Temporally Controlled Photothermal/Photodynamic and Combined Therapy for Overcoming Multidrug Resistance of Cancer by Polydopamine Nanoclustered Micelles.

Currently, the simple integration of multiple therapeutic agents within a single nanostructure for combating multidrug resistance (MDR) tumors yet remains a challenge. Herein, we report a photoresponsive nanocluster (NC) system prepared by installing polydopamine (PDA) nanoparticle clusters on the surface of d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) (a drug efflux inhibitor) micelles solubilized with IR780 (a photosensitizer) to achieve a combined chemotherapy (CT)/photothermal therapy (PTT)/photodynamic therapy (PDT) for drug-resistant breast cancer. Mediated by the fluorescence resonance energy transfer and radical scavenging properties of PDA, NC shows prominently quenched fluorescence emission (∼78%) and inhibited singlet oxygen generation (∼67%) upon exposure to near-infrared (NIR) light (808 nm, 0.5 W cm-2), favoring a highly efficient PTT module. Meanwhile, the photothermal heat can also boost the release of doxorubicin hydrochloride whose intracellular accumulation can be greatly enhanced by TPGS. Interestingly, the first NIR irradiation and subsequent incubation (∼24 h) can induce the gradual relocation and disintegration of PDA nanoparticles, thereby leading to activated PDT therapy under the second irradiation. Upon the temporally controlled sequential application of PTT/PDT, the developed NC exhibited a great potential to treat MDR cancer both in vitro and in vivo. These findings suggest that complementary interactions among PTT/PDT/CT modalities can enhance the efficiency of the combined therapy for MDR tumor.

CaP coated mesoporous polydopamine nanoparticles with responsive membrane permeation ability for combined photothermal and siRNA therapy.

Combined photothermal and gene therapy provides a promising modality toward cancer treatment, yet facile integration and controlled codelivery of gene payloads and photothermal conversion agents (PTCAs) remains a great challenge. Inspired by the robust wet adhesion of marine mussels, we present a rationally designed nanosystem constructed by using hybrid mesoporous polydopamine nanoparticles (MPDA) with sub-100 nm sizes and a high photothermal conversion efficiency of 37%. The surface of the particles were modified with tertiary amines by the facile Michael addition/Schiff base reactions of PDA to realize high siRNA loading capacity (10 wt%). Moreover, a successful calcium phosphate (CaP) coating via biomineralization was constructed on the cationic nanoparticle to prohibit premature release of siRNA. The CaP coating underwent biodegradation in weakly-acidic subcellular conditions (lysosomes). The synergistic integration of tertiary amines and catechol moieties on the subsequently exposed surfaces was demonstrated to feature the destabilization/disruption ability toward model cellular membranes via the greatly enhanced interfacial adhesion and interactions. Consequently, sufficient permeability of lysosomal membranes, and in turn, a high lysosomal escape efficiency, was realized, which then resulted in high gene silencing efficiencies via sufficient cytosolic delivery of siRNA. When an efficient knocking down (65%) of survivin (an inhibitor of apoptosis proteins) was combined with a subsequent photothermal ablation, remarkably higher therapeutic efficiencies were observed both in vitro and in vivo, as compared with monotherapy. The system may help to pave a new avenue on the utilization of bio-adhesive surfaces for handling the obstacles of combined photothermal and gene therapy. STATEMENT OF SIGNIFICANCE: Polydopamine (PDA) based porous photothermal-conversion agent (PTCA) with sufficiently high conversion efficiency was employed to deliver photothermal/gene therapy modalities towards cancer treatment. CaP coating via PDA-induced biomineralization was constructed to prohibit premature release of siRNA loaded in the pore space of the nanocarriers. Responsive degradation of CaP also led to the exposure of membrane-lytic surfaces built through the synergistic integration of tertiary amines and catechol moieties, and in turn the significantly enhanced lysosomal escape and cytosol siRNA delivery. Therapeutic targeting of survivin was successfully applied for activation of apoptosis and programmed cell death. Combined photothermal and gene therapy improved therapeutic effectiveness.