Reduction- and pH-Sensitive Hyaluronan Nanoparticles for Delivery of Iridium(III) Anticancer Drugs

The organoiridium(III) complex (Ir(III)) [(η⁵-Cp^xbiph)Ir(phpy) (py)]PF₆ containing π-bonded biphenyltetramethylcyclopentadienyl(Cp^xbiph), C∧N-chelated phenylpyridine(phpy), and pyridine (py) ligands has more potent antitumor activity as a new generation of drug than cisplatin toward various cancer cells. However, poor site-specific delivery, low solubility, and poor tumor penetration are common limitations of chemotherapy drugs. To develop CD44-targetable, pH-, and reduction-responsive drug delivery systems for Ir(III) drugs, the amphiphilic hyaluronan (HA)-based conjugates of HA-cystamin-pyrenyl (HA-ss-Py) containing disulfide bonds and HA-pyrenyl (HA-Py) were designed. The Ir(III) drug was readily loaded into these two amphiphilic conjugates and nanoparticles were formed. Dynamic light scattering (DLS) studies showed that the micelles formed from HA-ss-Py were sufficiently stable under physiological conditions, but were prone to rapid dissociation in reducing environments (20 mM glutathione (GSH)). In subsequent confocal microscopy analyses, A549 cancer cells efficiently internalized HA-based micelles. Moreover, in vitro cytotoxicity assays in A549 cells demonstrat that Ir-loaded HA-based nanoparticles have higher cytotoxicity than the free Ir(III) anticancer drug. Finally, systemic administration of Ir(III)-loaded HA-ss-Py nanoparticles enhanced tumor inhibition in vivo, and the corresponding biodistribution experiments showed that HA-ss-Py micelles accumulate in tumors. Overall, our results suggest that HA-ss-Py micelles have a great potential to be used as an effective Ir(III) drug carrier for targeted cancer therapy.