Complexation, Layer-by-Layer Assembly And Drug Carrier Fabrication Of Polyelectrolytes Based On Poly (α, L-glutamic Acid)

Drug carriers driven by electrostatic force always possess pH, temperature-stimulative ability. Much related work has been devoted to natural polymers, like CS, alginate,glutin and so on. However, some disadvantages of natural polymers limit their broad application in controlled release. In the work, two polyelectrolyte systems PGA/CS and mPEGGA/CS were used to fabricate novel drug-loaded microspheres. Effect of different factors on polyelectrolyte complexation between neutral-block-polyanion and polycation in dilute solution and solid state were scrutinized. We also investigated alternate depostion of PGA (or mPEGGA) and CS on 2D template and the influence of different factors on layer-by-layer. Based on the theory on polyelectrolyte complexation and alternate deposition, novel drug carrier was fabricated.Amino-monomethoxypoly (ethylene glycol) (mPEG-NH₂) was synthesized by converting terminal hydroxyl groups of mPEG to primary amino groups. Monomethoxypoly (ethylene glycol) tosyalte (mPEG-oTs) was prepared at first, and then reaction with salt of phthalimide and finally hydrazinolysis. N-carboxy anhydride ofγ-benzyl-L-glutamate (NCA) was synthesized fromγ-benzyl-L-glutamate and triphosegen. Methoxy poly(ethylene glycol)-b-poly(γ-benzyl-L-glutamate) (mPEGBG) diblock copolymer was obtained by ring-opening polymerization NCA of using amino-terminated methoxy polyethylene glycol (mPEG) as macroinitiator. Theγ-benzyl protection groups were removed in the presence of HBr and the resultant polymer monomethoxy poly(ethylene glycol)-b-poly(γ-benzyl-L-glutamate) (mPEGGA) was obtained.Polyelectrolyte complexation between mPEGGA as neutral-block-polyanion and chitosan (CS) as polycation has been scrutinized in aqueous solution as well as in the solid state. Water-soluble polyelectrolyte complexes (PEC) can be formed only under nonstoichiometric condition while phase separation is observed when approaching 1:1 molar mixing ratio in spite of the existence of hydrophilic mPEG block. This is likely due to mismatch in chain length between polyanion block of the copolymer and the polycation or hydrogen bonding between the components. Hydrodynamic size of primary or soluble PEC is determined to be about 200nm, which is larger than those reported in some literature. The increase in polyion chain length of the copolymer leads to the increase in the hydrodynamic size of the water-soluble PEC. Formation of spherical micelles by the mPEGGA/CS complex at nonstoichiometirc condition has been confirmed by the scanning electron microscopy observation (SEM) and transmission electron microscopy (TEM) observations. The homopolymer CS experiences attractive interaction with both mPEGA and PGA blocks within the copolymer. Competition of hydrogen bonding and electrostatic force in the system or hydrophilic mPEG segments weakens the electrostatic interaction between the oppositely charged polyions. The existence of hydrogen bonding restrains the mobility of mPEG chains of the copolymer and completely prohibits crystallization of mPEG segments.Multilayer films based on PGA and CS were fabricated by Layer-by-Layer Assembly technique. The growths of CS and PGA deposition are both exponential to the deposition steps at first,although at different steep growth. We further studied the factors of the growth by UV-vis spectroscopy. QCM measurements combined with UV-vis spectra revealed the increase of the multilayer film growth at different pHs: pH=4.4>pH=5.0>pH=5.5. When at pH=6.5, the build-up of the multilayer stoped after the deposition of a few layers. Meanwhile, the (PGA/CS) multilayer film grows more rapidly with increasing concentration of the polyelectrolytes'solutions and ionic strength. The multilayer films of mPEGGA/CS grew exponentially as the function of the deposition steps. The molecular weight of the block copolymer could significantly influence the growth of films. The film of mPEGGA/CS with high molecular weight of PGA segment grows faster than that of low molecular weight.We described an approach to fabricate microspheres by a combination of emulsion-crosslinking method and LbL assembly technique. Firstly, bare CS microspheres were obtained by a typical emulsion-crosslinking method. The multilayer microspheres were fabricated by a template-assisted assembly in a LbL manner, using poly(α, L-glutamic acid) and its copolymer methoxy poly(ethylene glycol)-b-Poly(α, L-glutamic acid) as polyanion and CS as polycation. The results determined byξ-potential measurement show thatξ-potential at the same layer does not depend on the surface charge of the template. For polyelectrolytes of a lower charge density, lower values ofξ-potential can be obtained. The system is believed to be effective to entrap hydrophilic ionic drug as shown in the paper. Using 5-Fu as model drug, controlled release behaviour of novel drug-loaded microspheres using (PGA/CS)4 as inner layers and mPEGGA as outmost layer were investigated. It is found that the release rate is slower than that of typical CS microspheres and microcapusles.