Abstract:
Biodegradable polymeric nanoparticles containing doxorubicin were prepared from 4-arm and 6-arm star-branched folate-terminated poly(L-lactide) (PLLA)-poly(ethylene glycol) (PEG) copolymers, respectively, to investigate their potential as anticancer drug carrier. The star-branched copolymers were synthesised by a ring-opening polymerisation and carbodiimide chemistry, with all the intermediates and target copolymers being characterised by 1H NMR, FTIR, GPC and DSC. The doxorubicin encapsulated copolymer nanoparticles were fabricated using nanoprecipitation method. Dynamic light scattering measurement showed that the doxorubicin loaded 4-arm and 6-arm folate-PLLA-PEG nanoparticles have average diameter of 185.88 ± 27.53 nm and 203.66 ± 20.69 nm, respectively, and both polymeric nanoparticles are spherical with smooth surfaces as evidenced from their TEM images. Both of the 4-arm folate-PLLA-PEG and 6-arm folate-PLLA-PEG nanoparticles were negatively charged with zeta potential of -19.54 ± 0.57 mV and -14.77 ± 1.16 mV, respectively. The encapsulation efficiency of 6-arm folate-PLLA-PEG nanoparticles (87.54% ± 0.003) was higher than that of 4-arm folate-PLLA-PEG nanoparticles (77.29% ± 0.039), indicating that the 6-arm copolymer nanoparticles are significantly superior to the 4-arm ones in doxorubicin encapsulation. In vitro release studies over 7 days showed that an initial burst release of doxorubicin was followed by a sustained release. The drug release was higher at pH 5.3 (76.45% at 24 h) than at pH 7.4 (66.39% at 24 h) for 6-arm polymeric nanoparticles. Similar results were obtained with the 4-arm polymeric nanoparticles, with higher release at pH 5.3 (74.05% at 24 h) than at pH 7.4 (59.86% at 24 h). The overall release rates of doxorubicin from the 6-arm folate-PLLA-PEG nanoparticles (100% at 168 h) were higher than that of 4-arm folate-PLLA-PEG nanoparticles (97% at 168 h). Both doxorubicin loaded multi-arm copolymer nanoparticles showed increased cytotoxicity against MCF-7, MCF-10a, HepG2 and Chang liver cell lines in a time- and dose-dependent manner. The overall results demonstrate that both star-branched folate-terminated PLLA-PEG copolymer nanoparticles could serve as ideal anticancer therapeutic carriers that possess sustained release characteristics and are suitable for anticancer delivery application.
