pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects - 13/11/21
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Abstract |
Side effects often limit the use of doxorubicin (DOX) in cancer treatment. We have recently developed a nanostructured lipid carrier (NLC) formulation for synergistic chemotherapy, encapsulating DOX and the anticancer adjuvants docosahexaenoic acid (DHA) and α-tocopherol succinate (TS). Hydrophobic ion-pairing with TS allowed a high DOX entrapment in the nanocarrier. In this work, we investigated the pharmacokinetics of this formulation after intravenous administration in mice. The first data obtained led us to propose synthesizing covalent DOX-TS conjugates to increase DOX retention in the NLC. We successfully conjugated DOX to TS via an amide or hydrazone bond. In vitro studies in 4T1 tumor cells indicated low cytotoxicity of the amide derivative, while the hydrazone conjugate was effective in killing cancer cells. We encapsulated the hydrazone derivative in a DHA-based nanocarrier (DOX-hyd-TS/NLC), which had reduced particle size and high drug encapsulation efficiency. The pH-sensitive hydrazone bond allowed controlled DOX release from the NLC, with increased drug release at acidic conditions. In vivo studies revealed that DOX-hyd-TS/NLC had a better pharmacokinetic profile than free DOX and attenuated the short-term cardiotoxic effects caused by DOX, such as QT prolongation and impaired left ventricular systolic function. Moreover, this formulation showed excellent therapeutic performance by reducing tumor growth in 4T1 tumor-bearing mice and decreasing DOX-induced toxicity to the heart and liver, demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that DOX-hyd-TS/NLC may be a promising nanocarrier for breast cancer treatment.
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Highlights |
• | Covalent coupling of DOX and TS via amide and hydrazone bonds. |
• | Preparation and characterization of a DHA-based NLC formulation loading the hydrazone conjugate. |
• | DOX-hyd-TS/NLC had better pharmacokinetics than free DOX after intravenous injection in mice. |
• | DOX-hyd-TS/NLC prevented DOX-induced QT prolongation and impairment of left ventricular systolic function. |
• | Administration of DOX-hyd-TS/NLC resulted in high antitumor efficacy and low systemic toxicity in 4T1 tumor-bearing mice. |
Keywords : Doxorubicin, Nanomedicine, Ion-pairing, Amide, Hydrazone, Antitumor activity, Cardiotoxicity
Plan
Vol 144
Article 112373- décembre 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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