Aggregation behavior of self-assembling polylactide/poly(ethylene glycol) micelles for sustained drug delivery

A series of diblock copolymers were synthesized by ring-opening polymerization of l- or d-lactide in the presence of monomethoxy poly(ethylene glycol) (mPEG) with molar masses of 2000 and 5000. The aggregation behavior of the resulting water soluble PLA/PEG diblock copolymers in aqueous medium was studied with dynamic and static light scattering (DLS and SLS), in combination with aqueous gel permeation chromatography (GPC). The average hydrodynamic radius (Rh) of l-PLA/PEG and d-PLA/PEG mixed micelles is lower than that of l-PLA/PEG single micelles due to the stereocomplexation effect between l-PLA and d-PLA blocks. It is also confirmed that the micelle size increases with increasing temperature and hydrophobic block length, but decreases after salt addition. Aqueous GPC and SLS were used to evaluate the molecular weight (Mw) and aggregation number (Nagg) of the micelles. Mixed micelles present lower Nagg than single copolymer micelles due to stereocomplexation. Nagg decreases with increasing hydrophobic block length, and decreases upon addition of NaCl, in agreement with a more compact structure. In contrast, Nagg increases with elevating temperature. The average radius of gyration (Rg) and Rg/Rh ratio data show that both increase with increasing temperature, suggesting that micelles exhibit a compact hard-sphere structure at 15 °C and a swollen structure at 35 °C. As the temperature increases from 15 °C to 35 °C, the second virial coefficient (A2) of PLA/PEG copolymers turns from negative to positive, which means that water changes from poor solvent to good solvent. The fact that the average density (ρ) of PLA/PEG micelles decreases with increasing temperature confirms that micelles exhibit a looser structure at higher temperatures due to water swelling effect. The higher ρ value of mixed micelles as compared to single micelles also confirms a more compact structure of the former. In addition, due to the much higher Nagg and lower Rh, PLA/PEG2000 micelles present higher ρ value than PLA/PEG5000 ones.