Aclarubicin-loaded cationic albumin-conjugated pegylated nanoparticle for glioma chemotherapy in rats.
Traditional glioma chemotherapy with those second-line drugs such as anthracyclines usually failed because they are inaccessible to blood-brain barrier (BBB) in tumor. In our study, we incorporated aclarubicin (ACL) into cationic albumin-conjugated pegylated nanoparticle (CBSA-NP-ACL) to determine its therapeutic potential of rats with intracranially implanted C6 glioma cells. When labeled with fluorescent probe, 6-coumarin, CBSA-NP was shown to accumulate much more in tumor mass than nanoparticle without conjugated CBSA (NP) 1 hr post intravenous injection, as well as better retention after 24 hr. Tumor drug concentration of CBSA-NP-ACL displayed 2.6- and 3.3-fold higher than that of NP-ACL and ACL solution 1 hr post injection, while 2.7 and 6.6-fold higher after 24 hr, respectively. Moreover, using tumor microdialysis sampling, AUC(0-24 hr) of free drug amount in tumor interstitium delivered by CBSA-NP-ACL was about 2.0- and 2.7-fold higher than that of NP-ACL and ACL solutions, respectively. When the tumor rat model was subjected to 4 cycles of 2 mg/kg of ACL in different formulations, a significant increase of median survival time was found in the group of CBSA-NP-ACL compared with that of saline control animals, animals treated with NP-ACL and ACL solution. By terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, CBSA-NP-ACL can extensively make the tumor cell apoptosis. Histochemical evaluation by periodic acid Shiff staining and biochemical analysis depicted that the incorporation of ACL into CBSA-NP reduced its toxicity to liver, kidney and heart. Besides, CBSA-NP-ACL was not shown to open tight junction evaluated by BBB coculture. It was concluded that CBSA-NP-ACL could have a therapeutic potential for treatment of glioma.
Lu
Wei
W
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
Wan
Jin
J
Zhang
Qing
Q
She
Zhenjue
Z
Jiang
Xinguo
X
D015250:Aclarubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004337:Drug Carriers / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D011092:Polyethylene Glycols; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D012709:Serum Albumin; D011092:Polyethylene Glycols; D015250:Aclarubicin