Solid lipid nanoparticles of mitoxantrone for local injection against breast cancer and its lymph node metastases.
In an attempt to improve the therapeutic effect of mitoxantrone (MTO) against breast cancer and its lymph node metastases, solid lipid nanoparticles (SLN) of MTO were prepared, characterized and evaluated on mice. Film dispersion-ultrasonication method was used to prepare MTO-SLN, optimized by central composite design. MTO-SLN were prepared with a mean size of 61 nm, drug content (DC) of 4.18+/-0.10% and encapsulation yield (EY) of 87.23+/-2.16%. MTO-SLN were lyophilized and their mean size became 79 nm without significant change in DC and EY. The in vitro release study revealed a profile of sustained release of MTO from MTO-SLN without burst effect: the cumulative release rate Q24 h = 25.86 +/- 0.82%, t50 = (5.25 +/- 1.10)d and t90 = (28.38 +/- 4.50)d. The drug concentration of MTO-SLN in local lymph nodes was much higher and the drug concentrations in other tissues lower than that of MTO solution (MTO-Soln). Human MCF-7 breast cancer in nude mice and animal model of P388 lymph node metastases in Kunming mice were applied to investigate the therapeutic effects. There was no observed toxicity to the main tissues after local injection of MTO-SLN, but, for MTO-Soln, medium to serious toxicity to liver and lung was produced. The percent inhibition of MTO-SLN against breast cancer was 81.81 +/- 14.03%, while that of MTO-Soln with a double dose was 82.86 +/- 11.13%. The tests for lymph node metastases showed that MTO-SLN gave a mean size of lymph node of 41.85 +/- 27.42 mm3, while that of the MTO-Soln was 119.32 +/- 57.30 mm3 and that of the placebo was 186.83 +/- 77.71 mm3. This study opens a new perspective of active delivery of antitumor drug against breast cancer and its lymph node metastases with inspiring therapeutic effect and little side effects.
Key Lab of Drug Targeting of the Ministry of Education of P.R. China, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. lubin@wcums.edu.cn
Bin
B
Lu
Su-Bin
SB
Xiong
Hong
H
Yang
Xiao-Dong
XD
Yin
Ruo-Bing
RB
Chao
D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002725:Chloroform / Q000032:analysis; D004339:Drug Compounding; D005260:Female; D005612:Freeze Drying; D006801:Humans; D007202:Indicators and Reagents; D007267:Injections; D007700:Kinetics; D007928:Lethal Dose 50; D007941:Leukemia P388 / Q000188:drug therapy; D008207:Lymphatic Metastasis; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D049329:Nanostructures; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013242:Sterilization; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D012997:Solvents; D002725:Chloroform; D008942:Mitoxantrone