Development and characterization of stimuli-responsive drug delivery systems to prevent HIV infection and the treatment of chronic wounds
Bibliographic record
Abstract
Patient compliance is very important and highly depends on the drug dosage form which correlates with the success of therapy. Drug delivery systems can be adapted to different pharmaceutical ingredients and to different delivery routes depending on the application. This thesis focuses on the development and characterization of different types of drug delivery systems with a focus on stimuli-responsive biomaterials. Stimuli-responsive biomaterials are a promising approach for achieving on-demand drug release. They are intended to deliver their active compound at the appropriate time and site of action in response to specific triggers. The aim of this thesis was the development and characterization of a pH-responsive intravaginal ring (IVR) and a thermo-responsive wound dressing. The IVR is intended for the prevention of HIV infection while the wound dressing is to treat chronic wounds that develop as a co-morbidity associated with immune-compromised patients. \nThe behavior of polyvinyl alcohol (PVA) films containing nanoparticles (NPs) for vaginal drug delivery was evaluated first. In this study, we demonstrated that the amount of NPs had little effect on film dissolution and on the storage and loss modulus. However, the percentage of PVA used and the amount of plasticizer (polyethylene glycol) and carrageenan (a film-forming agent) greatly affected the physico-mechanical properties of the film and play an important role in film dissolution time and nanoparticle (NP) release. \n Secondly, we fabricated an IVR with polyurethane HP-60D-35 containing hydroxychloroquine (HCQ) as a prevention strategy against HIV. The safety of the IVR and HCQ were assessed on the vaginal epithelial cells VK2/E6E7, the ectocervical cells ECT1 and more importantly, on vaginal normal microflora lactobacillus crispatus and jensenii. No significant toxicity was observed. \n We then designed a segmented IVR with half of the ring delivering HCQ while the second-half was coated with a pH-responsive polymer to deliver anti-CCR5 siRNA NPs. HCQ was released continuously for over 25 days with a mean daily release of 31.17±3.06 µg/mL. Anti-CCR5 siRNA NPs were released from the pH-responsive coated segment only when the pH was 7.3 (e.g. in the presence of simulated seminal fluid) with a total release of 5.12 ±0.9 mg compared to vaginal fluid simulant alone (0.42 ±0.19 mg). Anti-CCR5 siRNA NPs knocked down CCR5 gene expression by 83±5.1% in vitro in the CD4+ T-cell line Sup-T1. \n In the second part of the thesis, we made a thermo-responsive wound dressing using gelatin crosslinked with chitosan. LL37 and vancomycin were encapsulated into solid lipid nanoparticles (SLN) and mixed into the gelatin-chitosan hydrogel. The hydrogel itself liquefied rapidly (30min) at 33ºC (human skin temperature) than at room temperature (remained semisolid). We evaluated LL37/vancomycin-SLN using a microtiter plate-based biofilm assay formed using S. aureus. 6mg/mL of LL37/vancomycin was capable of significantly reducing S. aureus biomass. \nOverall, the development of stimuli-responsive drug delivery systems is appealing as it can release drugs only when needed, which will reduce toxicity and unwanted side-effects. Furthermore, it can potentially improve patient compliance resulting in improved therapeutic efficacy.
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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) | 0.001 | 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 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".