Design and Synthesis of New PEGylated Polydopamine-Based Nanoconstructs Bearing ROS-Responsive Linkers and a Photosensitizer for Bimodal Photothermal and Photodynamic Therapies against Cancer.

Polydopamine (PDA) nanoparticles (NPs) have recently acquired considerable attention for the development of nanoplatforms with multifunctional properties including photothermal (PTT) and photodynamic (PDT) activities. In addition to their high PTT performance, they can be easily conjugated to different types of photosensitizers (PSs) to acquire PDT activity. However, because of PDA free-radical scavenging properties, grafting the PSs directly to PDA surfaces may lead to an inefficient PDT outcome. Thus, the present work aims at synthesizing and characterizing a new PEGylated PDA-based nanoplatform with bifunctional PTT and PDT properties, which allows bimodal cancer therapy with the possibility to release the PS on demand in a spatiotemporal fashion. To do so, PDA NPs with a well-defined size and shape were prepared by the auto-oxidative self-polymerization process of dopamine hydrochloride in mild alkaline solution. The impact of the size on the PTT conversion efficiency was then determined. This allowed us to choose the optimal PDA NP size for PTT applications. Next, PDA NPs were decorated with SH-PEG polymers that bear at their extremity a thioketal reactive oxygen species-cleavable linker coupled to trisulfonated-tetraphenylporphyrin (TPPS3) chosen as a hydrophilic PS. The grafting efficiency of PS-conjugated PEG on PDA was demonstrated in situ using a quartz crystal microbalance with dissipation monitoring. In addition, the photoinduced release of the PS was demonstrated by 1H NMR. Finally, PTT/PDT bimodal therapy was assessed in vitro on human squamous esophageal cells by illuminating the PDA NPs at two different wavelengths, which showed the strong synergistic effect of combining PTT and PDT within this nanoplatform.

Bioinspired polydopamine nanoparticles: synthesis, nanomechanical properties, and efficient PEGylation strategy.

Polydopamine (PDA) is a bioinspired fascinating polymer which is considered nowadays as a material of choice for designing drug delivery nanosystems. Indeed, PDA exhibits multiple interesting features including simple preparation protocols, biocompatibility, simple functionalization procedures, free radicals scavenging and photothermal/photoacoustic properties. However, because of its heterogeneous structure, clear procedures about PDA nanoparticles synthesis and PEGylation with well-defined and reproducible physicochemical properties such as size, shape and nanomechanics are still needed. In this work, we established tightly controlled experimental conditions to synthesize PDA nanoparticles with well-defined size and yield. This allowed us to identify the factors that affect the most these two parameters and to construct surface response plots with accurate predictive values of size and yield. The nanomechanical properties of PDA NPs exhibiting different sizes have been studied with AFM nanoindentation experiments. Our results demonstrated for the first time that the elasticity of PDA NPs was decreasing with their size. This could be explained by the higher geometric packing order of the stacked oligomeric fractions inside the core of the biggest PDA NPs. Next, in order to determine the best PEGylation experimental conditions of PDA NPs using thiol-terminated PEG that allow grafting the highest polymer density with proteins repelling properties, we have first optimized the PEGylation strategy on PDA films. By using a combination of QCM-D and AFM experiments, we could demonstrate that efficient PEGylation of PDA films could be done even at low PEG concentration but in the presence of NaCl which exerts a salting out effect on PEG chains improving thus the grafting density. Finally, we transposed these experimental conditions to PDA NPs and we could synthesize PEGylated PDA NPs exhibiting high stability in physiological conditions as revealed by FTIR and DLS experiments respectively.