Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption
Bibliographic record
Abstract
Abstract Colloidal drug aggregates enable the design of drug‐rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo‐lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, this approach is hindered by toxicity associated with phospholipidosis. It is hypothesized that tuning the p K a of the drug would enable endosomal disruption while avoiding phospholipidosis and minimizing toxicity. To test this idea, 12 analogs of the nonionizable colloidal drug fulvestrant are synthesized with ionizable groups to enable pH‐dependent endosomal disruption while maintaining bioactivity. Lipid‐stabilized fulvestrant analog colloids are endocytosed by cancer cells, and the p K a of these ionizable colloids influenced the mechanism of endosomal and lysosomal disruption. Four fulvestrant analogs—those with p K a values between 5.1 and 5.7—disrupted endo‐lysosomes without measurable phospholipidosis. Thus, by manipulating the p K a of colloid‐forming drugs, a tunable and generalizable strategy for endosomal disruption is established.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".