Comparative PK/PD and efficacy data of liposomal doxorubicin and EXODS (bio-engineered exosomes loaded with doxorubicin) in metastatic triple-negative breast cancer.

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Background: Adverse reactions like vomiting, fatigue, oral sores, severe tissue ulceration, and necrosis are common in patients after doxorubicin administration. Some adverse effects manifest and worsen over time, including cardiac toxicity. Similar side effects are also observed for liposomal doxorubicin. Doxorubicin hydrochloride (HCl) liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was observed to be 11%. To tackle these toxic side effects, we have developed EXODS, which is a bio-engineered exosomal formulation of doxorubicin. Methods: To investigate the PK parameters of EXODS and Liposomal Doxorubicin 0.42mg/kg of the drugs was injected into BALB/C mice. The plasma and tissue concentration of doxorubicin was measured by HPLC. To understand the efficacy of EXODS as compared to Liposomal Doxorubicin, MDA-MB-231 cells were injected into NOD-SCID mice, and following tumor development 4.5mg/kg, 2.5mg/kg and 0.42mg/kg of EXODS and 4.5mg/kg Liposomal Doxorubicin were injected. The parameters observed were tumor volume reduction, signs of toxicity, and CA 15-3 biomarker. Results: Plasma concentration of Liposomal Doxorubicin was significantly higher with a C _max of 1412.6 ng/ml, whereas only 2.5ng/ml of Doxorubicin was observed at 15mins time point following EXODS treatment. All other time-points were observed to be below the limit of quantification in the case of EXODS. Tissue distribution studies on Liposomal Doxorubicin showed considerable accumulation of Doxorubicin in the healthy organs like liver (42.26 ng/g), spleen (67.88 ng/g), pancreas (67.97 ng/g), and kidney (61.44 ng/g), whereas for EXODS, the presence of Doxorubicin was not observed in the liver, pancreas, or kidney. Although 42.45 ng/g of Doxorubicin was observed in the spleen. No other organs showed any accumulation of Doxorubicin in both the treatment groups. Tumor efficacy evaluation of EXODS and Liposomal Doxorubicin revealed that both treatment groups had a significant reduction in tumor volume as compared to the tumor control group. EXODS groups demonstrated better survival as compared to the standard Doxorubicin formulation. Further assessment revealed that EXODS significantly reduced CA-15-3 biomarker expression as compared to Liposomal Doxorubicin. Conclusions: Pooled data analysis revealed that EXODS displayed significant improvement in the survivability. EXODS demonstrated a remarkable safety profile and was also able to reduce the expression of CA-15-3, indicating a reduction in the chances of cancer metastasis as compared to standard Doxorubicin and Liposomal Doxorubicin.