Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(D,L-lactide-co-glycolide) with varying compositions.
Thermally sensitive block copolymers, poly(N-isopropylacrylamide-co-N, N-dimethylacrylamide)-b-poly(d,l-lactide-co-glycolide) [P(NIPAAm-co-DMAAm)-b-poly(D,L-lactide-co-glycolide) (PLGA)] with different compositions and lengths of PLGA block are synthesized and utilized to fabricate micelles containing doxorubicin (DOX), a model anticancer drug, by a membrane dialysis method for targeted anticancer drug delivery. The critical association concentration (CAC) of the polymers ranges from 4.0 to 25.0 mg/L. An increased length of core-forming block PLGA leads to a decrease in the CAC. The clearly defined core-shell structure of micelles is proved by 1H-NMR analyses of the micelles in CDCl3 and D2O. The morphology of the micelles is analyzed by transmission electron microscopy, showing a spherical structure of both blank and drug-loaded micelles. The results obtained from dynamic light scattering show that the blank and drug-loaded micelles have an average size below 200 nm. The lower critical solution temperature (LCST) of the micelles made from the various polymers is similar, around 39 degrees C in phophate-buffered solution (PBS). The presence of serum in PBS does not alter the LCST significantly. The drug loading capacity varies depending on the PLGA block. The polymers are degradable, and the degradation of PLGA-based polymers is faster than that of poly(lactide) (PLA)-based polymer. The DOX-loaded micelles are stable in PBS containing serum at 37 degrees C but deform at 39.5 degrees C above the normal body temperature, thus triggering DOX release. It is revealed by confocal laser scanning microscopy that free DOX molecules enter cell nuclei very fast and DOX-loaded micelles accumulate mostly in cytoplasm after endocytosis. At a temperature above the LCST, more DOX molecules release from the micelles and enter the nuclei as compared to the temperature below the LCST. DOX-loaded micelles show greater cytotoxicity at a temperature above the LCST. The P(NIPAAm-co-DMAAm)-b-PLGA micelles developed may be a good carrier for anticancer drug delivery.
Liu
S Q
SQ
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01 Singapore 138669, Singapore.
Tong
Y W
YW
Yang
Yi-Yan
YY
D000178:Acrylamides / Q000737:chemistry*; D000180:Acrylic Resins / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D008422:Materials Testing; D051379:Mice; D008823:Micelles; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*
D000178:Acrylamides; D000180:Acrylic Resins; D000970:Antineoplastic Agents; D020099:Coated Materials, Biocompatible; D003692:Delayed-Action Preparations; D008823:Micelles; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; C052970:poly-N-isopropylacrylamide; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin; C099046:N,N-dimethylacrylamide