Encapsulation of crystalline topotecan in sphingosomes: a formulation suitable for clinical development
Bibliographic record
Abstract
Proc Amer Assoc Cancer Res, Volume 46, 2005 1397 Topotecan (9-dimethylaminomethyl-10-hydroxy-camptothecin) is a semi-synthetic, water-soluble derivative of camptothecin used for the second-line treatment of metastatic ovarian and small-cell lung cancer. Although topotecan is clinically active, its full potential is compromised by the rapid loss of antitumor activity at physiological pH due to hydrolysis of the closed lactone E ring to form a ring-opened carboxylate moiety. The closed ring configuration is stable at acidic pH; therefore clinically active topotecan can be maintained in the circulation when the drug is encapsulated in liposomes with an acidic interior. Several formulations of this type have been described in the literature and shown to exhibit enhanced antitumor activity compared to free drug in animal models. Here we describe the detailed characterization of a novel liposomal topotecan formulation. The drug is encapsulated to high concentration into preformed egg sphingomyelin/cholesterol (ESM/CH, 55:45 mol ratio) vesicles (sphingosomes) using a chemical gradient of Mg2+ or Mn2+ and the divalent cation/H+ ionophore A23187 to generate a pH gradient (inside acidic). Greater than 90 % encapsulation of topotecan occurs after 40 minutes at pH 6 and 60oC employing incubation volumes ranging from 1 ml to 20 L. Topotecan is highly membrane permeable and difficult to retain inside conventional liposomes. However, sphingosomes provide a rigid bilayer structure, which is less permeable to drug than conventional phospholipid bilayers, and is very stable in blood. Using cryo electron microscopy and 1H-NMR we show that >98 % of the encapsulated drug is in the form of solid, needle-like crystals. Increasing drug retention increases efficacy and the pharmacokinetics and greatly enhanced antitumor activity of this formulation are described in an accompanying abstract.
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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 | 0.001 |
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".