Toxicity and Safety Evaluation of Doxorubicin-Loaded Cockleshell-Derived Calcium Carbonate Nanoparticle in Dogs.

Abubakar Danmaigoro,Rozi Mahmud,Mohd Hezmee Mohd Noor,Md Zuki Abu Bakar,Gayathri Thevi Selvarajah

doi:10.1155/2018/4848602

Abstract

Doxorubicin (DOX) is a potent anticancer agent with cytotoxic effects which limit its clinical usage. This effect is due to its nonselective nature causing injury to the cells as a result of reactive free oxygen radical's release. Cockleshell-derived calcium carbonate nanoparticle (CS-CaCO3NP) is a pH-responsive carrier with targeted delivery potentials. This study aimed at evaluating the toxicity effects of repeated dose administration of DOX-loaded CS-CaCO3NP in healthy dogs. Fifteen dogs with an average body weight of 15 kg were randomized equally into 5 groups. Dogs were subjected to 5 doses at every 3-week interval with (i) normal saline, (ii) DOX, 30 mg/m2, and the experimental groups: CS-CaCO3NP-DOX at (iii) high dose, 50 mg/m2, (iv) clinical dose, 30 mg/m2, and (v) low dose, 20 mg/m2. Radiographs, electrocardiography, and blood samples were collected before every treatment for haematology, serum biochemistry, and cardiac injury assessment. Heart and kidney tissues were harvested after euthanasia for histological and ultrastructural evaluation. The cumulative dose of DOX 150 mg/m2 over 15 weeks revealed significant effects on body weight, blood cells, functional enzymes, and cardiac injury biomarkers with alterations in electrocardiogram, myocardium, and renal tissue morphology. However, the dogs given CS-CaCO3NP-DOX 150 mg/m2 and below did not show any significant change in toxicity biomarker as compared to those given normal saline. The study confirmed the safety of repeated dose administration of CS-CaCO3NP-DOX (30 mg/m2) for 5 cycles in dogs. This finding offers opportunity to dogs with cancer that might require long-term administration of DOX without adverse effects.

Highlights

Doxorubicin (DOX) is one of the potent chemotherapeutic agents used in the management of both haematopoietic and solid malignant tumours of different origin [1,2,3]
A decrease in body weight of dogs given 30 mg/m2 free DOX was observed immediately after the 2nd dose with about 9% of the body weight lost after a cumulative dose of 150 mg/m2
It is well known that chemotherapy causes general body weight loss [43]. e body weight loss observed in the dogs given a cumulative dose of free DOX agrees with the report of Boussada et al [43] in Wister rats and was in line with ndings of Sato et al [47] in mice and DeFrancesco et al [48] in dogs

Summary

Introduction

Doxorubicin (DOX) is one of the potent chemotherapeutic agents used in the management of both haematopoietic and solid malignant tumours of different origin [1,2,3]. E mitochondrial, sarcoplasmic reticulum, and nuclear material damages are due to the reactive oxygen radicals released during the biotransformation of DOX to semiquinone [6, 7] and a decrease in ATP synthesis [8]. TM sembled polymers in the delivery of DOX as seen in Doxil TM and Myocet which are still associated with mild toxic effects on organs by eliciting proinflammatory cell release [12], with some other formulations shown having an increase in therapeutic efficiency with few setbacks, such as instability and biphasic release kinetic mechanism [13, 14]. Decrease in toxicity was recorded with liposome conjugated with DOX in a mouse model, the longtime cumulative effect of the liposome was not documented [15]. Several organic macromolecules have been employed in nanomedicine for drug delivery [16, 17]

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