Photosensitizer cross-linked nano-micelle platform for multimodal imaging guided synergistic photothermal/photodynamic therapy

The multifunctional nano-micelle platform holds great promise to enhance the accuracy and efficiency of cancer diagnosis and therapy. In this work, an amphiphilic poly[(poly(ethylene glycol) methyl ether methacrylate)-co-(3-aminopropyl methacrylate)]-block-poly(methyl methacrylate) (P(PEGMA-co-APMA)-b-PMMA) block copolymer was synthesized by successive RAFT polymerizations and subsequent chemical modification. Then the multifunctional micelles with high solubility in physiological environments were developed by a self-assembly and crosslinking processes. The photosensitizer segment, 5,10,15,20-tetrakis (4-carboxyphenyl) porphyrin (TCPP), serves as a tetra-functional cross-linker, photodynamic agent, fluorescence indicator, as well as magnetic resonance (MR) contrast agent after labelling with manganese ions (Mn(2+)), while IR825 simultaneously locating in the interior of the fabricated micelles contributed to the photoacoustic (PA) imaging ability and the photothermal effect. The prepared nanoparticles show great stability in a physiological environment with uniform morphology and diameters of around 80 nm as disclosed by stability investigation, TEM and DLS analysis. IR825@P(PEGMA-co-APMA)-b-PMMA@TCPP/Mn nanoparticles displayed high in vivo tumor uptake with a long blood circulation half-life (∼3.64 h) by the EPR effect after intravenous (i.v.) injection, as revealed by fluorescence, MR and PA imaging models. In vivo anti-tumor effects were achieved via a combined photothermal and photodynamic therapy without noticeable dark toxicity, and this strategy was able to induce a remarkably improved synergistic therapeutic effect to both superficial and deep regions of tumors under mild conditions compared with either single photothermal or photodynamic mechanisms.