Co-delivery of doxorubicin, docosahexaenoic acid, and α-tocopherol succinate by nanostructured lipid carriers has a synergistic effect to enhance antitumor activity and reduce toxicity

• Published in: Biomedicine & pharmacotherapy 2020-12, Vol.132, p.110876, Article 110876
• Main Authors: Lages, Eduardo Burgarelli, Fernandes, Renata Salgado, Silva, Juliana de Oliveira, de Souza, Ângelo Malachias, Cassali, Geovanni Dantas, de Barros, André Luís Branco, Miranda Ferreira, Lucas Antônio
• Format: Article
• Language: English
• Subjects: alpha-Tocopherol - administration & dosage; alpha-Tocopherol - chemistry; alpha-Tocopherol - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antitumor activity; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cardiotoxicity; Cell Line, Tumor; Combination therapy; Delayed-Action Preparations; Docosahexaenoic Acids - administration & dosage; Docosahexaenoic Acids - chemistry; Docosahexaenoic Acids - pharmacology; Dose-Response Relationship, Drug; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Carriers; Drug Compounding; Drug Liberation; Drug Synergism; Female; Hydrophobic and Hydrophilic Interactions; Ion-pairing; Lipids - chemistry; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Mice; Mice, Inbred BALB C; Nanoparticles; Synergism; Tumor Burden - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110876

[Display omitted] •Design of a novel nanostructured lipid carriers (NLC) formulation loading DOX, DHA, and TS.•Hydrophobic ion-pairing with TS allows high DOX encapsulation efficiency and controlled release.•DOX, DHA, and TS have synergistic effects against 4T1 breast cancer cells.•NLC-DHA-DOX-TS showed the greatest antitumor efficacy by reducing tumor growth in 4T1 tumor-bearing mice.•NLC-DHA-DOX-TS also reduces mice mortality, prevents lung metastasis, and decreases DOX-induced toxicity. 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 α-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 encapsulation 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 NLC-DHA-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.