Poly(Lactic Acid)/Poly(Ethylene Glycol) Block Compolymers Linked By Covalent And Multiple Hydrogen Bond:Preparation And Solution Self-Assembly

Amphiphilic block copolymer can form many self-assembled nanostructures such as core-shell micelles in aqueous solution. The chemical structure, crystallinity, chain packing mode of core-forming block affect the structure and properties of micelles significantly. As a typical amphiphilic block copolymer. poly(lactic acid)/poly(ethylene glycol) (PLA/PEG) has so many advantages that has attracted extensive attentions. Poly(lactic acid) (PLA) has three stereoisomers, that is. semicrystalline poly (L-lactic acid) (PLLA), poly(D-lactide) (PDLA). and non-crystallizable poly(D, L-lactic acid) (PDLLA). Equimolar PLLA/PDLA mixture can form a stereocomplexed polymorph in melting state or solution. Therefore, tuning of stereo-chemical structure of PLA can feasibly control the chain packing mode and crystallization behavior of PLA segment, as well the structures and properties of copolymer micelles. Furthermore, supramolecular block copolymer can be prepared when hydrophilic block and hydrophobic block were linked through non-covalent bond. Because the non-covalent bond is sensitive to external stimuli, the stimuli-responsive micelle materials could be prepared through self-assembly of amphiphilic supramolecular block copolymers.Firstly, a series of PLA/PEG block copolymers with different PLA lengths and stereo-chemical structure ncluding the poly(ethylene glycol)-b-poly(L-lactic acid)-b-poly(D-lactic acid) (PEG-b-PLLA-b-PDLA) with isotactic stereoblock, the poly(ethylene glycol)-b-poly(L-lactic acid) (PEG-b-PLLA) and poly(ethylene glycol)-b-poly(D-lactic acid) (PEG-b-PDLA) with homo-crystalline PLA block, and the poly(ethylene glycol)-b-poly(D. L-lactic acid) (PEG-b-PDLLA) with non-crystallizable PLA block were synthesized via ring-opening polymerization of lactide. The micelle formation, precise micelle structure, enzymatic degradation, and drug release behavior were investigated nuclear magnetic resonance (NMR) and synchrotron radiation small-angle X-ray scattering (SAXS),etc. As indicated by differential scanning calorimeter (DSC) and wide angle X-ray diffraction (WAXD) results, the PEG-b-PLLA-b-PDLA stereoblock copolymers bearing comparable PLLA and PDLA block length and PEG-b-PLLA/PEG-b-PDLA enantiomerically-mixed copolymers assemble into stereocomplexed micelles, while the isotactic PEG-b-PLLA or PEG-b-PDLA and atactic PEG-b-PDLLA copolymers formed the homo-crystalline and amorphous micelles, respectively. As indicated by DSC results, increasing the PLA block length leads to the increased crystallinity. Furthermore, the PLA segments in PEG-b-PLLA-b-PDLA stereoblock copolymer micelles show-smaller crystallinity than those in PEG-b-PLLA/PEG-b-PDLA enantiomericaliy mixture. Critical micelle concentrations (CMC) of PEG/PLA block copolymers, which were determinated by surface tension method, were in the range of 8.9-15.5 mg/L and decreased with increasing length of core-forming PLA block. The block copolymers formed micelles with stereocomplexed core show smaller CMC than the copplymers formed micelles with homocrystallized or amorphous core. Hydrodynamic diameters (Dh) of PLA/PEG micelles determined by DLS ranged from 25.2 to 43.2 nm, and the micelles with stereoblock core-forming segment have larger Dh. As indicated by SAXS results, the PEG-b-PLLA-b-PDLA stereoblock copolymer micelles have larger core radius (Rin), size (Rout), micellar aggregation number (Nagg), smaller core density (ρcore),and looser packing of core-forming segments than the isotactic and enantiomerically-mixed copolymer micelles. These unique structural characteristics cause the stereoblock copolymer micelles to possess higher drug loaded content (DLC), slower degradation and drug release rates. The PEG-b-PLLA/PEG-b-PDLA enantiomerically-mixed micelles possess smaller Rin, larger Nagg and ρcore, and closer packing of core-forming segments, which render them a lower DLC, lowest enzymatic degradation rate and drug release rate.Secondly, the thymine-terminated PLLA (PLLA-THY) and diaminotriazine-terminated PEG (PEG-DAT) were synthesized through ring-opening polymerization of lactide and modification of end groups, respectively. The molecular weight of PLLA-THY was controlled by varying the ratio of initiator and monomer. Temperature-variable 1H NMR spectroscopy was used to prove the formation of multiple hydrogen bonds between PLLA-THY and PEG-DAT in solution. PEG-DAT:THY-PLLA supramolecular block copolymer self-assemble into core-shell supramolecular micelles with PEG corona and PLLA core in the neutral aqueous solution. CMC of supramolecular block compolymers, determinated by surface tension method, ranged from 6.1～15.0 mg/L and decreased with increasing the PLLA length. As indicated by the DLS results, Dhs of supramolecular micelles ranged from 115.6 to 199.2 nm and increased with the length of PLLA, resulting in the increase of DLC. Due to the reversibility of hydrogen bonds, the micelles supramolecular block compolymers were stimuli-responsive and their aggragates of them were influenced by temperature, pH value and salt concentration. Under the acidic conditions, the size of supramolecular block compolymer micelles became larger due to the protonation of amines and dissociate of hydrogen bonds. The size of supramolecular block compolymer micelles increased at pH> 13 and kept nearly constant at 5< pH< 11. The size of supramolecular block copolymer micelles is nearly unchanged at a low temperature. The concentration of salt had a significant influence on the structure of supramolecular micelles and Rh of supramolecular block copolymer micelles increased remarkably with increasing the salt concentration.