Design, Self - Assembly And Bio - Application Of Novel Structural Copolymers Based On PNIPAM For Thermosensitive Blocks

The amphiphilic block polymers show many remarkable features, they have been widely used as a kind of important short-term drug release carriers. The synthesis and micellization of amphiphilic block polymers is currently a hot subject in the field of polymer research, especially, in biomaterial applications. As a drug release carrier, low critical solution temperature (LCST) is a critical index for its application. It is an important method to adjust the LCST of amphiphilic block polymers by changing the rate of hydrophilic/hydrophobic monomers. Star block copolymers, as a class of the polymer materials with unique architecture, has some unique characters, such as smaller hydrodynamic radius, higher molecular surface functionality, and a large number of independent cavities inside the molecular interior. Those characters may play an important role in improving the drug loading and releasing behavior. Therefore, Star block copolymers are widely used as drug-loaded micelles. Poly(N-isopropylacrylamide)(PNIPAM) is a widely used thermosensitive polymer, which has a phase transition of about32℃. However, the polymer drug carrier can cause drug early leakage in the normal blood circulation since phase transition temperature is lower than normal body temperature. In view of this, thermosensitive linear poly(N-isopropylacrylamide-co-acrylamide)-block-poly (D,L-lactide)(P(NIPAM-co-AM)-b-PLA) and tri-armed star polystyrene-block-poly(N-isopropylacrylamide)(C3-(PS-b-PNIPAM)) block copolymers were designed and synthesized in this work. The micellization behavior of these block copolymers was studied in aqueous solution. The loading and release performances of different anticancer drugs from these copolymer micelles were investigated. The concrete contents include the following three aspects:1. The synthesis of a series of thermosentive amphiphilic block copolymers, P(NIPAM-co-AM)-b-PLA, was achieved by a ring-opening polymerization avenue of D,L-lactide in the case of hydroxyl-terminated (PNIPAM-co-AM)-OH precursors, while the latter was synthesized by a free radical polymerization route based on a bifunctional initiator2,2’-azobis(2-methylpropion amidine) dihydrochloride. FT-IR,]H NMR and GPC were employed to characterize and confirm the chemical structure and molecular weight of polymer. The solution behaviors were investigated by surface tension technique, UV-vis transmittance, TEM and DLS measurements. The experimental results show that the prepared copolymer micelles assumed regular sphere in shapes, with hydrodynamic particle diameters between71and81nm by DLS. This kind of small size micellar nanoparticles has a great application in drug delivery systems. Surface tension measurements showed that the block copolymer micelles displayed higher stability even in an infinite dilution condition, with CAC values lower than16.2mg L-1. Hydrophilic acrylamide units with different contents can be used to regulate the temperature of the phase transition, making the LCST or cloud points (CP) slightly higher than the body temperature. By this way, drug leakages can be avoided during blood circulation in the human body, and accelerated drug release can be achieved in lesion or cancer sites, and finally the purpose of targeted therapy can be attained. The optimal ratios of NIPAM to AM should be less than90:10.2. Novel tri-armed star C3-(PS-b-PNIPAM) block copolymers with trimesic acid as central molecules were synthesized by esterification, amination, amidation reaction and successive two-step atom transfer radical polymerization. The chemical structure of the star block copolymers was confirmed by FT-IR,1H NMR and GPC measurements. The star block copolymers could spontaneously assemble and form core-shell micelle nanoparticles due to their hydrophilic-hydrophobic trait in aqueous media. The surface tension measurements showed that the CAC values of the star block copolymer micelles were in the range from14.67to47.61mg L-1. The micelles were regularly spherical in shapes with particle diameters from200to220nm. The copolymer micelles exhibited thermo-triggered phase transition behavior, and the LCST values could be regulated by varying copolymer compositions or molecular weights.3. The loading and releasing of insoluble10-hydroxy camptothecin (HCPT) from the two different polymeric micelles, P(NIPAM-co-AM)-b-PLA and C3-(PS-b-PNIPAM), and selective encapsulation and release behaviors of various water-insoluble drugs in the same polymer micelle were studied. The experimental results show that the linear block copolymer P(NIPAM-co-AM)-b-PLA micelle has different loading abilities for three different drugs (prednisone, HCPT, and paclitaxel (PTX)), and the copolymer micelles with different compositions exhibite various encapsulation capability for HCPT. The star block copolymer micelles with longer hydrophilic chains produce larger loading capabilities for HCPT. The linear P(NIPAM-co-AM)-b-PLA block copolymer micelles are more suitable for loading and release of PTX, whereas the star C3-(PS-b-PNIPAM) copolymer micelles may be more suitable as HCPT delivery carriers. In addition, the cytotoxicity studies on a series of block copolymer micelles and drug-loaded copolymer micelles were also carried out by MTT assays. The MTT data reveale that no significant cytotoxicity or significantly low cytotoxicity was observed for the block copolymer micelles or drug-loaded copolymer micelles. Consequently, no damage to normal cells was found when drugs reach to the nidus sites. Overall, the as-prepared thermosensitive block copolymer micelles have great potentials in controlled release of hydrophobic drugs.