A new brain delivery system for therapeutic molecules to treat brain primary or metastatic tumors
Bibliographic record
Abstract
C99 Background: The blood-brain barrier (BBB) is the rate limiting factor for the penetration of anticancer drugs into the brain. Angiochem has discovered a new peptide based drug delivery technology (AngioPep) that provides a non-invasive and flexible platform for transporting drugs of any size to the brain. The small molecule of paclitaxel is impeded to reach its target in the brain by the presence of the BBB’s P-glycoprotein (P-gp) efflux pump; therapeutic monoclonal antibodies (MAbs) do not cross the BBB because of their size and hydrophilicity. They have been conjugated to AngioPep to create paclitaxel-AngioPep (ANG1005) and MAb-AngioPep (ANGMAb). They then have been assessed in vitro and in-vivo using different experimental approaches. Material and methods: An in vitro model of the BBB and in situ brain perfusion were used to assess the brain uptake. Distribution, Pharmacokinetic and Toxicity studies were done in rodents and dogs. Efficacy was assessed using xenograft models of glioblastoma (U87) and non-small cell lung carcinoma (NCI-H460) by subcutaneous and intracranial stereotaxic implantation in immunodeficient mice nu/nu. Results: ANG1005: We demonstrate that ANG 1005 is actively transported across the BBB and bypasses the P-gp driven efflux pump leading to a high concentration of paclitaxel in the brain parenchyma. ANG1005 levels in the brain and brain tumors were quantified by LC-MS. In vitro cytotoxicity is comparable to Paclitaxel. In vivo efficacy studies confirm that this vector platform technology delivers a therapeutic amount of paclitaxel to the brain and the tumors. Furthermore the tolerability of ANG-1005 is better than paclitaxel. ANGMAb: Using the in-vitro BBB model and in-situ brain perfusion assay, we show that MAbs are very efficiently transcytosed leading to a high concentration of MAb in the brain parenchyma. In vivo pharmacology studies are on-going to demonstrate therapeutic efficacy. Conclusion: Overall, chemical conjugation of AngioPep to compounds such as small hydrophobic chemotherapeutics (paclitaxel) and larger hydrophilic drugs (MAbs) allow access to the brain parenchyma and reach therapeutic levels for the treatment of brain cancers (primary and secondary brain tumors).
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".