1,720,981 research outputs found
Supramolecular assemblies from phthalocyanine building blocks
Full text linkContains fulltext :
mmubn000001_197782248.pdf (Publisher’s version ) (Open Access)Promotores : R. Nolte en A. SchoutenVIII, 175 p
Supramolecular assemblies from liquid-crystalline phthalocyanines
No full textItem does not contain fulltex
π-π Stacked Polymeric Micelles: From Optimization to Early Preclinical Evaluation
No full textPolymer-based nanomedicines are extensively investigated in the field of cancer therapy to improve the poor aqueous solubility, limited therapeutic efficacy and off-target side-effects of chemotherapeutic agents. Particularly polymeric micelles, self-assembled nanostructures consisting of a core and a shell with a diameter between 10-100 nm have attracted a lot of attention. Generally, the hydrophobic core of the micelles can accommodate hydrophobic drugs, while the hydrophilic shell renders colloidal stability and protection against the immune system. Sufficient stability and drug retention of the nanoformulations in the blood circulation are prerequisites for achieving a favorable anticancer outcome. As previously demonstrated by our colleagues, polymeric micelles based on poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)), stabilized by π–π stacking interaction between the aromatic groups, are associated with excellent particle stability and good drug retention, thereby significantly improved the circulation kinetics and therapeutic efficacy of the loaded drug compared to the unformulated drug. In this project, nanoformulations based on mPEG-b-p(HPMA-Bz) polymer were further developed and optimized to obtain a manufacturing process that is potentially suitable for upscale production and subsequent clinical translation. Micelles were prepared by nanoprecipitation technique. The formulation and processing parameters influencing the nanostructures in both batch mode and microfluidics system were studied to tune the sizes in the range suitable for drug delivery (25-100 nm). The block copolymer properties (e.g, molecular weight, their hydrophilic-to-hydrophobic ratio, homopolymer content), organic solvents, aqueous phases, polymer concentrations and addition rates were varied. Interestingly, the continuous flow process demonstrated excellent control over the size and morphology with the possibility of large continuous production. Curcumin, a hydrophobic compound with a potential anticancer activity, was selected to encapsulate in these micelles. Stability studies in plasma showed no change in micelle size during 24 h incubation at 37 °C. While curcumin was released over time and the release rate was inversely dependent on the size of the hydrophobic block. In vivo studies in mice using the most stable formulation showed that the circulation time of curcumin was significantly shorter than that of the micelles. In contrast, the circulation time was around 5 times longer than has been reported for free curcumin. Therefore, mPEG-b-p(HPMA-Bz) micelles only marginally improved the circulation kinetics of the loaded curcumin compared to the free form and essentially performed as a solubilizer. Despite the solubilizing effect of these micelles, therapeutic efficacy was not observed in the experimental mice model, which might be related to the relatively low sensitivity of the tumor cells for curcumin. Further research is still required to show the potential of these curcumin-loaded micelles in cancer treatment
Polymeric Micelles Loaded with mTHPC for Photodynamic Therapy: from synthesis to in vitro and in vivo evaluation
No full textm-Tetra(hydroxyphenyl)chlorin (mTHPC) is one of the most potent second generation photosensitizers (PSs), clinically used for photodynamic therapy (PDT) of head and neck squamous cell carcinomas. However, the very hydrophobic character of mTHPC encounters problems similar to that of many other PSs and chemotherapeutic drugs, such as low-water solubility, aggregation in aqueous media, and limited tumor specificity. These lead to difficulties of formulation and administration, suboptimal PDT efficacy, and off-target effects, such as skin sensitivity. Nanoparticulate drug delivery systems for mTHPC provide opportunities to tackle these drawbacks, by their capacity to encapsulate hydrophobic PS to yield aqueous dispersions facilitating its administration and increase accumulation of the PS at targeted tissues via passive targeting (i.e. enhanced permeability and retention (EPR) effect) and/or active targeting strategies. Among different drug delivery systems, polymeric micelles, composed of a hydrophilic stealth corona (most commonly based on PEG) for ensuring long circulation and colloidal stability, and a hydrophobic core for accommodating hydrophobic drugs, are suitable and attractive systems for delivery of mTHPC. In this thesis, different polymeric micelles based on poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG) block copolymers were prepared to load mTHPC with the aim to develop suitable micellar systems for targeted delivery of mTHPC. The stability of polymeric micelles and the retention of mTHPC in the micelles are essential for improved pharmacokinetics, selective biodistribution and consequently effective PDT. Therefore, this thesis reports on studies of in vitro stability, in vivo circulation kinetics, and biodistribution of different micellar mTHPC formulations. Further emphasis is given on the synthesis and characterization of a variety of amphiphilic block copolymers based on PEG (as hydrophilic block) and PCL (as hydrophobic blocks). To modulate and tailor the properties of the hydrophobic block, CL is copolymerized with carbonates functionalized by aromatic groups (Chapter 4) and crosslinkable dithiolanes (Chapters 5 and 6), respectively, to design π-π stacked and core crosslinked micelles with the aim to improve the stability of the micelles in the circulation and the retention of mTHPC in the core of the micelles.
In conclusion, the research presented in this thesis explores the possibility of preparation of stable PCL-PEG based polymeric micelles with small sizes as targeted delivery systems of mTHPC for PDT. We focused on the stabilization of small micelles exploiting chemical (disulfide crosslinking) and physical crosslinking (crystallization or π-π stacking), thus improving the retention of PS in vivo by tailoring the compositions and architectures of amphiphilic block copolymers using different strategies. The results of the pharmacokinetics, including circulation kinetics and biodistribution of these different stabilized micelles and their loaded mTHPC, provide important scientific insights for the further rational development of the polymeric micelles as nanocarriers for targeted drug delivery
Pharmaceutical formulations for poorly water-soluble drugs: From technology to solutions for clinical use
No full textThe thesis, titled 'Pharmaceutical formulations for poorly water-soluble drugs - From technology to solutions for clinical use' explores various formulation strategies to improve the water solubility of poorly water-soluble drugs. Such drugs are often associated with poor drug absorption, which can compromise their therapeutic efficacy and necessitate innovative formulation strategies to enhance their solubility, dissolution, and ultimately, their bioavailability in the human body. While the challenges tied with poorly water-soluble drugs are longstanding, so are the established strategies employed to address them. The formulator’s toolbox, though limited, still contains overlooked possibilities to overcome these challenges. Some of these options are often, but not exclusively, linked with parenteral applications. Two of these strategies are detailed in this thesis and include mixed micelles (of bile salts and phospholipids) and lipid nanoemulsions. Additionally, it explores the more established technique of self-emulsifying drug delivery systems. The (re-)formulation of three existing poorly-water soluble drugs, known for issues related to their (bio)availability, are described using the aforementioned strategies. This includes vitamin K, propofol and idebenone, respectively. Special emphasis is giving to vitamin K. Despite our understanding of the function of vitamin K for nearly a century, the availability of various formulations since the nineteen fifties, and the global awareness for many years that current oral formulations are ineffective in preventing vitamin K deficiency bleedings (VKDBs) in infancy, progress towards a solution has been slow and is primarily driven by academic research. In thesis, for the first time, we present an oral solution which protects newborns against life-threatening bleedings. Furthermore, we provide a physicochemical explanation how the long known, but unexplained, incidence difference of VKDBs in formula-fed versus breastfed can be explained. This thesis further increases our fundamental understanding of why vitamin K deficiency bleedings still occurs, details the extemporaneous preparation of a propofol emulsion without specialized manufacturing equipment and describes how the oral bioavailability of idebenone can be improved by targeting lymphatic uptake. This thesis brings us one step closer to various technological solutions
Functional supramolecular materials : Self-assembly of phthalocyanines and porphyrazines
Full text linkContains fulltext :
10619.pdf (Publisher’s version ) (Open Access
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
- …
