Characterization of classical pathway complement activation by liposomes and modulation by incorporated poly (ethylene glycol)
Bibliographic record
Abstract
Complement activation causes opsonization of foreign particles leading to particle elimination from the blood. Complement-mediated opsonization of charged and large liposomes presents a fundamental problem in their use to deliver therapeutic agents in vivo. To prolong the circulation half-lives of such liposomes, complement activation must be curtailed. The two overall aims of this study were to characterize complement activation through antibody-independent C1q binding to anionic liposomes and to assess the ability of poly(ethylene glycol)-lipids (PEG-lipids) to inhibit this complement activation. This study determined that both electrostatic and chemical forces contributed to C1q binding to anionic liposomes. Negative phospholipids in the liposome composition were required to detect C1 q binding to liposomes. At close to physiologic pH (7.2) and ionic strength (0.145 M) and in the absence or presence of serum, anionic liposomes bound a measurable but small amount of C1q . However, as the concentration of negative phospholipid in the liposomes increased, C1q binding increased. C1q binding increased even more as the ionic strength or the pH decreased. C1q peptide studies also demonstrated the importance of electrostatics. Peptides composed of residues 14-26 of the C1qA chain (C1qA₁₄[sub -]₂₆ ) bearing a net charge of plus five inhibited C1q binding and complement activation by anionic liposomes. This inhibitory capacity was dependent on the peptide's five positive charges and was independent of conformation or amino acidsequence. While electrostatics were important in determining C1q saturation binding, C1q binding affinity constants were independent of the electrostatic component suggesting that chemical forces were also involved. Clq-mediated complement activation was also affected by liposome size. For cardiolipin-containing liposomes, 240 nm vesicles bound more C1q and activated complement more readily than 100 nm vesicles. Multilamellar vesicles (∽1-8 μm) bound 15 times more C1q than 240 nm liposomes. This study is the first to show the ability of PEG-lipids to act as a barrier against complement activation by anionic liposomes. Incorporation of either cholesterol-PEG₆₀₀ (CH-PEG₆₀₀) , cholesterol-PEG₁₀₀₀ (CH-PEG₁₀₀₀) , or phosphatidylethanolamine-PEG₂₀₀₀ (PE-PEG₂₀₀₀) caused PEG-lipid dose-dependent inhibition of C1q binding to and complement activation by large anionic liposomes. Complement activation was strongly inhibited when 15 mole % of CH-PEG₆₀₀, 10 mole % CH - PEG₁₀₀₀, or 5 mole % PE - PEG₂₀₀₀ were incorporated into 100 nm anionic liposomes.
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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".