4.7 Article

pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects

Journal

BIOMEDICINE & PHARMACOTHERAPY
Volume 144, Issue -, Pages -

Publisher

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2021.112373

Keywords

Doxorubicin; Nanomedicine; Ion-pairing; Amide; Hydrazone; Antitumor activity; Cardiotoxicity

Funding

  1. Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil)
  2. Coordenacao de Aperfeicoa-mento de Pessoal de Nivel Superior (CAPES, Brazil)
  3. Fundacao de Amparo a` Pesquisa do Estado de Minas Gerais (FAPEMIG, Brazil)
  4. France Life Imaging [ANR-11-INBS-0006]
  5. FAPEMIG
  6. CAPES

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This study developed a DOX-hyd-TS/NLC nano carrier for breast cancer treatment, which controlled DOX release via a hydrazone bond, reducing drug release under acidic conditions and demonstrating good therapeutic efficacy.
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 alpha-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-hydTS/NLC may be a promising nanocarrier for breast cancer treatment.

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