Redox- and light-responsive alginate nanoparticles as effective drug carriers for combinational anticancer therapy

Nanoparticles have been extensively explored as effective means to deliver chemotherapeutic agents or photosensitizers for chemotherapy or photodynamic therapy (PDT) against cancer. In the present work, pheophorbide A (PheoA), a hydrophobic photosensitizer, was conjugated via a redox-sensitive disulfide linkage to alginate (PheoA-ALG). Anticancer agent, doxorubicin (DOX), was also loaded within the PheoA-ALG nanoparticles (DOX/PheoA-ALG NPs) and used as drug carriers for combinational antitumor treatment. The DOX/PheoA-ALG NPs were spherical in shape with a uniform diameter of approximately 210 nm. Redox-responsive drug releasing properties were shown by the DOX/PheoA-ALG NPs, with an accelerated amount of DOX and PheoA release observed in the presence of a high glutathione level (10 mM). Cellular uptake results showed that DOX/PheoA-ALG NPs were readily taken up by B16 tumor cells (murine melanoma) and enhanced DOX and PheoA uptake were detectable in the DOX/PheoA-ALG NPs-treated B16 cells in comparison to carrier free drugs. DOX/PheoA-ALG NPs also elicited intracellular ROS generation, which leads to enhanced toxicity in B16 cells. In vivo studies using B16 tumor-bearing mice further demonstrated that DOX/PheoA-ALG NPs were preferentially accumulated in tumor tissues, resulting in substantial inhibition of B16 tumor growth by chemotherapy and photodynamic therapy, which is also attributable to DOX/PheoA-ALG NP-elicited increase of serum INF-lambda levels. Our results demonstrate a major potential of DOX/PheoA-ALG NPs for combinational cancer therapy.