Celastrol Derivative/DOX Co-Assembled Nanodrug for Enhanced Antitumor Therapy.

Background: Multidrug resistance (MDR) is a key challenge in clinical chemotherapy. The combination of drugs can effectively reverse multi-drug resistance.

Objective: In this study, doxorubicin (DOX) was capsulated into nanoparticles formed by an amphiphilic PEGylated-poly (α-lipoic acid)-methanamide analogue of celastrol (mPEG-PαLA-CEN) prodrug polymer. CEN was linked to the branched chain of poly (α-lipoic acid) by forming ester bonds. DOX was physically trapped inside the nanoparticles via electrostatic interaction. Both drugs can be simultaneously released in response to low pH and high GSH in order to overcome DOX resistance.

Methods: The chemical structure of the mPEG-PαLA-CEN-DOX NPs was confirmed through 1H NMR, FT-IR spectroscopy, UV-Vis spectrum, DLS, and TEM. Drug-loading content, efficacy, and drug release were measured using HPLC. Cell toxicity was examined using an MTT assay.

Results: CEN/DOX-loaded nanoparticles were found to have spherical shapes with diameters of around 229.7 nm. The NPs exhibited high biocompatibility and released 92% DOX and 71.8% CEN in response to low pH and high GSH of tumor microenvironments. As dual drug-loaded nanoparticles, the efficacy of mPEG-PαLA-CEN-DOX NPs against tumor cell lines in vitro was enhanced for both MCF-7 and MCF-7/ADR compared to free DOX. Compared to free DOX, the IC50 of mPEG-PαLA-CEN-DOX NPs reduced from 46.10 μM to 8.36 μM for the MCF-7/ADR cell line.

Conclusion: In conclusion, this study demonstrated that PEGylated poly (α-lipoic acid)-CEN copolymers can be used not only as biocompatible, stimulation-responsive anticancer drug nanocarriers but also as chemosensitizers to overcome multidrug resistance, which provide a theoretical base for clinical application of CEN/DOX nanodrug.