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Polyelectrolyte capsules fabricated by layer-by-layer (LbL) technique are introduced as a simple and efficient carrier system for spontaneous deposition of proteins and low molecular water soluble drug. The objective of the work was to investigate the applicability of polyelectrolyte capsules as vehicles for sustained or controlled delivery of drugs. Two different polymeric systems composed of weak and strong polyelectrolytes were chosen to study the loading and release behavior in order to meet the requirements of biomedical applications. In the first system, the wall permeability of weak polyelectrolyte (PAH/PMA) capsules could be readily manipulated from open to closed state by simply varying the pH. The open and closed state of the capsules could be attributed to the charge density variation of weak polyelectrolytes, which induces the capsule wall to undergo a transition from continuous to nanoporous morphology due to phase segregation. Bovine Serum Albumin (BSA) was spontaneously deposited in the hollow capsules and deposition was investigated by CLSM, SEM and AFM techniques. The driving force for spontaneous deposition was electrostatic interaction between the preloaded polystyrene sulfonate (PSS) and BSA. The deposition was uniform and concentration of BSA in the capsule interior reached a few hundred times greater than that of bulk. The amount of loading was significantly influenced by the loading pH, loading concentration and charge density of substance to be loaded at the corresponding pH. The deposition was successful up to the isoelectric point of BSA (pH = 4.8) and there was no loading observed above that, since the deposition is based on electrostatic attraction between PSS and BSA. During the release at physiological pH of 7.4, charge reversal of BSA occurred which induced electrostatic repulsion between PSS and BSA thereby triggering the movement of BSA from the interior to the bulk. Release continued up to 5 h in water and a total release of 63 % was observed which increased to 72 % when release was performed in PBS. Spontaneous deposition of low molecular weight, water soluble drug, ciprofloxacin hydrochloride was performed in the same manner and its release profile was studied. Controlling diffusion of smaller drug molecules is extremely difficult in drug delivery applications. Cross linking of capsule wall components could be used to control the release rates of smaller drug molecules. Cross linking density is dependent on the cross linking time and increases the stiffness of the capsule wall. Release of ciprofloxacin hydrochloride was possible even up to 6 h after cross linking. Antibacterial studies showed that the drug released even after 25 h has a significant effect on the bacterial pathogen E.coli. The second system included weak and strong polyelectrolytes (PAH & DS) and a novel route was employed to fabricate optically addressable capsules that could be laser activated for delivery of drugs. This approach involved a combination of LbL assembly and polyol reduction method wherein PEG was used to reduce AgNO3 to Ag nanoparticles (NPs). The capsules were prepared via LbL assembly of PAH and DS on silica template followed by synthesis of silver NPs in the layers and subsequent dissolution of the silica core. The sulfonate groups of DS present in the polyelectrolyte film act as binding sites for the adsorption of silver ions which are then reduced to silver NPs in the presence of PEG. The size of the silver NPs formed was influenced by the AgNO3 concentration used. At lower concentration, smaller particles of uniform distribution were observed which turned into larger particles of random distribution when the concentration of AgNO3 is increased. Silver NPs embedded capsules ruptured when exposed to laser and was significantly influenced by silver NPs size, their distribution, laser intensity and time of exposure. The synthesis of silver NPs increased the permeability of the capsules to higher molecular weight substances like dextran caused by the defects, discontinuities and pores created on the polymeric network due to the newly formed silver NPs. Encapsulation of FITC-dextran was performed using thermal encapsulation method by exploiting temperature induced shrinking of the capsules at elevated temperatures. During heat treatment the porous morphology transformed into smooth pore free structure which prevented the movement of dextran into the bulk and hence enrichment inside the capsules. The loaded dextran was readily released when exposed to laser and the release could be controlled from linear to burst release in order to meet practical requirements in biomedical applications.

Les sphéroïdes multicellulaires tumoraux (SMT) constituent un outil prometteur dans le domaine de l’étude biologique des tumeurs. Le but de la thèse était de développer une technique de la formation de SMT et de démontrer la disponibilité de ces sphéroïdes comme modèle in vitro 3D pour tester l’efficacité de principes actifs anticancéreux ainsi que celle de formulations de délivrance de médicaments. L'effet d’auto-assemblage de cellules induit par une addition des peptides RGD cycliques a été étudié pour 16 lignées cellulaires de différentes origines. Le peptide cyclique RGDfK et sa modification avec le cation triphenylphosphonium (TPP) ont permis de mettre en évidence l’induction de formation de sphéroïdes. Les sphéroïdes ont été employés comme modèles pour évaluer la cytotoxicité de principes actifs antitumoraux (doxorubicine, curcumine, temozolomide) et un certain nombre de formulations nano- et micrométriques (microréservoirs, nano-émulsions et micelles). / Multicellular tumor spheroids (MTS) are a promising tool in tumor biology. The aim of the Thesis was to develop a novel highly reproducible technique for MTS formation, and to demonstrate the availability of these spheroids as 3D in vitro model to test anticancer drugs and drug delivery vehicles. Cell self-assembly effect induced by an addition of cyclic RGD-peptides directly to monolayer cultures was studied for 16 cell lines of various origin. Cyclo-RGDfK peptide and its modification with triphenylphosphonium cation (TPP) were found to induce spheroid formation. The spheroids were used as a model to evaluate the cytotoxicity of antitumor drugs (doxorubicin, curcumin, temozolomide) and a number of nano- and micro- formulations (microcontainers, nano-emulsions and micelles).