Search

The controlled delivery of anticancer drugs is driven by their interaction with carrier molecules. By creating complicated micelle-like complexes, amphiphilic polymers provide an opportunity to load drugs of various kinds. In this work, the interaction of the comb-like PEG-containing polymer poly(VEP-co-GMA)-graft-PEG with the water-soluble antitumor antibiotic doxorubicin and new water-insoluble derivatives of thiozalidinone Les-3883 characterized by a high anticancer efficiency has been studied in aqueous solutions by means of the SAXS, DLS, TEM, and photoluminescence methods. The formation of polymer micelles and their complexes with drugs, as well as their structural changes, is observed. The obtained results give evidence that the mechanism of organization of supramolecular complexes depends on the drug solubility in water. A potential capability of poly(VEP-co-GMA)-graft-PEG to prolong the drug circulation lifetime is confirmed., Контрольована доставка протипухлинних лiкiв базується на їх взаємодiї з молекулами-носiями. Амфiфiльнi полiмери, завдяки формуванню складних мiцелярних нанокомплексiв, дають змогу завантажити рiзноманiтнi лiки. Взаємодiя гребiнчастого ПЕГ-вмiсного полiмеру (полi(ВЕП-ко-ГМА)-графт-ПЕГ) з водорозчинним протипухлинним антибiотиком доксорубiцин i водонерозчинними новими похiдними тiозалiдiнону Les 3883 з високою протипухлинною дiєю дослiджувалась у водних розчинах за допомогою малокутового рентгенiвського розсiювання, динамiчного розсiювання свiтла, електронної мiкроскопiї та люмiнесценцiї. Було спостережено формування i структурнi змiни полiмерних мiцел та їх комплексiв з лiкарськими препаратами. Аналiз даних вказує на вiдмiнний характер в органiзацiї супрамолекулярних комплексiв в залежностi вiд водорозчинностi лiкарських препаратiв. Пiдтверджено потенцiйнi властивостi полi(ВЕП-ко-ГМА)-графт-ПЕГ для подовження циркуляцiї лiкiв.

The use of cell transplantation to treat enzyme deficiency disorders is limited by the immune response targeted against foreign tissue or the use of life-long immunosuppressants. Hiding cells from the immune system in an encapsulation device is promising. Cells encapsulated within an anionic calcium alginate hydrogel bead are protected through a semi-permeable membrane formed by polycation, poly-L-lysine (PLL). A final layer of alginate is added to hide the cationic PLL surface but this has proved to be difficult creating capsules which are prone to fibrotic overgrowth, blocking exchange of nutrients, waste and therapeutic enzymes through the capsule. For long term applications these capsules need to be both biocompatible and mechanically robust. This thesis aims to address the biocompatibility issue of high cationic surface charge by synthesizing polycations of reduced charge using N-(3- aminopropyl)methacrylamide hydrochloride (APM) and N-(2- hydroxypropyl)methacrylamide (HPM) and study the associated mechanical properties of the capsules using micropipette aspiration. Micropipette aspiration was applied and validated for alginate based capsules (gel and liquid core) to quantify stiffness. Varying ratios of APM were used to control the overall charge of the polycations formed while HPM was incorporated as a neutral, hydrophilic, nonfouling comonomer. The molecular weight (MW) was controlled by using reversible addition-fragmentation chain transfer (RAFT) polymerization. The biocompatibility of these polymers was tested by cell adhesion and proliferation of 3T3 fibroblasts onto APM/HPM copolymer functionalized surfaces and by solution toxicity against C2C12 myoblasts. The ability for the APM/HPM copolymers to bind to alginate and form capsules was also assessed, along with the integrity and stiffness of the capsule membrane with or without additional covalent cross-linking by reactive polyanion, poly(methacrylic acid-co-2-vinyl-4,4- dimethylazlactone) (PMV60). Thermo-responsive block copolymers of N-isopropylacrylamide (NIPAM) and 2- hydroxyethylacrylamide (HEA) were also synthesized as potential drug delivery nanoparticles, showing control over micelle morphology with varying NIPAM to HEA ratios. Thesis Doctor of Science (PhD) The treatment of enzyme deficiency disorders by cell transplantation is limited by the immune attack of foreign tissue in absence of immunosuppressants. Cells protected in an encapsulation device has shown promise. Poly-L-lysine, a widely used membrane material in these protective capsules, binds to the anionic gel entrapping living cells because it is highly cationic. The high cationic charge is difficult to hide causing the immune system to build tissue around the capsule, preventing the encapsulated cells from exchanging nutrients and therapeutic enzymes. This thesis aims to replace poly-L-lysine by synthesizing a series of more biocompatible materials of decreasing cationic charge. These materials were studied for the ability to support tissue growth and form stable capsules. The membrane strength was measured using an aspiration method validated for these types of capsules. Reducing the cationic charge of the materials increased the biocompatibility of the capsule membrane but also made for weaker membranes.

The self-association characteristics of very short and well-defined poly(butyl acrylate)-b-poly(acrylic acid) (PBA-b-PAA) block copolymers in water have been studied. The diblocks are asymmetric with the PBA block longer than the PAA block, giving rise to hollow sphere morphology. This is affirmed by experimental data and theoretical evaluations of the hydrophilic and hydrophobic domain sizes, as well as a value close to 1 for the ratio of the hydrodynamic to the gyration radius of the micelles. Besides, the untypically short PBA blocks (polymerization number around 15) render the micelles dynamic. Indications in support include among others the following: the CMC (critical micellar concentration) values depend, together with the aggregation numbers and the micellar sizes, on the block lengths, as predicted by theory; above the CMC their sizes are concentration-independent, while the micelles disappear below CMC. A comparison was also made with a random PBA-co-PAA copolymer of similar length, which self-associates at an apparent CMC 1 order of magnitude larger than those of the block copolymers, but the size of the formed micelles depends on the concentration., Colloid & polymer science, 292 (3), ISSN:0303-402X, ISSN:1435-1536

The structure of large block copolymer micelles is traditionally determined by small-angle neutron scattering (SANS), covering a large range of scattering vectors and employing contrast variation to determine the overall micelle morphology as well as the internal structure on shorter length scales. The present work shows that the same information can be obtained by combining static light scattering (SLS) and small-angle X-ray scattering (SAXS), which provide information on, respectively, large and short length scales. Micelles of a series of block copolymers of poly(ethylene propylene)-b-poly(ethylene oxide) (PEP–PEO) in a 70% ethanol solution are investigated. The polymers have identical PEP blocks of 5.0 kDa and varying PEO blocks of 2.8–49 kDa. The SLS contrasts of PEP and PEO are similar, providing a homogeneous contrast, making SLS ideal for determining the overall micelle morphology. The SAXS contrasts of the two components are very different, allowing for resolution of the internal micelle structure. A core–shell model with a PEP core and PEO corona is fitted simultaneously to the SAXS and SLS data using the different contrasts of the two blocks for each technique. With increasing PEO molecular weight, a transition from cylindrical to spherical micelles is observed. This transition cannot be identified from the SAXS data alone, but only from the SLS data.