Abstract
Doxorubicin (DOX) is one of the most widely used anticancer agents. DOX is known for inducing cardiotoxicity, resulting in the long-term development of heart failure. Intravascular delivery of DOX may benefit from the carriage by red blood cells (RBCs), as they can limit the systemic toxicity while delivering the DOX to the tumor. This study proposes a methodology for the synthesis of electrophoretically DOX-loaded red blood cells (RBC-DOX), as well as the assessment of its antitumorigenic effects in human colon cancer cells (HT-29), and in colon cancer xenograft models. In addition, healthy mice without tumors were dosed with RBC-DOX to assess cardiotoxicity via assessment of indexes of cardiac function after multiple doses of RBC-DOX. The HT-29 IC50 was found to be lower for RBC-DOX compared to free DOX. Tumor volume for the RBC-DOX group was smaller than the free DOX groups in HT-29 xenografts models. Statistically higher concentrations of DOX were found in the liver, spleen, and lungs for the RBC-DOX group compared to the free DOX group. However, the heart and the skin had statistically lower DOX concentrations for the RBC-DOX group compared to the free DOX group, with no significant differences in tumor biodistribution. All hemodynamic and cardiac function parameters were closer to control parameters for the RBC-DOX treated compared to for the free DOX-treated mice. These results suggest that RBC-DOX can be an alternative to prolong treatments with DOX, with superior antitumorigenic effects, decreased myelosuppression, and limited cardiac toxicity compared to equivalent doses of free DOX.
Highlights
Colorectal cancer is the third most common cause of cancerassociated deaths (Jemal et al, 2010), with a high percentage of subjects presenting metastatic disease
We propose a methodology for the synthesis of red blood cells (RBCs)-DOX, as well as the assessment of its antitumorigenic effects in vitro in human adenocarcinoma HT-29 cells, and in vivo in HT-29 implanted athymic mice
This study shows several important points: (a) RBC-DOX was readily taken up by colon cancer cells and displayed prolonged intravascular retention; (b) encapsulation of DOX in RBC resulted in a decreased distribution of the drug to the principal sites of acute and chronic toxicity of free DOX, namely the heart and the skin, as well as markedly lowered cardiotoxicity and myelosuppression; (c) RBC-DOX displayed an enhanced therapeutic efficacy in a xenograft mouse model of human colorectal adenocarcinoma
Summary
Colorectal cancer is the third most common cause of cancerassociated deaths (Jemal et al, 2010), with a high percentage of subjects presenting metastatic disease. Subjects with colorectal cancer eventually succumb to metastatic diseases. The success of radiotherapy and chemotherapy in colorectal cancer is limited by the resistant cancer cells and the dose-limiting toxicities (Segal & Saltz, 2009). Doxorubicin (DOX) is one of the most common anthracyclines, been proven effective against soft tissue and bone sarcomas, and breast, ovary, bladder, and thyroid cancer. It has been used for the treatment of small cell lung cancer, Hodgkin’s lymphoma, and acute myeloblastic and lymphoblastic leukemia (Johnson-Arbor & Dubey, 2018). The severity of the cardiomyopathy is dosedependent (Alexander et al, 1979), so is the drug’s effectiveness, methods to decrease the exposure of noncancerous tissue to DOX, while still maintaining a sufficient tumor DOX exposure
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