Folate-Conjugated Polymer Micelles with pH-Triggered Drug Release Properties

Folate has been applied as a targeting moiety for various anticancer drug-delivery agents to avoid non-specific attack of normal tissues as well as to increase cellular uptake at the target tumor cells. Polymer micelles made of poly[(D,L-lactide)-co-glycolide)]-poly(ethylene glycol)-folate (PLGA-PEG-FOL) was fabricated as a tumor targeting carrier for encapsulating the anticancer drug doxorubicin. To accelerate the drug release in the endosome after folate-mediated cellular uptake, pH-sensitive poly(β-amino ester)-PEG-FOL (PAE-PEG-FOL) was added together with PLGA-PEG-FOL to form mixed micelles. The results showed that the drug release can be triggered at different pH due to the ionization of PAE. The IC(50) of PLGA-PEG-FOL micelles is 0.46 × 10(-6) M. With 20% PAE in the mixed micelles (20:80 mixed micelles), the IC(50) decreases to 0.34 × 10(-6) M, which is comparable to that of pure PAE-PEG-FOL micelles at pH 7.4. As a result of the pH sensitivity, the PAE-PEG-FOL micelles are not stable at pH 6.5 or lower, and the drug may be released from the micelles into the extracellular environment before uptake by the cells. The 20:80 mixed micelles are relatively stable at this condition. As a result, the micelles retain more drug in the micelles for a higher degree of cellular uptake by folate receptor-mediated endocytosis, and exhibit higher cytotoxicity.