PH-Responsive Star-Like Polymer Unimolecular Micelles For Anticancer Drug Delivery And CT Imaging

Theranostic nanohybrids can simultaneously achieve tumor targeted imaging and drug delivery, realizing the integration of diagnosis and therapy. In the proposal, we designed and synthesized multifunctional star-like polymeric unimolecular micelles, with which stable gold nanoparticls(GNPs) were prepared by in situ reduction in one step, and anticancer drug doxorubicin(DOX) were loaded. The following work was carried out to preliminarily explore the cancer theranostic application of the versatile nanohybrids.Amphiphilic 21-arm star-like block copolymers β-cyclodextrin-{poly(lactide)-poly(2-(dimethylamino) ethyl methacrylate)-poly[oligo(2-ethyl-2-oxazoline)methacrylate]}21[β-CD-(PLA-PDMAEMA-PEtOxMA)21] and the precursors were synthesized by the combination of ring-opening polymerization(ROP) and activators regenerated by electron transfer atom transfer radical polymerization(ARGET ATRP). The copolymers in aqueous solution existed as unimolecular micelles with β-CD as the core, hydrophobic PLA as the internal layer, reducing and pH-responsive PDMAEMA as the middle layer, and hydrophilic PEtOxMA as the outer shell. The tertiary amine groups of PDMAEMA block reduced the AuCl4- counterion to zerovalent gold in situ without additional reductants and organic solvents,and these gold atoms combined mutually to form final GNPs. Polymer structures and unimolecular micelles properties were measured with various experimental methods, such as gel permeation chromatography(GPC), proton nuclear magnetic resonance(1H NMR) spectra,fourier transform infrared spectroscopy(FT-IR), dynamic light scattering(DLS) and transmission electron microscopy(TEM). The influence of several factors, such as DMAEMA block length, molar ratio of DMAEMA to HAuCl4 and concentrations of both polymer and HAuCl4 on GNPs size and morphology, as well as the stability of GNPs were discussed. The results showed that unimolecular micelles made of β-CD-(PLA-PDMAEMA-PEtOxMA)21possessed a uniform spherical shape with hydrodynamic diameters no more than 29 nm and narrow size distribution. More DMAEMA block in copolymer, or higher molar ratio of DMAEMA to HAuCl4 in aqueous solution, resulted GNPs with smaller sizes. While theconcentrations of both copolymer and HAuCl4 increased, the collision among the nanoparticles forced the increase in GNPs sizes. The formed GNPs were not only stable for at least 4 months, but also showed good stability under different pH conditions.The hydrophobic DOX was selected as the model drug to develop novel nanohybrids carrying both GNPs and DOX. The results showed that the drug release rate obviously depended on pH. In weak acid condition simulating the tumor sites, the pH-responsive block PDMAEMA was transformed to hydrophilic because of the protonation of the amine groups,leading to controlled fast release of DOX. Compared with conventional micromolecular contrast agent omnipaque, GNPs owned preferable CT imaging effects as the CT imaging experiments revealed, thereby making cancer diagnosis and pH-responsive drug delivery possible.