Amphiphilic Star Copolymers: Synthesis, Characterization And Primary Applications In Drug Delivery System

In this dissertation, a series of amphiphilic star block, miktoarm star copolymers and drug-conjugated amphiphilic star copolymers based on resorcinarene, calixarene and cyclodextrin cores have been synthesized by combination of CROP, ATRP and "Click" reaction. Primary studies on the self-assembly behaviors of these copolymers and drug-loading capacities of the drug-conjugated amphiphilic star copolymers have been performed.Two kinds of novel multifunctional resorcinarene precursors with eight alcoholic hydroxyls were synthesized and used as initiators to prepare well-defined eight-arm star-shaped poly(s-caprolactone) (SPCL) in the presence of yttrium tris(2,6-di-tert-butyl-4-methylphenolate) [Y(DBMP)3] under mild conditions. End group 1H NMR and SEC-MALLS analyses confirmed the well-defined eight-arm star structures. Subsequently, novel amphiphilic star triblock copolymers, star poly(ε-caprolactone)-block-poly(acrylic acid)-block-poly(ε-caprolactone)s (SPCL-PAA-PCL) consisting eight PCL-b-PAA-b-PCL triblock arms were prepared by combination of ATRP, "Click" reaction, and selective hydrolysis using SPCL as starting material. These amphiphilic star triblock copolymers could self-assemble into spherical micelles in aqueous solution which were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM).Considering the influence of the initiators'solubilities for preparing well-defined star polymers, per-2,3-acetyl-β-cyclodextrin with seven primary hydroxyl groups was synthesized and used as multifunctional initiator for CROP of CL. Well-defined P-cyclodextrin-centered seven-arm star poly(ε-caprolactone) (CDSPCL) with narrow molecular weight distributions (≤1.15) have been successfully prepared in the presence of Sn(Oct)2 for the first time. Both the "core" and the "arm" of these star polymers are biodegradable. Subsequently, two kinds of amphiphilic seven-arm star block copolymers were synthesized from CDSPCL:one was amphiphilic seven-arm star poly(ε-caprolactone-b-ethylene glycol) (CDSPCL-b-PEG), which was synthesized by the coupling reaction of CDSPCL with carboxyl-terminated mPEGs. CDSPCL-b-PEG could self-assemble into spherical micelles in water with the particle size ranging from 10-40 nm. The other one was amphiphilic seven-arm star poly(ε-caprolactone-b-tert-butyl acrylate-b-ethylene glycol) (CDSPCL-PrBA-PEG), which was synthesized by combination of ATRP, and "Click" reaction from CDSPCL. Some CDSPCL-PtBA-PEG with proper components could self-assemble into novel "core-shell-corona" micelles and "multi-wall" vesicles, which were characterized by DLS, TEM, and AFM. The possible reason for the formation of these novel aggregates was the differential crystallinity between PCL and PtBA. Furthermore, seven-arm amphiphilic star copolymers (CDSPCL-PAA-PEG) with two different hydrophilic chains (PAA and PEG) were synthesized by the selective hydrolysis of CDSPCL-PtBA-PEG, which could self-assemble into pH-response aggregates in water.Only few papers concerned the synthesis of well-defined miktoarm star copolymers based on macrocyclic compounds. In this dissertation, novel heterotetrafunctional A2B2 and A14B7 initiators were synthesized from selective substitution reactions of calix[4]arene and P-cyclodextrin. A2B2 miktoarm star copolymers [C4S(PCL)2-(PEG)2] consisting of two PCL arms and and two PEG arms were synthesized from calix[4]arene-based A2B2 initiator by the combination of CROP, and "Click" reaction; while A14B7 miktoarm star copolymers [CDS(PCL-PAA)] consisting of fourteen PCL arms and seven PAA arms were synthesized by the combination of CROP, and ATRP.1H NMR, SEC-MALLS, FT-IR analyses confirmed that they had well-defined miktoarm star architectures, controlled molecular weight and reasonably narrow molecular weight distribution. DLS, TEM, and AFM were used to characterize the morphologies of the self-assembled aggregates from these amphiphilic A14B7 and A2B2 miktoarm star copolymers. In general, the weight fraction of hydrophilic chains was the keypoint to control the morphologies of the aggregates:amphiphilic star copolymers with low weight fraction of hydrophilic chains preferred to form large aggregates, such as worm like micelles and vesicles; while amphiphilic star copolymers with high weight fraction of hydrophilic chains preferred to form small aggregates, such as spherical micelles.Novel two kinds of drug-conjugated miktoarm star copolymers, A2B2 miktoarm star copolymers (PCL)2-(PEG)2-D and A14B7 miktoarm star copolymers CDS(PCL)14-(PEG)7-D with ibuprofen conjugated on the end of the PCL chains have been synthesized by the combination of CROP and "Click" chemistry using 2,2-bis(bromomethyl)propane-1,3-diol and per-6-(tert-butyldimethylsilyl)-β-CD as starting material, respectively.'H NMR, SEC-MALLS, FT-IR analyses suggested that these copolymers had designed well-defined miktoarm star architectures and controlled molecular weight. These copolymers could self-assemble into various morphologies (such as spherical micelles, lamellar aggregates, and worm-like aggregates) in aqueous solution, which can be controlled by the composition of the copolymers. The drug-loading efficiency and drug-encapsulation efficiency of the drug-conjugated miktoarm star copolymers were significantly higher than those of the corresponding non-drug-conjugated miktoarm star copolymers.Novel main chain drug-grafted amphiphilic seven-arm star copolymers CDS-P(CL-co-DTC)-D-b-PEG with tunable amount of drug molecules have been prepared in this dissertation. The synthetic route was as follows:bromide functionalized cyclic carbonate monomer had been designed and used to copolymerize with CL in the presence of per-2,3-acetyl-β-CD to prepare seven-arm star copolymers [CDS-P(CL-co-DBTC)]. Then, amphiphilic star copolymers CDS-P(CL-co-DBTC)-b-PEG had been synthesized by esterification coupling reaction between CDS-P(CL-co-DBTC) and carboxyl-terminated mPEGs. Subsequently, bromide groups on the main chains of CDS-P(CL-co-DBTC)-b-PEG had been converted into azide groups by treating with NaN3. Finally, the targeted CDS-P(CL-co-DTC)-D-b-PEG had been synthesized by "Click" reation between alkyne functionalized ibuprofen and azide functionalized amphiphilic star copolymers. Furthermore, CDS-P(CL-co-DTC)-D-b-PEG could self-assemble into spherical micelles, worm-like aggregates and vesicles with a diameter of several hundreds nm, according to the composition of the copolymer.