: Doxorubicin (DOX) is a widely used chemotherapeutic agent; nevertheless,
cardiotoxicity limits its effectiveness. Orlistat (Orli) is an irreversible lipase enzyme inhibitor with
poor solubility and bioavailability. Furthermore, Orli has a favorable impact on the decrease in
cardiometabolic risk variables. Thus, this study aimed to investigate the novel use of Orlistat
Nanocrystals (Orli-Nanocrystals) to mitigate DOX-induced cardiotoxicity and to identify probable
pathways behind the cardioprotective effects. Methods: The pharmacokinetic parameters—area
under % dose/g heart time curve (AUC0→4h), Drug targeting index (DTI), and relative targeting
efficiency (RTE)—were calculated. Furthermore, experimental design mice were categorized into six
groups: a (1) Normal control group, (2) Orli-Free group, (3) Orli-Nanocrystals group, (4) DOX group,
(5) Orli-Free-DOX group, and (6) Orli-Nanocrystals-DOX group. All treatments were intraperitoneally
injected once daily for 14 days with a single dose of DOX (15 mg/kg) on the 12th day for 4, 5, and
6 groups. Results: The pharmacokinetic parameters (Cmax, AUC) following oral administration of
Orli-Nanocrystals presented a significant difference (higher values) in comparison to Orli due to the
enhanced extent of the absorption of nanocrystals and, subsequently, their distribution to the heart.
The study results indicated that DOX caused significant cardiotoxicity, as revealed by a remarkable rise
in cardiac function biomarkers like LDH and CK-MB, which involve enzyme activities. Additionally,
cardiac MDA content also increased; however, glutathione peroxidase, catalase, and superoxide
dismutase activities were decreased. In the same context, DOX was found to have a remarkable
downregulation in Nrf2, HO-1, Sirt-1, and Bcl2, while the upregulation of NF-κB, TNF-α, and BAX
gene and protein expression occurred. Pretreatment with Orli-Nanocrystals displayed the most
notable recovery of the altered immunohistochemical, histological, and biochemical characteristics as
compared to the Orli-Free group. Conclusions: This work is the first investigation into the potential
use of antioxidant, anti-inflammatory, and anti-apoptotic characteristics of Orli-Nanocrystals to
protect against DOX-induced cardiotoxicity in vivo. |
