Abstract
Biodegradable block copolymer chemical structures were engineered as drug nanocarriers to precisely program the enzyme-controlled release of anticancer drugs at intracellular compartments in cancer cells. New classes of amide and ester side chain-substituted caprolactone monomers were designed by multistep organic synthesis and polymerized under ring opening processes to make new classes of substituted polycaprolactone-
-polyethylene glycol copolymers. These block copolymers were self-assembled as stable nanoparticles of <200 nm in water. The polymer nanoparticles were found to be excellent scaffolds for loading a wide range of anticancer drugs and stabilized them at extracellular circulating conditions (37 °C in PBS). At the intracellular level, lysosomal-esterase enzyme biodegraded the aliphatic polyester PCL backbone and facilitated the release of drugs in a steady and controlled manner. In vitro drug release studies confirmed that the amide-PCL block copolymers exhibited controlled drug release compared to that of their non-hydrogen-bonded ester-PCL blocks or unsubstituted PCL blocks. The influence of hydrogen bonding interactions on the drug release profiles of PCL nanoparticles were studied by FT-IR and time-resolved fluorescent decay measurements. Cytotoxicity experiments in cervical cancer (HeLa) and breast cancer (MCF-7) cell lines demonstrated that amide diblock copolymer nanoassemblies show slow and prolonged cell killing. The new block copolymers were capable of loading multiple anticancer drugs like doxorubicin (DOX), curcumin (CUR), camptothecin (CPT), and methotrexate (MTX) that largely differ in pharmacokinetics as well as fluorescent regions for cellular imaging. Interestingly, these different drugs could be delivered to the intracellular compartments of the cancer cells by an identical enzyme-controlled delivery pathway from a single biodegradable block copolymer nanoscaffold. Confocal microscopic images exhibited that the engineered block copolymer nanoparticles were capable of transporting all of these drugs across the cell membrane and accumulating them predominantly in the cytoplasm and peri-nuclear region. The present investigation presents a new opportunity in the structural engineering of biodegradable diblock copolymer nanoassemblies for enzyme-controlled multiple-anticancer-drug administration in cancer therapy.
