Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs

Biomaterials. 2007 Mar;28(7):1423-33. doi: 10.1016/j.biomaterials.2006.11.013. Epub 2006 Dec 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Biocompatible Materials* / chemical synthesis
  • Biocompatible Materials* / chemistry
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacokinetics
  • Drug Delivery Systems
  • Drug Implants
  • Female
  • Folic Acid / analogs & derivatives
  • Folic Acid / chemistry
  • Humans
  • Hydrogen-Ion Concentration
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Materials Testing
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Particle Size
  • Polymers / chemical synthesis
  • Polymers / chemistry

Substances

  • Antineoplastic Agents
  • Biocompatible Materials
  • Drug Implants
  • Micelles
  • Polymers
  • Doxorubicin
  • Folic Acid