Multistimuli-responsive
l-tyrosine-based amphiphilic
poly(ester-urethane) nanocarriers were designed and developed for the first time to administer anticancer drugs in
cancer tissue environments via thermoresponsiveness and lysosomal enzymatic biodegradation from a single
polymer platform. For this purpose, multifunctional
l-tyrosine monomer was tailor-made with a PEGylated side chain at the phenolic position along with
urethane and carboxylic
ester functionalities. Under melt dual
ester-
urethane polycondensation, the
tyrosine monomer reacted with diols to produce high molecular weight amphiphilic
poly(ester-urethane)s. The
polymers produced 100 ± 10 nm spherical nanoparticles in aqueous medium, and they exhibited thermoresponsiveness followed by phase transition from clear
solution into a turbid
solution in heating/cooling cycles. Variable temperature transmittance, dynamic light scattering, and 1H NMR studies revealed that the
polymer chains underwent reversible phase transition from coil-to-expanded chain conformation for exhibiting the thermoresponsive behavior. The lower critical
solution temperature of the nanocarriers was found to correspond to
cancer tissue temperature (at 42-44 °C), which was explored as an extracellular trigger (stimuli-1) for
drug delivery through the disassembly process. The
ester bond in the
poly(ester-urethane) backbones readily underwent enzymatic biodegradation in the lysosomal compartments that served as intracellular stimuli (stimuli-2) to deliver drugs.
Doxorubicin (DOX) and
camptothecin (
CPT)
drug-loaded
polymer nanocarriers were tested for cellular uptake and cytotoxicity studies in the normal WT-MEF cell line and cervical (HeLa) and breast (MCF7)
cancer cell lines. In vitro drug release studies revealed that the
polymer nanoparticles were stable under physiological conditions (37 °C, pH 7.4) and they exclusively underwent disassembly at
cancer tissue temperature (at 42 °C) and biodegradation by lysosomal-
esterase enzyme to deliver 90% of DOX and
CPT.
Drug-loaded
polymer nanoparticles exhibited better cytotoxic effects than their corresponding free drugs. Live cell confocal microscopy imaging experiments with lysosomal tracker confirmed the endocytosis of the
polymer nanoparticles and their biodegradation in the lysosomal compartments in
cancer cells. The increment in the
drug content in the cells incubated at 42 °C compared to 37 °C supported the enhanced
drug uptake by the
cancer cells under thermoresponsive stimuli. The present work creates a new platform for the l-
amino acid multiple-responsive
polymer nanocarrier platform for
drug delivery, and the proof-of-concept was successfully demonstrated for
l-tyrosine polymers in cervical and
breast cancer cells.