In Vitro and In Vivo Investigation on PLA–TPGS Nanoparticles for Controlled and Sustained Small Molecule Chemotherapy
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The aim of this work was to evaluate in vivo poly(lactide)-d-α-tocopheryl polyethylene glycol 1,000 succinate nanoparticles (PLA–TPGS NPs) for controlled and sustained small molecule drug chemotherapy.
The drug-loaded PLA–TPGS NPs were prepared by the dialysis method. Particle size, surface morphology and surface chemistry, in vitro drug release and cellular uptake of NPs were characterized. In vitro and in vivo therapeutic effects of the nanoparticle formulation were evaluated in comparison with Taxol®.
The PLA–TPGS NP formulation exhibited significant advantages in in vivo pharmacokinetics and xenograft tumor model versus the PLGA NP formulation and the pristine drug. Compared with Taxol®, the PLA–TPGS NP formulation achieved 27.4-fold longer half-life in circulation, 1.6-fold larger area-under-the-curve (AUC) with no portion located above the maximum tolerance concentration level. For the first time in the literature, one shot for 240 h chemotherapy was achieved in comparison with only 22 h chemotherapy for Taxol® at the same 10 mg/kg paclitaxel dose. Xenograft tumor model further confirmed the advantages of the NP formulation versus Taxol®.
The PLA–TPGS NP formulation can realize a way of controlled and sustained drug release for more than 10 days, which relieves one of the two major concerns on cancer nanotechnology, i.e. feasibility.
KEY WORDSchemotherapeutic engineering controlled release nanomedicine nanopharmaceutical engineering paclitaxel
The authors are grateful of Mr. Min Sung Chong, FYP students in Department of Chemical and Biomolecular Engineering, National University of Singapore, for their assistance in experiments and Dr. Linyun Zhao for the HPLC analysis method on plasma samples. This research was supported by A*STAR BMRC Singapore Cancer Syndicate Grant UU0028 (SS Feng, PI) and NUS FRC Grant R279-000-226-112 (SS Feng, PI). Zhang ZP thanks NUS for the financial support for his Ph.D. study and Lee SH thanks EDB and NUSNNI for the financial support for her M.Eng. study.
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