Multifunctional biomimetic porphyrin-lipid nanoparticles – novel nanoscale theranostics for atherosclerotic cardiovascular disease
Bibliographic record
Abstract
ABSTRACT Background High-density lipoprotein (HDL) nanoagents have unrealized potential for atherosclerosis theranostics. Porphyrin-lipid HDL mimetic nanoparticles (Por-HDL-NPs) incorporate porphyrin-lipid which permits near infrared fluorescence imaging and positron emission tomography (PET) through chelation of Copper-64 ( 64 Cu). The outer shell contains apolipoprotein A-I mimetic peptide R4F that interacts with scavenger receptor SR-BI, enabling macrophage targeting and therapeutic effects. We leveraged the theranostic properties of Por-HDL-NPs for testing in atherosclerosis. Methods and Results In vitro , Por-HDL-NPs were internalised by immortalised bone marrow-derived macrophages (iBMDMs), visualised via fluorescence microscopy and flow cytometry. Por-HDL-NPs increased cholesterol efflux from [ 3 H]-cholesterol-loaded iBMDMs, (49%, P <0.05), compared to reconstituted HDL. Incubation of iBMDMs with Por-HDL-NPs reduced mRNA levels of inflammatory mediators Il-1β (88%), Il-18 (54%) and Ccl5 (75%), and protein secretion of IL-1β (69%) and CCL5 (82%), P <0.05. Por-HDL-NPs suppressed inflammasome components Nlrp3 (69%) and Asc (36%), P <0.05. Studies using siRNA deletion of SR-B1 and methyl-β-cyclodextrin, revealed the anti-inflammatory properties of Por-HDL-NPs were independent of SR-B1 and cholesterol efflux. However, Por-HDL-NPs suppressed activation of inflammatory transcription factor NF-κB (53%, P <0.05). In Apoe -/- mice, PET imaging showed 64 Cu-Por-HDL-NPs localised in hearts and detected increases in plaque over time with high-cholesterol diet. Por-HDL-NP fluorescence was visualised in aortic sinus plaques, co-localised with CD68 + macrophages, and by fluorescence IVIS imaging in aortic arch plaque. Por-HDL-NP-treated mice had smaller early-stage (22%) and unstable plaques (52%) and fewer circulating monocytes (32%) than control PBS-treated mice, P <0.05 for all. Conclusions Por-HDL-NPs have theranostic properties, exhibiting both multi-modal imaging capabilities for identifying plaque and athero-protective therapeutic effects. Clinical Perspective: What is new? Porphyrin high-density lipoprotein (HDL) mimetic nanoparticles (Por-HDL-NPs) have theranostic application in atherosclerosis. Por-HDL-NPs are internalized by macrophages in vitro and plaque macrophages in vivo , enabling the visualization of atherosclerosis by both positron emission tomography and multiple fluorescence imaging modalities. Por-HDL-NPs exhibit atheroprotective effects and suppress inflammation, promote cholesterol efflux, reduce atherosclerotic plaque development and lower the number of circulating monocytes. What are the clinical implications? The PET imaging and plaque targeting capabilities of Por-HDL-NPs have implications for improved non-invasive tracking of human atherosclerosis development. The excellent fluorescence imaging and plaque targeting properties of Por-HDL-NPs have clinical significance for improved detection of early-stage plaque using intravascular imaging strategies. Por-HDL-NPs provide therapeutic capabilities that target plaque directly, independent of lipid-lowering, suggestive of their potential to provide benefit on top of current lipid-lowering strategies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".