Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 132, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.110876
Keywords
Doxorubicin; Combination therapy; Ion-pairing; Synergism; Antitumor activity; Cardiotoxicity
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil)
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, Brazil)
- FAPEMIG
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Doxorubicin (DOX) is widely used in cancer treatment, however, its use is often limited due to its side effects. To avoid these shortcomings, the encapsulation of DOX into nanocarriers has been suggested. Herein, we proposed a novel nanostructured lipid carrier (NLC) formulation loading DOX, docosahexaenoic acid (DHA), and alpha-tocopherol succinate (TS) for cancer treatment. DHA is an omega-3 fatty acid and TS is a vitamin E derivative. It has been proposed that these compounds can enhance the antitumor activity of chemotherapeutics. Thus, we hypothesized that the combination of DOX, DHA, and TS in NLC (NLC-DHA-DOX-TS) could increase antitumor efficacy and also reduce toxicity. NLC-DHA-DOX-TS was prepared using emulsification-ultrasound. DOX was incorporated after preparing the NLC, which prevented its degradation during manufacture. High DOX encap-sulation efficiency was obtained due to the ion-pairing with TS. This ion-pairing increases lipophilicity of DOX and reduces its crystallinity, contributing to its encapsulation in the lipid matrix. Controlled DOX release from the NLC was observed in vitro, with increased drug release at the acidic environment. In vitro cell studies indicated that DOX, DHA, and TS have synergistic effects against 4T1 tumor cells. The in vivo study showed that NLCDHA-DOX-TS exhibited the greatest antitumor efficacy by reducing tumor growth in 4T1 tumor-bearing mice. In addition, this formulation reduced mice mortality, prevented lung metastasis, and decreased DOX-induced toxicity to the heart and liver, which was demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that NLC-DHA-DOX-TS may be a promising carrier for breast cancer treatment.
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