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Background: There is a high demand for evidence-based and cost-effective treatment concepts for convicted individuals who sexually abused children (ISAC) and individuals who consumed child sexual exploitation material (ICCSEM) under community supervision (CS). The @myTabu-consortium developed a guided web-based intervention for convicted ISAC and ICCSEM under CS consisting of six online modules targeting psychological meaningful risk factors. The study aims to evaluate the effectiveness of this guided web-based intervention in reducing dynamic risk factors and the risk to re-offend compared to a placebo condition. Furthermore, these dynamic risk factors are measured before and after every module to evaluate their individual effectiveness to reduce the respective risk factor as well as risk to re-offend. This clinical trial protocol describes the planned methods as well as the intervention concept. Methods: The methodological design is a placebo controlled randomized add-on trial (N = 582) with follow-ups at 8 points in time. The placebo condition controls for attention and expectation effects and comprises the same amount of modules with a comparable temporal effort as the experimental intervention. The trial is conducted as an add-on to community supervision as usually done. Primary outcomes are dynamic risk factors assessed by self-report risk assessment tools and officially recorded re-offenses. Discussion: To the best of our knowledge, the study is the first to compare the (cost-) effectiveness of a guided web-based intervention for convicted ISAC and ICCSEM under community supervision against a placebo condition. Methodological limitations (e.g., potential ceiling- or volunteers-effects) are discussed. Clinical Trial Registration: German Clinical Trial Register (DRKS 00021256). Prospectively registered: 24.04.2020.
RESUMO
Parthenolide (PTL) has shown great promise as a novel anti-leukemia agent as it selectively eliminates acute myeloid leukemia (AML) blast cells and leukemia stem cells (LSCs) while sparing normal hematopoietic cells. This success has not yet translated to the clinical setting because PTL is rapidly cleared from blood due to its hydrophobicity. To increase the aqueous solubility of PTL, we previously developed micelles formed from predominantly hydrophobic amphiphilic diblock copolymers of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (e.g., PSMA100-b-PS258) that exhibit robust PTL loading (75%efficiency, 11% w/w capacity) and release PTL over 24 h. Here, PTL-loaded PSMA-b-PS micelles were thoroughly characterized in vitro for PTL delivery to MV4-11 AML cells. Additionally, the mechanisms governing micelle-mediated cytotoxicity were examined in comparison to free PTL. PSMA-b-PS micelles were taken up by MV4-11 cells as evidenced by transmission electron microscopy and flow cytometry. Specifically, MV4-11 cells relied on clathrin-mediated endocytosis, rather than caveolae-mediated endocytosis and macropinocytosis. In addition, PTL-loaded PSMA-b-PS micelles exhibited a dose-dependent cytotoxicity towards AML cells and were capable of reducing cell viability by 75% at 10 µM PTL, while unloaded micelles were nontoxic. At 10 µM PTL, the cytotoxicity of PTL-loaded micelles increased gradually over 24 h while free PTL achieved maximal cytotoxicity between 2 and 4 h, demonstrating micelle-mediated delivery of PTL to AML cells and stability of the drug-loaded micelle even in the presence of cells. Both free PTL and PTL-loaded micelles induced NF-κB inhibition at 10 µM PTL doses, demonstrating some mechanistic similarities in cytotoxicity. However, free PTL relied more heavily on exofacial free thiol interactions to induce cytotoxicity than PTL-loaded micelles; free PTL cytotoxicity was reduced by over twofold when cell surface free thiols were depleted, where PTL-loaded micelle doses were unaffected by cell surface thiol modulation. The physical properties, stability, and efficacy of PTL-loaded PSMA-b-PS micelles support further development of a leukemia therapeutic with greater bioavailability and the potential to eliminate LSCs.
RESUMO
Amphiphilic diblock copolymers of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) and poly(styrene-alt-maleic anhydride)-b-poly(butyl acrylate) (PSMA-b-PBA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerizations. Polymers were well-controlled with respect to molecular weight evolution and polydispersity indices (PDI < 1.2). Additionally, RAFT allowed for control of diblock compositions (i.e., ratio of hydrophilic PSMA blocks to hydrophobic PS/PBA blocks) and overall molecular weight, which resulted in reproducible self-assembly of diblocks into micelle nanoparticles with diameters of 20-100 nm. Parthenolide (PTL), a hydrophobic anticancer drug, was loaded and released from the micelles. The highest loading and prolonged release of PTL was observed from predominantly hydrophobic PSMA-b-PS micelles (e.g., PSMA100-b-PS258), which exhibited the most ordered hydrophobic environment for more favorable core-drug interactions. PSMA100-b-PS258 micelles were further loaded with doxorubicin (DOX), as well as two hydrophobic fluorescent probes, nile red and IR-780. While PTL released quantitatively within 24 h, DOX, IR-780, and nile red showed release over 1 week, suggesting stronger drug-core interactions and/or hindrance due to less favorable drug-solvent interactions. Finally, uptake and intracellular localization of PSMA100-b-PS258 micelles by multidrug resistant (MDR) ovarian cancer cells was observed by transmission electron microscopy (TEM). Additionally, in vitro analyses showed DOX-loaded PSMA-b-PS micelles exhibited greater cytotoxicity to NCI/ADR RES cells than equivalent free DOX doses (75% reduction in cell viability by DOX-loaded micelles compared to 40% reduction in viability by free DOX at 10 µM DOX), likely due to avoidance of MDR mechanisms that limit free hydrophobic drug accumulation. The ability of micelles to achieve intracellular delivery via avoidance of MDR mechanisms, along with the versatility of chemical constituents and drug loading and release rates, offer many advantages for a variety of drug delivery applications.
