Amphiphilic copolymers of ε-caprolactone and γ-substituted ε- caprolactone. Synthesis and functionalization of poly(D,L-lactide) nanoparticles

Fully biodegradable and surface-functionalized poly(D,L-lactide) (PLA) nanoparticles have been prepared by a co-precipitation technique. Novel amphiphilic random copolyesters P(CL-co-γXCL) were synthesized by controlled copolymerization of ε-caprolactone and ε-caprolactone substituted in the γ-position by a hydrophilic X group, where X is either a cationic pyridinium (γPyCL) or a non-ionic hydroxyl (γOHCL). Nanoparticles were prepared by co-precipitation of PLA with the P(CL-co-γXCL) copolyester from a DMSO solution. Small amounts of cationic P(CL-co-γPyCL) copolymers are needed to quantitatively form stable nanoparticles (ca. 10 mg/100 mg PLA), although larger amounts of non-ionic P(CL-co-γOHCL) copolymers are needed (≥12.5 mg/100 mg PLA). Copolymers with a low degree of polymerization (ca. 40) are more efficient stabilizers, probably because of faster migration towards the nanoparticle-water interface. The nanoparticle diameter decreases with the polymer concentration in DMSO, e.g. from ca. 160 nm (16 mg/ml) to ca. 100 nm (2 mg/ml) for PLA/P(CL-co-γPyCL) nanoparticles. Migration of the P(CL-co-γXCL) copolyesters to the nanoparticle surface was confirmed by measurement of the zeta potential, i.e. ca. +65 mV for P(CL-co-γPyCL) and -7 mV for P(CL-co-γOHCL). The polyamphiphilic copolyesters stabilize PLA nanoparticles by electrostatic or steric repulsions, depending on whether they are charged or not. They also impart functionality and reactivity to the surface, which opens up new opportunities for labelling and targeting purposes.