Abnormal biochemical alteration such as unbalanced reactive oxygen species (ROS) levels has been considered as a potential disease-specific trigger to deliver therapeutics to target sites. However, in view of their minute variations in concentration, short lifetimes, and limited ranges of action, in situ generation of ROS with specific manipulations should be more effective for ROS-responsive drug delivery. Here we present a new delivery nanoplatform for photodynamic therapy (PDT) with on-demand drug release regulated by light irradiation. Rose bengal (RB) molecules, which exhibit a high yield of ROS generation, were encapsulated in a mixture of chitosan (CTS), poly(vinyl alcohol) (PVA), and branched polyethylenimine ( bPEI) with hydrophobic iron oxide nanoparticles through an oil-in-water emulsion method. The as-prepared magnetic nanoclusters (MNCs) with a tripolymer coating displayed high water dispersibility, efficient cellular uptake, and the cationic groups of CTS and bPEI were effective for RB loading through electrostatic interaction. The encapsulation efficiency of RB in MNCs could be further improved by increasing the amount of short bPEI chains. During the photodynamic process, controlled release of the host molecules (i.e., RB) or guest molecules (i.e., paclitaxel) from the bPEI-based nanoplatform was achieved simultaneously through a photooxidation action sensitized by RB. This approach promises specific payload release and highly effective PDT or PDT combined therapy in various cancer cell lines including breast (MCF-7 and multidrug resistant MCF-7 subline), SKOV-3 ovarian, and Tramp-C1 prostate. In in vivo xenograft studies, the nanoengineered light-switchable carrier also greatly augments its PDT efficacy against multidrug resistant MCF-7/MDR tumor as compared with free drugs. All the above findings suggest that the substantial effects of enhanced drug distribution for efficient cancer therapy was achieved with this smart nanocarrier capable of on demand drug release and delivery, thus exerting its therapeutic activity to a greater extent.

Dual functional drug carrier has been a modern strategy in cancer therapy because it is a platform to elicit additive and synergistic effects through combination therapy. Photo-activated external stimuli such as reactive oxygen species (ROS) also ensure adequate drug delivery in a precise temporal and spatial manner. However, current ROS-responsive drug delivery systems usually require tedious synthetic procedures. A facile one-pot approach has been reported herein, to obtain self-assembled polymeric nanocarriers (NCs) for simultaneous paclitaxel (PTX)- and Rose Bengal (RB)-loading to achieve combined chemo-photodynamic therapy and controlled drug release in responsive to a light-induced ROS stimulus. To encapsulate these hydrophobic and hydrophilic drugs, chitosan (CTS), branched polyethylenimine (bPEI) and polyvinyl alcohol (PVA) were selected and fabricated into nanoblended matrices through an oil-in-water emulsion method. The amphiphilic properties of CTS permit simultaneous entrapment of PTX and RB, while the encapsulation efficiency of RB was further improved by increasing the amount of short-chain bPEI. During the one-step assembly process, bovine serum albumin (BSA) was also added to condense the cationic tripolymer mixtures into more stable nanocarriers (BNCs). Hyaluronic acid (HA) was subsequently grafted onto the surface of BNCs through electrostatic interaction, leading to the formation of HA-BSA/CTS/PVA/bPEI-blended nanocarriers (HBNCs) to achieve an efficient prostate-cancer-cell uptake. Importantly, in response to external light irradiation, HBNCs become destabilized owing to the RB-mediated photodynamic action. It allows an on-demand dual-payload release to evoke a simultaneous photodynamic and chemo treatment for cancer cell eradication. Thus, HBNCs present a new promising approach that exhibits a specific vulnerability to RB-induced photosensitization. The consequent dual-cargo release is also expected to successfully combat cancer through a synergistic anti-tumor effect.