Facile Synthesis of High Molecular Weight Poly(ethylene glycol)-b-poly(amino acid)s by Relay Polymerization

Poly(amino acid)s (PAAs) are one kind of favorable biopolymer that can be used as a drug or gene carrier. However, conventional ring-opening polymerization of PAAs is slow and needs a strict anhydrous environment with an anhydrous reagent as well as the product without enough high molecular weight (M_n), which limits the expanding of PAAs' application. Herein, we took BLG-NCA as the monomer to quickly synthesize one kind of high M_n amphiphilic copolymer, poly(ethylene glycol)-b-poly(γ-benzyl-l-glutamic acid) (PEG-PBLG), by relay polymerization with a simple one-pot method within 3 h in mild conditions (open air, moisture insensitive). In the polymerization process, ring-opening polymerization-induced self-assembly in sodium bicarbonate aqueous solution first occurred to obtain low M_n PEG-PBLG seeds without purification. Then γ-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA) dichloromethane solution was added into PEG-PBLG seeds directly and stirred vigorously to form am emulsion; during this process, the amphiphilic PEG-PBLG seeds will anchor on the interface of DCM and water to ensure the concentration of α-helix rigid PBLG in DCM to maintain the following relay polymerization. Then, high M_n PEG-PBLG was obtained in mild conditions in one pot. We found that the α-helix rigid structure was essential for relay polymerization by studying the synthetic speed of amphiphilic copolymer with different secondary structures. MOE simulation results showed that PBLG and BLG-NCA tended to form a double hydrogen bond, which was beneficial to relay polymerization because of higher local concentrations that can produce more double hydrogen bonds. Our strategy can quickly obtain high M_n PEG-PBLG (224.9 KDa) within 3 h from PEG-NH₂ and BLG-NCA in one pot and did not need an extra initiator. After deprotection, the poly(ethylene glycol)-b-poly(l-glutamate acid) (PEG-PGA) with high M_n as a second product can be used as an excellent antitumor drug carrier. The high M_n PEG-PGA can achieve an encapsulation rate of 86.7% and a drug loading rate of 47.3%, which is twice that of the low M_n PEG-PGA. As a result, the synthesis of PEG-PBLG by relay polymerization simplified the process of PEG-PAA polymerization and increased the M_n. In addition, this method opened a way to obtain other kinds of high M_n PEG-PBLG values in the future.