other intravenously administered nanomaterials, hemostatic nanomaterials can lead to complement-mediated infusion reactions. These infusion reactions are observed in about 10% of the population and can be lethal in a small fraction of people. In the context of trauma, complement proteins including C5a trigger vasodilation which exacerbates injury. Thus, nanomaterials that avoid complement and infusion responses while promoting hemostasis are critical to developing new therapeutics to manage bleeding. By screening complement responses to nanoparticles, we identified nanocapsules based on polyurethane as candidates that did not promote upregulation of C5a. We explored the PEGylation of these nanocapsules and functionalization with the GRGDS peptide to create a new class of hemostatic nanomaterials. We found that these polyurethane-based hemostatic nanocapsules do not activate complement or the major proinflammatory cytokines. We evaluated the hemostatic nanocapsules and controls using clinically relevant rotational thromboelastography (ROTEM). We determined that the hemostatic nanocapsules promote faster clotting than controls and maintain the maximum clot firmness associated with normal coagulation, which is critical for reducing bleeding and maintaining hemostasis until patients can get to definitive care. This study is a critical step in developing a new platform that is safe, effective, and translatable to preclinical models of trauma and, ultimately, the clinic. Table of Contents Figure Manuscript Main TextWith 30 to 40% of trauma mortality due to blood loss and 33 to 56% of this mortality occurring during the prehospital period, trauma is a leading cause of death, especially for young people (5-45 years). 1 Early post-trauma intervention is essential to maximize survival. [2][3] Having a technology deployed in the field to manage bleeding could transform trauma care. We previously developed hemostatic nanoparticles based on block copolymers of a degradable polyester (polylactic-co-glycolic acid) (PLGA) or poly(lactic acid), poly(ethylene glycol), and the peptide RGD. These nanoparticles were highly effective in reducing bleeding in several of rodent trauma models 4-7 . However, these particles activated complement when administered in porcine trauma models 8 . We developed a variant with a nearly neutral zeta potential that effectively stopped bleeding in the porcine model without complement activation at most doses. However, at the highest doses, complement was activated, and bleeding was exacerbated by the nanoparticles, including the control nanoparticles 8 .

show abstract

Application of Nanotechnology in the Diagnosis and Treatment of Brain Metastases

Schonfeld,

Sunshine,

Guss

et al. 2024

The Textbook of Nanoneuroscience and Nanoneurosurgery

View full text Add to dashboard Cite

Engineering PEGylated Polyester Nanoparticles to Reduce Complement-Mediated Infusion Reaction

Cited by 11 publications

References 64 publications

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events

Getting to the Core of It All: Nanocapsules to Mitigate Infusion Reactions Can Promote Hemostasis and Be a Platform for Intravenous Therapies

Application of Nanotechnology in the Diagnosis and Treatment of Brain Metastases

Contact Info

Product

Resources

About