Preparation Of PH Sensitive Amphiphilic Block Copolymers And Study On The Behavior Of Micelles

Polymeric micelles as drug delivery system for cancer treatment have received great attention in recent years. It offers numerous advantages, such as increased aqueous solubility of the drug, enhanced cancer therapy and reduced normal tissue toxicity. Nowadays, most of the polymeric micelles utilized to construct polymeric micelles are made of linear amphiphilic polymers. Compared with linear polymers, the multiarm star polymers have attracted attention in drug delivery applications because they have narrow molecular weight distribution and low solution viscosity. In addition, their cores could encapsulate drugs, and the surface groups could be used for drug conjugation or labeling. In this paper, based on poly(ethylene glycol) (PEG), a polymer with excellent biocompatibility, was used to fabricate a series of amphiphilic star block copolymers with different hydrophobic length; the self-assembly characteristics, application on drug encapsulation and release from these copolymers were investigated. The research contents of this project include:(1) By using living anionic ring opening polymerization (AROP) of ethylene oxide (EO) and ethoxy ethyl glycidyl ether (EEGE), a series of amphiphilic star block copolymers poly(ethylene glycol)-block-poly(ethoxy ethyl glycidyl ether) (PEG-b-PEEGE) PEO-b-PEEGE with DPMK as initiator and pentaerythritol as the core. The copolymers with different hydrophobic length were obtained by changing the feed ratio of the monomer. The products were characterized using nuclear magnetic resonance spectroscopy (1H-NMR) and gel permeation chromatography (GPC). The self-assembly characteristics of PEG-b-PEEGE was detected by fluorescence-probe technique, dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results showed that the critical aggregation concentration (CAC) values decreased with an increase in hydrophobic chain length. The DLS and TEM results showed that these copolymers could self-assemble in aqueous solution to form micellar structure with controlled size and morphologies. Very surprisingly, sphere-to-nanorod morphological transition was observed with increasing the hydrophobic mass fractions. Using nile red as drug model molecule, the encapsulation and release behavior in different pH environment was investigated. The results showed a pH sensitive release behavior, that is, the releasing rate is significantly faster at mildly acidic condition than that at physiological condition. The pH-responsive release may be ascribe to the pH dependent hydrolysis of acetal. Under neutral conditions, the structural integrity of the aggregates could be maintained. However, a lower pH leads to the higher degree of acetal hydrolysis, and therefore the aggregates dissociated, leading to this rapid release.(2) Besides, amphiphilic linear copolymer PEEGE-PEO-(OH), star polymer PEEGE-PEO-(OH)3 and dendrimer-like copolymer PEEGE-PEO-(OH)24 were prepared using the same polymerization method. These copolymers were used as drug carrier and applied on the drug delivery. All the synthetic copolymers were characterized by 1H-NMR and GPC. The drug loaded polymer micelles were prepared by dialysis method. The drug loaded content and encapsulation efficiency varied with different polymer structure. The dendrimer-like copolymer with large hydrophobic interior had the highest drug loaded content and encapsulation efficiency. In vitro drug release showed that three of copolymers had an excellent drug-retention capability at the neutral pH while be able to release drug under acidic conditions. Besides, the dense structure of the outer layer of the dendrimer-like block copolymer can effectively reduce the release of the drug in the neutral environment.