Fabrication of Microspheres via Solvent Volatization Induced Aggregation of Self-Assembled Nanomicellar Structures and Their Use as a pH-Dependent Drug Release System

A series of oleamide derivatives, (C₁₈H₃₄NO)₂(CH₂)_n [n = 2 (1a), 3 (1b), 4 (1c), or 6 (1d); C₁₈H₃₄NO = oleic amide fragment] and (C₁₈H₃₄NO)­(CH₂)₆NH₂ (2), have been synthesized and their self-assembly is investigated in ethanol/water media. Self-assembly of 1a and 1b in ethanol/water (1/0.1 v/v) solution (5 mg mL^–1) yields microspheres (MSs) with the average diameter ∼10 μm via a gradual temperature reduction and solvent volatilization process. Under the same self-assembly conditions, microrods (average diameter ∼6 μm and several tens of micrometers in length), micronecklace-like, and shape-irregular microparticles are formed from the self-assembly of 1c, 1d, and 2, respectively. The kinetics of evolution for their self-assemblies by dynamic light scattering technique and in situ observation by optical microscopy reveals that the microstructures formation is from a well-behaved aggregation of nanoscale micelles induced by solvent volatilization. The FT–IR and temperature–dependent ¹H–NMR spectra demonstrate the hydrogen bonding force and π–π stacking, which drove the self-assembly of all oleamide derivatives in ethanol/water. Among the fabricated microstructures, the MSs from 1a exhibit the best dispersity, which thus have been used as a scaffold for the in vitro release of doxorubicin. The results demonstrate a pH-sensitive release process, enhanced release specifically at low pH 5.2.