Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction

Q: What is the clinical evidence from this study?

Population: Myocardial infarction (permanent LAD artery occlusion in mice) (n=43). Intervention: CCR2-targeting PEG-DSPE lipid micelles loaded with CCR2 small molecule antagonist (BMS CCR2 22) vs. PBS control or plain (non-targeted) PEG-DSPE micelles (33 mg/kg) loaded with 1.5 mg/kg CCR2 antagonist. Primary outcome: Accumulation of inflammatory Ly-6C high monocytes (% of live cells within the monocyte gate) in the infarcted heart at 96 hours post-MI.

Q: What does this research mean for the field?

CCR2-targeting PEG-DSPE lipid micelles loaded with a CCR2 antagonist reduce cardiac Ly-6C high inflammatory monocyte recruitment and decrease infarct size after myocardial infarction. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Jinli Wang; Min Jeong Seo; Michael B. Deci; Brian R. Weil; John M. Canty; Juliane Nguyen

doi:10.2147/ijn.s178650

October 1, 2018International Journal of NanomedicineOpen Access

Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction

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Key result

CCR2-targeting micelles reduce cardiac inflammatory monocytes to ~ and limit infarct size post-MI.

n=43

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Why the study?

Do CCR2-targeting PEG-DSPE lipid micelles loaded with a small molecule CCR2 antagonist reduce inflammatory monocyte infiltration and infarct size and improve cardiac function in a mouse model of myocardial infarction?

Key Points

To evaluate the efficacy of PEG-DSPE lipid micelles loaded with a CCR2 small molecule antagonist and decorated with an anti-CCR2 antibody in reducing inflammatory cell infiltration and improving cardiac function after myocardial infarction.
Formulated PEG-DSPE lipid micelles loaded with a small molecule CCR2 antagonist and surface-functionalized them with an anti-CCR2 antibody.
Evaluated cellular binding and migration inhibition using CCR2-expressing RAW 264.7 monocytes in vitro.
Administered micelles intravenously at post-operative days 2 and 3 in a mouse model of myocardial infarction, assessing immune cell counts, infarct size via Masson trichrome staining, and cardiac function on day 12.
Targeted micelles demonstrated an eight-fold greater binding to RAW 264.7 cells than plain micelles, showing a peak mean fluorescence intensity of 6,483 compared with 821.
In mice with myocardial infarction, CCR2-targeting micelles reduced cardiac inflammatory Ly-6C high monocytes from 10.2±5.7% in PBS controls to 3.2±2.2% (and to 3.2±2.2% from 11.2±2.8% in spleen).

Structured PICO

Do CCR2-targeting PEG-DSPE lipid micelles loaded with a small molecule CCR2 antagonist reduce inflammatory monocyte infiltration and infarct size and improve cardiac function in a mouse model of myocardial infarction?

P

Population

43 male C57BL/6 mice (10-12 weeks old) across three experimental cohorts subjected to permanent LAD ligation to induce myocardial infarction (or sham surgery) and followed for up to 12 days post-infarction.

I

Intervention

CCR2-targeting poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) lipid micelles surface-decorated with anti-CCR2 antibody (0.3 mol%) and loaded with a small molecule CCR2 antagonist (BMS CCR2 22, 4.5% w/w), administered intravenously via tail vein at 33 mg/kg (1.5 mg/kg antagonist dose) at 48 and 72 hours after MI.

C

Comparator

PBS-treated controls and plain (non-targeted) PEG-DSPE micelles (33 mg/kg) loaded with the same CCR2 small molecule antagonist (1.5 mg/kg) administered via tail vein at 48 and 72 hours after MI (plus sham-operated controls in the functional cohort).

O

Outcome

Infiltration of inflammatory Ly-6C high monocytes (CD11b hi [CD90/B220/CD49b/NK1.1/Ly-6G/I-Ab] lo [F4/80b/CD11c] lo Ly-6C hi) in the infarcted heart and spleen at 96 hours post-MI (24 hours after final injection), and infarct size (based on epicardial/endocardial arc lengths and LV area %) and cardiac function (LVEF and fractional shortening by echocardiography) at 12 days post-MI (10 days after final injection).surrogate

Main Result

Absolute Event Rate: 3.2% vs 10.2%

Antibody-directed CCR2-targeting PEG-DSPE lipid micelles encapsulating a small-molecule CCR2 antagonist effectively suppress post-MI inflammatory monocyte recruitment to the heart and reduce infarct arc length in mice when administered 48 hours after infarction, offering a potential nanocarrier platform for delayed post-MI anti-inflammatory therapy.

Limitations

In vivo pilot studies were focused only on acute effects with a short time interval after treatment to assess pathology and functional parameters, where LV remodeling is not yet fully established.
Effective inhibition of inflammatory monocytes translated into only modest, statistically non-significant improvements in cardiac function (ejection fraction) and area-based infarct size in vivo.
Timing of initial therapy and short duration of therapy (two boluses) may have limited physiological effects, requiring more chronic studies with longer-term and repeated administration.
In vivo pilot studies focused only on acute effects of delayed therapy administered 48 hours after infarction
Short time interval after treatment to assessing pathology and functional parameters (12 days post-MI), where LV remodeling is not yet fully established
Modestimprovements in cardiac function and area-based infarct size did not reach statistical significance
Timing of initial therapy and limited duration of dosing (only two boluses) require further optimization in longer-term chronic studies

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Implication

CCR2-targeted micelles reduce post-MI inflammation and infarct size in mice; leaves open translation of this nanocarrier approach to clinical therapy.

Abstract

Background: After myocardial infarction (MI), inflammatory cells infiltrate the infarcted heart in response to secreted stimuli. Monocytes are recruited to the infarct via CCR2 chemokine receptors along a CCL2 concentration gradient. While infiltration of injured tissue with monocytes is an important component of the reparatory response, excessive or prolonged inflammation can adversely affect left ventricular remodeling and worsen clinical outcomes. Materials and methods: Here, we developed poly(ethylene glycol) (PEG)-distearoylphosphatidylethanolamine (PEG-DSPE) micelles loaded with a small molecule CCR2 antagonist to inhibit monocyte recruitment to the infarcted myocardium. To specifically target CCR2-expressing cells, PEG-DSPE micelles were further surface decorated with an anti-CCR2 antibody. Results: Targeted PEG-DSPE micelles showed eight-fold greater binding to CCR2-expressing RAW 264.7 monocytes than plain, non-targeted PEG-DSPE micelles. In a mouse model of MI, CCR2-targeting PEG-DSPE micelles loaded with a CCR2 small molecule antagonist significantly decreased the number of Ly6C high inflammatory cells to 3% of total compared with PBS-treated controls. Furthermore, CCR2-targeting PEG-DSPE micelles significantly reduced the infarct size based on epicardial and endocardial infarct arc lengths. Conclusion: Both non-targeted and CCR2-targeting PEG-DSPE micelles showed a trend toward improving cardiac function. As such, PEG-DSPE micelles represent a promising cardiac therapeutic platform.

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Cite This Study

Wang et al. (2018) studied Myocardial infarction (permanent LAD artery occlusion in mice) (n=43). CCR2-targeting PEG-DSPE lipid micelles loaded with CCR2 small molecule antagonist (BMS CCR2 22) vs. PBS control or plain (non-targeted) PEG-DSPE micelles (33 mg/kg) loaded with 1.5 mg/kg CCR2 antagonist was evaluated on Accumulation of inflammatory Ly-6C high monocytes (% of live cells within the monocyte gate) in the infarcted heart at 96 hours post-MI. CCR2-targeting PEG-DSPE micelles loaded with a CCR2 antagonist decreased cardiac Ly-6C high inflammatory monocytes to in PBS controls and reduced length-based infarct size to.

synapsesocial.com/papers/6a831b6f24ad758e22e8e7c4 https://doi.org/10.2147/ijn.s178650

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Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Effect of CCR2 inhibitor-loaded lipid micelles on inflammatory cell migration and cardiac function after myocardial infarction

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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