Identification of a mitochondria-targeting fluorescent small molecule for dual phototherapy

Phototherapy, mainly including photodynamic therapy (PDT) and photothermal therapy (PTT), is a noninvasive and effective approach for cancer treatment. Since integration of PDT and PTT for simultaneous synergistic PDT/PTT treatment enables us to improve phototherapeutic efficacy significantly, it has been attracting a lot of investigations in current days. Here, we introduce IR-52, a new mitochondria-targeting near infrared (NIR) fluorescent small molecule, which possesses structure-inherent PTT and PDT synergistic phototherapeutic effects without conjugation to specific ligands. After NIR light irradiation (808[Formula: see text]nm, 2[Formula: see text]W/cm2, 5[Formula: see text]min), both the hyperthermia and excessive singlet oxygen levels were determined when dissolving IR-52 in aqueous solutions. In vitro photoinduced cytotoxicity studies showed significant lower cell viabilities and higher necrotic/apoptotic rates when cancer cells were treated with IR-52 and irradiation, and its’ mitochondrial localization in cancer cells would partially explain its high cytotoxicity. Further in vivo synergetic PDT and PTT effects were demonstrated by high tumor surface temperature and significant inhibition of tumor growth. Our results strongly suggest that IR-52, which possesses excellent photosensitivity, may provide a promising strategy for tumor treatment with decreased side effects.

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[Mn(PaPy2Q)(NO)]ClO4, a Near-Infrared Light activated release of Nitric Oxide drug as a nitric oxide donor for therapy of human prostate cancer cells in vitro and in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111388 ◽

2021 ◽

Vol 137 ◽

pp. 111388

Author(s):

Yuwan Zhao ◽

Zhuo Li ◽

Huancheng Tang ◽

Shanhong Lin ◽

Wenfeng Zeng ◽

...

Keyword(s):

Prostate Cancer ◽

Nitric Oxide ◽

Cancer Cells ◽

Near Infrared ◽

Nitric Oxide Donor ◽

Infrared Light ◽

Human Prostate Cancer ◽

Prostate Cancer Cells

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Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

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Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16534 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16534-e16534 ◽

Cited By ~ 1

Author(s):

Lisa Butler ◽

Swati Irani ◽

Margaret Centenera ◽

Natalie Ryan ◽

Neil Pegg ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Small Molecule ◽

Single Agent ◽

Specific Antigen ◽

Resistance Mechanisms ◽

Prostate Cancer Cells ◽

In Vivo Models

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.

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Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in Tumor-Bearing Mice

Prostate Cancer ◽

10.1155/2014/104248 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Joy L. Kovar ◽

Lael L. Cheung ◽

Melanie A. Simpson ◽

D. Michael Olive

Keyword(s):

Small Molecule ◽

Near Infrared ◽

Image Guided Surgery ◽

Tumor Delineation ◽

Guided Surgery ◽

Image Guided ◽

Tumor Bearing ◽

Tissue Contrast

Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds.In vivotargeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy.In vitroandin vivoblocking studies confirmed YC-27 specificity.In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections.

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Hyperbaric Oxygen Enhanced Mitochondria-Targeted Chemotherapy in Bladder Cancer

10.21203/rs.3.rs-111008/v1 ◽

2020 ◽

Author(s):

Chongxing Shen ◽

Xiaofeng Yue ◽

Linyong Dai ◽

Jianwu Wang ◽

Jinjin Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Hyperbaric Oxygen ◽

Cell Uptake ◽

Bladder Cancer Cells ◽

First Time ◽

Mitochondria Targeting

Abstract Background: Bladder cancer has a high rate of recurrence and drug resistance due to a lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types. In the study, we aimed to investigate the anti-tumor effect of IR-780 combined with hyperbaric oxygen (HBO) on bladder cancer.Methods: Using in vitro cell line data, in vivo model data and clinical data, we tested the ability of IR-780 to selectively accumulate in bladder cancer. We also evaluated the anti-tumor effect of IR-780 combined or not with HBO both in vitro and in vivo, and explored the potential mechanism of its anti-tumor effect. Results: We revealed for the first time that IR-780 selectively accumulated in bladder cancer (bladder cancer cells, xenografts and bladder cancer samples from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. Further study displayed that the combination with HBO could significantly enhance the antitumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial reactive oxygen species (ROS) production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. Conclusions: These data identify for the first time a combination of IR-780 and HBO (IR-780+HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.

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A near-infrared multifunctional fluorescent probe with an inherent tumor-targeting property for bioimaging

Chemical Communications ◽

10.1039/c5cc03878b ◽

2015 ◽

Vol 51 (58) ◽

pp. 11721-11724 ◽

Cited By ~ 32

Author(s):

Xu Zhao ◽

Yang Li ◽

Di Jin ◽

Yuzhi Xing ◽

Xilong Yan ◽

...

Keyword(s):

Fluorescent Probe ◽

Tumor Targeting ◽

Near Infrared ◽

Mitochondria Targeting

A mitochondria-targeting near-infrared switchable probe for in vitro and in vivo tumor-targeting imaging.

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Synthetic circular miR-21 RNA decoys enhance tumor suppressor expression and impair tumor growth in mice

NAR Cancer ◽

10.1093/narcan/zcaa014 ◽

2020 ◽

Vol 2 (3) ◽

Author(s):

Simon Müller ◽

Alice Wedler ◽

Janina Breuer ◽

Markus Glaß ◽

Nadine Bley ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Growth ◽

Cancer Cells ◽

Circular Rna ◽

Significant Inhibition ◽

Circular Rnas ◽

Cell Vitality ◽

Inhibition Of Tumor Growth ◽

Functional Relevance

Abstract Naturally occurring circular RNAs efficiently impair miRNA functions. Synthetic circular RNAs may thus serve as potent agents for miRNA inhibition. Their therapeutic effect critically relies on (i) the identification of optimal miRNA targets, (ii) the optimization of decoy structures and (iii) the development of efficient formulations for their use as drugs. In this study, we extensively explored the functional relevance of miR-21-5p in cancer cells. Analyses of cancer transcriptomes reveal that miR-21-5p is the by far most abundant miRNA in human cancers. Deletion of the MIR21 locus in cancer-derived cells identifies several direct and indirect miR-21-5p targets, including major tumor suppressors with prognostic value across cancers. To impair miR-21-5p activities, we evaluate synthetic, circular RNA decoys containing four repetitive binding elements. In cancer cells, these decoys efficiently elevate tumor suppressor expression and impair tumor cell vitality. For their in vivo delivery, we for the first time evaluate the formulation of decoys in polyethylenimine (PEI)-based nanoparticles. We demonstrate that PEI/decoy nanoparticles lead to a significant inhibition of tumor growth in a lung adenocarcinoma xenograft mouse model via the upregulation of tumor suppressor expression. These findings introduce nanoparticle-delivered circular miRNA decoys as a powerful potential therapeutic strategy in cancer treatment.

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1187 THE EFFECT OF A SELECTIVE AKT SMALL MOLECULE INHIBITOR, GSK690693C, IN PROSTATE CANCER CELLS IN VITRO AND IN VIVO

The Journal of Urology ◽

10.1016/j.juro.2010.02.688 ◽

2010 ◽

Vol 183 (4S) ◽

Author(s):

Norihiro Hayashi ◽

Aminna Zoubeidi ◽

Christopher Ong ◽

Martin Gleave

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Prostate Cancer Cells ◽

Molecule Inhibitor

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Amphipathic Small Molecule AZT Compound Displays Potent Inhibitory Effects in Cancer Cell Proliferation

Pharmaceutics ◽

10.3390/pharmaceutics13122071 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2071

Author(s):

Pethaiah Gunasekaran ◽

Ho Jin Han ◽

Jung hoon Choi ◽

Eun Kyoung Ryu ◽

Nam Yeong Park ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cell ◽

Small Molecule ◽

Ductal Carcinoma ◽

Membrane Integrity ◽

Significant Inhibition ◽

Cancer Cell Proliferation ◽

Average Life Expectancy

Cancer has been identified as a leading cause of death worldwide, and the increasing number of cancer cases threatens to shorten the average life expectancy of people. Recently, we reported a 3-azido-3-deoxythymidine (AZT)-based amphipathic small molecule, ADG-2e that revealed a notable potency against tumor metastasis. To evaluate the anticancer potential of ADG-2e, we assessed its anticancer potency in vitro and in vivo. Anticancer screening of ADG-2e against cervical cancer cells, HeLa CCL2, and BT549 mammary gland ductal carcinoma showed significant inhibition of cancer cell proliferation. Furthermore, mechanistic investigations revealed that cancer cell death presumably proceeded through an oncosis mechanistic pathway because ADG-2e treated cells showed severe damage on the plasma membrane, a loss of membrane integrity, and leakage of α-tubulin and β-actin. Finally, evaluation of the antitumorigenic potential of ADG-2e in mouse xenograft models revealed that this compound potentially inhibits cancer cell proliferation. Collectively, these findings suggest that ADG-2e can evolve as an anticancer agent, which may represent a model for nucleoside-based small molecule anticancer drug discovery.

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