Tetracycline-grafted PLGA nanoparticles as bone-targeting drug delivery system

PURPOSE Nanoparticles (NPs) that target bone tissue were developed using poly(lactic-co-glycolic acid) (PLGA) copolymers and tetracycline (TC)-based bone-targeting moieties. These NPs are expected to enable the transport of drugs, such as simvastatin (SIM), for the treatment of osteoporosis. METHODS The molecular structures of TC-PLGA were validated by (1)H-NMR, and the SIM-loaded NPs were prepared using the solvent emulsification method. The surface properties, cytotoxicity, cellular uptake, cell mineralization, bone targeting potential, and animal pharmacodynamics of the TC-PLGA NPs were evaluated and compared to those of PLGA NPs. RESULTS It was confirmed that the average particle size of the NPs was approximately 220 nm. In phosphate-buffered saline (PBS, pH 7.4), the SIM-loaded NPs exhibited a cumulative release of up to 80% within 72 hours. An in vitro cell evaluation indicated that the NPs had an excellent cellular uptake capacity and showed great biocompatibility with MC3T3-E1 cells, thereby reducing the cytotoxic effects of SIM. The cell mineralization assay showed that the SIM-loaded NPs induced osteogenic differentiation and mineralized nodule formation in MC3T3-E1 cells, thereby achieving the same effect as SIM. Preliminary findings from in vitro and in vivo bone affinity assays indicated that the TC-PLGA NPs may display increased bone-targeting efficiency compared to PLGA NPs lacking a TC moiety. The use of SIM-loaded TC-PLGA NPs in treating osteoporosis was tested through animal pharmacodynamics analyses performed in ovariectomized rats, and the results suggested that the SIM-loaded TC-PLGA NPs can improve the curative effects of SIM on the recovery of bone mineral density compared to either SIM-loaded PLGA NPs or SIM alone. CONCLUSION Bone-targeting NPs, which were based on the conjugation of TC to PLGA copolymers, have the ability to target bone. These NPs may be developed as a delivery system for hydrophobic drugs, and they are expected to improve the curative effects of drugs, reduce the administered drug doses, and reduce side effects in other organs.