Lung-specific delivery of paclitaxel by chitosan-modified PLGA nanoparticles via transient formation of microaggregates.
Chitosan-modified paclitaxel-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles with a mean diameter of 200-300 nm in distilled water were prepared by a solvent evaporation method. The mean diameter increased dramatically in contact with the mouse (CDF(1)) plasma, as a function of chitosan concentration in the modification solution (e.g., 2670.5 nm for 0.7% chitosan-modified nanoparticles, NP(3)), but reverted to almost its original size (i.e., 350.7 nm for NP(3)) following 5 min of gentle agitation. The zeta potential of PLGA nanoparticles was changed to positive by the chitosan modification. The in vitro uptake into, and cytotoxicity of the nanoparticles against, a lung cancer cell line (A549) were significantly increased by the modification. Most importantly, a lung-specific increase in the distribution index of paclitaxel (i.e., AUC(lung)/AUC(plasma)) was observed for chitosan-modified nanoparticles (e.g., 99.9 for NP(3) vs. 5.4 for Taxol) when nanoparticles were administered to lung-metastasized mice via the tail vein at a paclitaxel dose of 10 mg/kg. Transient formation of aggregates in the blood stream followed by enhanced trapping in the lung capillaries, and electrical interaction-mediated enhanced uptake across the endothelial cells of the lung tumor capillary appear to be responsible for the lung-tumor-specific distribution of the chitosan modified nanoparticles.
Yang
Rui
R
National Research Laboratory for Transporters Targeted Drug Design, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Yang
Su-Geun
SG
Shim
Won-Sik
WS
Cui
Fude
F
Cheng
Gang
G
Kim
In-Wha
IW
Kim
Dae-Duk
DD
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry; D003374:Coumarins / Q000493:pharmacokinetics; D019344:Lactic Acid / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D017239:Paclitaxel / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013499:Surface Properties; D013844:Thiazoles / Q000493:pharmacokinetics
D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D013844:Thiazoles; C517282:coumarin 6; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D048271:Chitosan; D017239:Paclitaxel