title: Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs.
abstract: In this study, a block copolymer, poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-co-2-aminoethyl methacrylate)-b-poly(10-undecenoic acid) (P(NIPAAm-co-DMAAm-co-AMA)-b-PUA) was synthesized, and folic acid was conjugated to the hydrophilic block through the amine group in AMA. This polymer was self-assembled into micelles, which exhibited pH-induced temperature sensitivity. They were smaller in size, and possessed a better-defined core-shell structure as well as more stable hydrophobic core than the random copolymer P(NIPAAm-co-DMAAm-co-UA), and provided a shell with folate molecules. An anti-cancer drug, doxorubicin (DOX) was encapsulated into the micelles. The mean diameter of the blank and DOX-loaded micelles was less than 100 nm. DOX release was pH-dependent, being faster at low pH (endosomes/lysosomes). Therefore, DOX was readily released from the micelles into the nucleus after being taken up. More importantly, IC50 of DOX-loaded micelles with folate against folate receptor-expressing 4T1 and KB cells was much lower than that of the DOX-loaded micelles without folate (3.8 vs. 7.6 mg/L for 4T1 cells and 1.2 vs. 3.0mg/L for KB cells). In vivo experiments conducted in a 4T1 mouse breast cancer model demonstrated that DOX-loaded micelles had a longer blood circulation time than free DOX (t(1/2): 30 min and 140 min, respectively). In addition, the micelles delivered an increased amount of DOX to the tumor when compared to free DOX. These bio-functional micelles may make a promising carrier to transport anticancer drugs specifically to tumor cells and release the drug molecules inside the cells to the cytosols for improved chemotherapy.
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Singapore 138669, Singapore.
authors.forename: Shao-Qiong
authors.initials: SQ
authors.lastname: Liu
authors.forename: Nikken
authors.initials: N
authors.lastname: Wiradharma
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Gao
authors.forename: Yen Wah
authors.initials: YW
authors.lastname: Tong
authors.forename: Yi-Yan
authors.initials: YY
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004343:Drug Implants; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010316:Particle Size; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004343:Drug Implants; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin; D005492:Folic Acid