Epidermal Growth Factor Receptor-Targeted Delivery of a Singlet-Oxygen Sensitizer with Thermal Controlled Release for Efficient Anticancer Therapy.

Photodynamic therapy (PDT) utilizing light-induced singlet oxygen has achieved attractive results in anticancer fields; however, its development is hindered by limited light penetration depth, skin phototoxicity, tumor hypoxia, and PDT-induced hypoxia. Inspired by our previous research work and the limitations of PDT, we introduce a small-molecule-targeted drug erlotinib into the singlet-oxygen chemical source endoperoxide to achieve an EGFR-targeted PDT-mimetic sensitizer (Y3-1) for anticancer therapy. We demonstrated the erlotinib-based precise delivery of the singlet-oxygen chemical source (in vitro photosensitization) to EFGR-overexpressing tumor cells and tissues. Moreover, the anticancer assays validated that the enhanced anticancer efficacy (in vitro and in vivo) of Y3-1 was due to reversible singlet-oxygen thermal release. This study is expected to provide a smart strategy to break through the current roadblock in targeted PDT and achieve a more efficient anticancer therapy model.

A MCL-1-targeted photosensitizer to combat triple-negative breast cancer with enhanced photodynamic efficacy, sensitization to ROS-induced damage, and immune response.

As growth factor receptor-2 (HER-2), progesterone receptor (PR) and estrogen receptor (ER) are scarce in triple-negative breast cancer (TNBC), it is a great challenge to combat TNBC with high tumor specificity and therapeutic efficacy. Most traditional treatments including surgical resection, chemotherapy, and radiotherapy would more or less cause serious side effects and drug resistance. Photodynamic therapy (PDT) has huge potential in the treatment of TNBC for minimal invasiveness, low toxicity, less drug resistance and high spatiotemporal selectivity. Inspired by the advantages of small-molecule-targeted PDT and the sensitization effect of myeloid cell leukemia-1 (MCL-1) inhibitor, a novel photosensitizer BC-Pc was designed by conjugating MCL-1 inhibitor with zinc phthalocyanines. Owning to 3-chloro-6-methyl-1-benzothiophene-2-carboxylic acid (BC) moiety, BC-Pc exhibits the high affinity towards MCL-1 and reduce its self-aggregation in TNBC cells. Therefore, MCL-1 targeted BC-Pc showed remarkable intracellular fluorescence and ROS generation in TNBC cells. Additionally, BC-Pc can selectively sensitize TNBC cells to ROS-induced damage, resulting in improved therapeutic effect to TNBC cells and negligible toxicity to normal cells. More importantly, BC-Pc can effectively inhibit the migration and invasion of TNBC cells, and enhance immune response, all of which will be beneficial to eradicate TNBC. To the best of our knowledge, BC-Pc is the novel MCL-targeted photosensitizer, which owns the amplified ROS-induced lethality and anticancer immune response for TNBC. Overall, our study provides a promising strategy to achieve targeting and highly efficient therapy of TNBC.

Novel Targeted Photosensitizer as an Immunomodulator for Highly Efficient Therapy of T-Cell Acute Lymphoblastic Leukemia.

Dasatinib is a kinase-targeted drug used in the treatment of leukemia. Regrettably, it remains far from optimal medicine due to insurmountable drug resistance and side effects. Photodynamic therapy (PDT) has proven that it can induce systemic immune responses. However, conventional photosensitizers as immunomodulators produce anticancer immunities, which are inadequate to eliminate residual cancer cells. Herein, a novel compound 4 was synthesized and investigated, which introduces dasatinib and zinc(II) phthalocyanine as the targeting and photodynamic moiety, respectively. Compound 4 exhibits a high affinity to CCRF-CEM cells/tumor tissues, which overexpress lymphocyte-specific protein tyrosine kinase (LCK), and preferential elimination from the body. Meanwhile, compound 4 shows excellent photocytotoxicity and tumor regression. Significantly, compound 4-induced PDT can obviously enhance immune responses, resulting in the production of more immune cells. We believe that the proposed manner is a potential strategy for the treatment of T-cell acute lymphoblastic leukemia.

A novel tumor and mitochondria dual-targeted photosensitizer showing ultra-efficient photodynamic anticancer activities.

We designed and synthesized a simple, but highly effective photosensitizer (G-Mito-Pc), which can precisely target the mitochondria of epidermal growth factor receptor (EGFR)-overexpressing cancer cells, to achieve dual targeting function at both cell and organelle levels in cancer therapy. We further explored the possible molecular mechanism of the enhanced bioactivity of G-Mito-Pc compared to that of the reference photosensitizer using molecular dynamics simulations on their interactions with a physiologically relevant mitochondrial membrane model.

A Molecular Combination of Zinc(II) Phthalocyanine and Tamoxifen Derivative for Dual Targeting Photodynamic Therapy and Hormone Therapy.

The combination of photodynamic therapy and other cancer treatment modalities is a promising strategy to enhance therapeutic efficacy and reduce side effects. In this study, a tamoxifen-zinc(II) phthalocyanine conjugate linked by a triethylene glycol chain has been synthesized and characterized. Having tamoxifen as the targeting moiety, the conjugate shows high specific affinity to MCF-7 breast cancer cells overexpressed estrogen receptors (ERs) and tumor tissues, therefore leading to a cytotoxic effect in the dark due to the cytostatic tamoxifen moiety, and a high photocytotoxicity due to the photosensitizing phthalocyanine unit against the MCF-7 cancer cells. The high photodynamic activity of the conjugate can be attributed to its high cellular uptake and efficiency in generating intracellular reactive oxygen species. Upon addition of exogenous 17ß-estradiol as an ER inhibitor, the cellular uptake and photocytotoxicity of the conjugate are reduced significantly. As shown by confocal microscopy, the conjugate is preferentially localized in the lysosomes of the MCF-7 cells.