Polylactide-graft-doxorubicin Nanoparticles with Precisely Controlled Drug Loading for pH-Triggered Drug Delivery
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Abstract
Nanoparticles (NPs) with high drug loading and pH-responsivity were prepared by nanoprecipitation of a hydrophobic polymer-drug conjugate (PDC). The PDC, polylactide-graft-doxorubicin (PLA-g-DOX), was synthesized by azide-alkyne click reaction to transform acetylene-functionalized PLA into PLA-graft-aldehyde (PLA-g-ALD), followed by DOX conjugation to form acid-sensitive Schiff base linkage between drug moieties and polymer scaffold. The DOX loading amount in PLA-g-DOX PDC was determined to be 32 wt % by (1)H NMR and UV-vis spectroscopies. PLA-g-DOX PDC was further used to prepare NPs with precisely controlled drug loading by nanoprecipitation in the presence of a PEGylated surfactant. The effects of organic solvent, PLA-g-DOX PDC concentration and PLA-g-DOX/surfactant mass ratio on size and size distribution of NPs were systematically examined based on analysis by dynamic light scattering (DLS) and transmission electron microscopy (TEM). NPs prepared under the optimal conditions exhibited well-defined spherical morphology with volume-average hydrodynamic diameter (Dh) around 100 nm. Due to the Schiff base conjugation linkage in PLA-g-DOX PDC, acid-sensitive drug release behavior of the NPs was observed. In vitro studies against MCF-7 breast cancer cells showed that the NPs can be readily taken up and result in enhanced therapeutic efficiency as compared to DOX·HCl, indicating their promising potential applications as anticancer nanomedicines.
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