To enhance anticancer efficacy and decrease side effects, the synergistic multi-agent therapy has now increasingly gotten great attention. Herein, the flexible polycaprolactone had been modified by histidine and formed assembles with PEGylated metallo-porphyrin via metal-coordinated supramolecular interaction. This supramolecular assembles showed excellent acid sensitivity. At neutral environment, the hydrophobic anticancer drug could be effectively co-encapsulated with photosensitizer Fe-TPP to improve the water solubility. While at the intracellular microenvironment, the changed acid environment would trigger the drug and Fe-TPP release due to the reduction of metal-coordinated interaction between histidine and metallo-porphyrin leading to the disintegration of assembles. The in vivo anticancer experiments toward HeLa and MCF-7 cells disclosed that this co-delivery system of anticancer drug and photosensitizer showed enhanced anticancer efficacy, implying that the synergistic chemo-photodynamic therapy could improve cellular proliferation inhibition. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2955-2962, 2018.

In order to improve the treatment efficacy and reduce the side effects, the synergistic therapy has been effectively exploited in cancer treatment. Herein, we fabricated a kind of acid-sensitive ROS-triggered dextran-based drug delivery system (DHTD/Zn-TPP) for synergistic therapy, in which chemotherapeutics doxorubicin was conjugated to the dextran backbone via ROS cleavable thioketal conjugates while photosensitizer porphyrin (Zn-TPP) was encapsulated via acid-responsive metallic coordinated interaction. The structure and acid-responsive self-assemble behavior of DHTD/Zn-TPP were measured by 1 H NMR, Fourier transform infrared, dynamic laser scattering, and transmission electron microscopy. Further, the in vivo ROS-triggered DOX release and anticancer efficiency were evaluated toward HeLa cells and MCF-7 cells. All the data obtained verified that DHTD/Zn-TPP had a significantly improved cell growth inhibitory effect with light irritation due to the combined application of photodynamicchemotherapy. K E Y W O R D S acid sensitive, dextran, photodynamic-chemotherapy, reactive oxygen species sensitive, supramolecular metallic coordination

In clinical treatment, multidrug resistance (MDR) is one of the major obstacles resulting in the failure of chemotherapy. It is still a challenge to overcome MDR. Herein, we fabricated intelligent dextran-based dual-drug delivery systems histidine modified dextran conjugated doxorubicin/zinc porphyrin/paclitaxel (DHTD/Zn-TPP/PTX) via supramolecular metallo-coordination for synergistic chemo-photodynamic therapy to overcome cancer drug resistance. In this designed DHTD/Zn-TPP/PTX, one anticancer drug (doxorubicin, DOX) was conjugated on the dextran backbone through a reactive oxygen species sensitive linker and the other drug PTX was encapsulated into the acid responsive supramolecular micelles formed by the photosensitizer Zn-TPP and histidine grafted on dextran. DHTD/Zn-TPP/PTX with excellent stability could be effectively internalized by tumour cells. In the acidic tumour environment, the loaded PTX and Zn-TPP as photosensitizer could be released; moreover, when irradiated with light the conjugated DOX could be specifically released because the linker broke. As the obtained data indicate, DHTD/Zn-TPP/PTX exhibited not only an enhanced anticancer therapeutic effect but also significant growth inhibition for drug-resistant MCF-7/ADR cells to reverse MDR, having great potential for synergistic treatments of cancer to overcome MDR.