Mitochondria are recognized as the ideal target for cancer treatment because they play a central role in oxidative metabolism and apoptosis. In this work, a mitochondria‐targeted near‐infrared (NIR) photosensitizer (PS) for synchronous cancer photodynamic therapy (PDT) and photothermal therapy (PTT) is synthesized. This multifunctional small‐molecule PS is developed from a variety of synthesized heptamethine cyanine dyes, which are modified with various N‐alkyl side chains on the lipophilic cationic heptamethine core. It is demonstrated to preferentially accumulate in cancer cells by organic‐anion transporting polypeptide mediated active transport and retain in mitochondria by its lipophilic cationic property. As mitochondria are susceptible to hyperthermia and excessive reactive oxygen species, this new PS integrating PTT and PDT treatment exhibits highly efficient phototherapy in multiple cancer cells and animal xenograft models. Furthermore, this targeted PS with NIR imaging property also enables tumors and their margins clearly visualized, providing the potential for precisely imaging‐guided phototherapy and treatment monitoring. This is the first report that a small‐molecule PS integrates both cancer PTT and PDT treatment by targeting mitochondria, significantly increasing the photosensitization. This work may also present a practicable strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.

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An urgent challenge for imaging-guided disease-targeted multimodal therapy is to develop the appropriate multifunctional agents to meet the requirements for potential applications. Here, a rigid cyclohexenyl substitution in the middle of a polymethine linker and two asymmetrical amphipathic N-alkyl side chains to indocyanine green (ICG) (the only FDA-approved NIR contrast agent) are introduced, and a new analog, IR-DBI, is developed with simultaneous cancer-cell mitochondrial targeting, NIR imaging, and chemo-/PDT/PTT/multimodal therapeutic activities. The asymmetrical and amphipathic structural modification renders IR-DBI a close binding to albumin protein site II to form a drug-protein complex and primarily facilitates its preferential accumulation at tumor sites via the enhanced permeability and retention (EPR) effect. The released IR-DBI dye is further actively taken up by cancer cells through organic-anion-transporting polypeptide transporters, and the lipophilic cationic property leads to its selective accumulation in the mitochondria of cancer cells. Finally, based on the high albumin-binding affinity, IR-DBI is modified into human serum albumin (HSA) via self-assembly to produce a nanosized complex, which exhibits significant improvement in the cancer targeting and multimodal cancer treatment with better biocompatibility. This finding may present a practicable strategy to develop small-molecule-based cancer theranostic agents for simultaneous cancer diagnostics and therapeutics.

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A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERβ, mediates the beneficial effects in microglia. In this study, we found that ERβ, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERβ agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERβ agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF - κB, as well as the NF-κB–induced gene inducible nitric oxide synthase in microglia and CD3 + T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERβ-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.

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The integration of photodynamic therapy (PDT) with photothermal therapy (PTT) offers improved efficacy in cancer phototherapy. Herein, a PDT photosensitizer (IR-808) with cancer-targeting ability and near-infrared (NIR) sensitivity was chemically conjugated to both polyethylene glycol (PEG)- and branched polyethylenimine (BPEI)-functionalized nanographene oxide (NGO). Because the optimal laser wavelength (808 nm) of NGO for PTT is consistent with that of IR-808 for PDT, the IR-808-conjugated NGO sheets (NGO-808, 20-50 nm) generated both large amounts of reactive oxygen species (ROS) and local hyperthermia as a result of 808 nm laser irradiation. With PEG- and BPEI-modified NGO as the carrier, the tumor cellular uptake of NGO-808 exhibited higher efficacy than that of strongly hydrophobic free IR-808. Through evaluation with both human and mouse cancer cells, NGO-808 was demonstrated to provide significantly enhanced PDT and PTT effects compared to individual PDT using IR-808 or PTT using NGO. Furthermore, NGO-808 preferentially accumulated in cancer cells as mediated by organic-anion transporting polypeptides (OATPs) overexpressed in many cancer cells, providing the potential for highly specific cancer phototherapy. Using the targeting ability of NGO-808, in vivo NIR fluorescence imaging enabled tumors and their margins to be clearly visualized at 48 h after intravenous injection, providing a theranostic platform for imaging-guided cancer phototherapy. Remarkably, after a single injection of NGO-808 and 808 nm laser irradiation for 5 min, the tumors in two tumor xenograft models were ablated completely, and no tumor recurrence was observed. After treatment with NGO-808, no obvious toxicity was detected in comparison to control groups. Thus, high-performance cancer phototherapy with minimal side effects was afforded from synergistic PDT/PTT treatment and cancer-targeted accumulation of NGO-808.