An Albumin Biomolecular Drug Design Stabilized through Improved Thiol Conjugation and a Modular Locked Nucleic Acid Assembly
Bibliographic record
Abstract
Introduction: Albumin-nucleic acid biomolecular drug designs offer modular multifunctionalisation and extended circulatory half-life for improved efficacy and reduced side-effects. However, the clinical potential is currently limited by poor stability of conventional thiol conjugation and DNA nucleotides. This work aims to improve the stability of thiol conjugation and nucleic acid assembly by employing a fast-hydrolysing monobromomaleimide (MBM) linker and nuclease-resistant nucleotide analogues, respectively. Methods: The biomolecular assemblies were formed by site-selective conjugation of an oligonucleotide to cysteine 34 (Cys34) of albumin using the MBM linker, followed by annealing of a complementary oligonucleotide functionalised with either a fluorophore or the cytotoxic drug monomethyl auristatin E (MMAE). Formation of conjugates and assemblies were confirmed by gel shift analysis and mass spectrometry, followed by investigation of serum stability and cancer cell killing by gel electrophoresis and MTT viability assay, respectively. Results: The MBM linker was shown to rapidly conjugate to Cys34 of albumin and remain attached during a stabilising hydrolysis step. Albumin-nucleic acid assemblies employing stabilised nucleotide analogues afforded very high serum stability as exhibited by retained integrity of these assemblies after 72 hrs of incubation in 50% serum at 37°C, in contrast to conventional DNA assemblies that are completely degraded after 24 hrs. The biomolecular assemblies showed retained neonatal Fc receptor (FcRn) engagement and FcRn-mediated cellular recycling that acts as a good predictor of in vivo circulatory half-life. The MMAE-functionalised assembly exhibited cytotoxicity in a human pancreatic cancer cell line with an IC50 of 342 nM, triggered by drug release from breakdown of an acid-labile linker. Conclusion: This work presents albumin-nucleic acid module-based assemblies with improved stability and retained module functionality, promoting the drug delivery potential of this biomolecular platform.
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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) | 0.000 | 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 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".