Synthesis of nanoparticles and nanocapsules for controlled release of the antitumor drug "Arglabin" and antituberculosis drugs

Abstract

The main tasks of controlled drug delivery are the targeted transport of drug to the designated location and its release within a determined period of time. Development of new formulations for already existing drugs is a promising approach in achieving this goal; giving opportunity to maintain the effective concentration of drug in the blood over a certain period of time it provides a prolonged therapeutic effect. Extensive research has been performed with the aim to synthesize controlled release systems for the treatment of cancer, tuberculosis and acute bacterial infections for the past 30 years. The research presented in this thesis contains the results of the investigation on the synthesis of polymeric nanoparticles and nanocapsules based on natural and synthetic polymers for controlled delivery of the antitumor drug and some antiTB drugs. The potential of using the novel antitumor drug Arglabin (created by Kazakhstani scientists) in tumor treatment gave an impulse to investigate the possibility of creation nanoparticulate systems for this drug. The other drugs used in this work served as model antiTB drugs. The promising outlook of polyalkyl cyanoacrylates and human serum albumin as carriers of different drugs was the reason to use them in combination with some antiTB drugs (capreomycin sulfate and p-aminosalicylic acid (PASA)) and the antitumor drug Arglabin. Particle size and particle size distribution are the most important characteristics of nanoparticles as they determine the in vivo fate (biodistribution) of nanoparticles loaded with drug. Therefore in this thesis special attention was paid to obtain monodisperse systems. It was possible to achieve narrow particle size distributions for polyethyl cyanoacrylate (PECA) nanoparticles loaded with drug. Molecular weight is another important characteristic of the polymer as it influences the circulation time of nanoparticles in the body. Being rapidly degradable, PECA both with and without drug (number molecular weights of PECA were around 2000) will not accumulate in the human body. The results of the drug release study have shown the possibility of controlling the release rate of capreomycin sulfate by incorporation of this drug into PECA nanoparticles. On the basis of the results it can be concluded that PECA nanoparticles would be a potential system to use them in tuberculosis treatment as carriers for the delivery of the antiTB drug capreomycin sulfate. The nanoparticles based on human serum albumin loaded with the antitumor drug Arglabin and antiTB drug PASA obtained by the desolvation method allowed to attain high loading efficiency for both drugs, which shows the perspective of using nanoparticulate forms of these drugs. In most cases high loading efficiency can be accomplished by encapsulation of the drug. Therefore attempts have been made to synthesize nanocapsules containing drugs by interfacial polymerization of ethyl cyanoacrylate in inverse miniemulsion polymerization. However in spite of the formation of hollow capsules with satisfactory characteristics, the method seems not to be suitable for encapsulation of antiTB drugs p-aminosalicylic acid and capreomycin sulfate, as the capsules leak through thin polymer wall during washing and drying. Recently a new technique has been developed, i.e. encapsulation of the drug using vesicle templating polymerization using RAFT technology. In theory this new technique might be very promising for those drugs which are not compatible with the polymerization conditions (e.g. radicals). Vesicle-templated pH-responsive DMAEMA, MMA, EGDMA nanocapsules loaded with capreomycin sulfate were successfully synthesized in this thesis. The results have shown a high entrapment efficiency of the drug (70 %). An initial study on the release of capreomycin sulfate from these polymeric nanocapsules performed at pH=6.5 have shown that the release is relatively fast; however we believe the time can be prolonged by increasing the shell thickness of the nanocapsules and the degree of crosslinking. This type of crosslinked responsive nanocapsules can find possible applications in pharmaceutics as drug carrier.