Multistimuli-Responsive Amphiphilic Poly(ester-urethane) Nanoassemblies Based on l-Tyrosine for Intracellular Drug Delivery to Cancer Cells

Abstract

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 H 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.

On-Demand and Long-Term Drug Delivery from Degradable Nanocapsules

“…The synthesis of hexanediol with IPDI leads to urethane linkages, as confirmed by the FTIR in Figure . Urethane linkages degrade either enzymatically , or by hydrolysis, which is a significant limitation on using polyurethanes for long-term applications in vivo, but it is a tremendous asset for a nanocapsule delivery system. − …”

Stimuli‐responsive polypeptide nanoassemblies: Recent progress and applications in cancer nanomedicine

“…Apart from the above‐mentioned stimuli‐responsive polypeptide nanoassemblies and nanodrugs, other endogenous stimuli‐responsive polypeptides were also designed for triggered drug delivery, such as enzyme‐responsive system (R. Aluri et al, 2018; X. Gu et al, 2018; R. Ni et al, 2020; J. Yoo et al, 2017), and ATP‐responsive system (M. Naito et al, 2018; N. Yoshinaga et al, 2017; T. Zhang, Yao, et al, 2020) as well.…”

Application and design of esterase-responsive nanoparticles for cancer therapy

“…Another disadvantage is that esterase activity in tumor cells is different from person to person (Niu et al., 2012). In that case, some nanoparticles can respond to multi-stimuli simultaneously, such as GSH/esterase (Lv et al., 2015), pH/esterase (Fernando et al., 2015; Saxena & Jayakannan, 2016), heat/esterase (Kashyap et al., 2016; Aluri et al., 2018), etc. A multi-stimulus responsive drug carrier can simultaneously respond to different stimulating factors in tumor tissues and cells, not only can promote the uptake of drug conjugates by cells, but also promote the releasing of drugs in tumors, allowing the drug to function better in target cells.…”