Mitochondrial NIR imaging probe mitigating oxidative damage by targeting HDAC6.

Despite the apparent copious fluorescent probes targeting mitochondria, the development of low cytotoxic probes is still needed for improving validation of mitochondrial function assessment. Herein, we report a novel cyanine-based NIR fluorescent probe, T2, which selectively targets mitochondria with significantly low toxicity by modulating the intracellular redox status. Additionally, T2 inhibits oxidative stress-induced cell death in cortical neurons. This study provides new insight into developing low-toxic mitochondrial imaging agents by regulating redox homeostasis.

The design of small-molecule prodrugs and activatable phototherapeutics for cancer therapy.

Cancer remains as one of the most significant health problems, with approximately 19 million people diagnosed worldwide each year. Chemotherapy is a routinely used method to treat cancer patients. However, current treatment options lack the appropriate selectivity for cancer cells, are prone to resistance mechanisms, and are plagued with dose-limiting toxicities. As such, researchers have devoted their attention to developing prodrug-based strategies that have the potential to overcome these limitations. This tutorial review highlights recently developed prodrug strategies for cancer therapy. Prodrug examples that provide an integrated diagnostic (fluorescent, photoacoustic, and magnetic resonance imaging) response, which are referred to as theranostics, are also discussed. Owing to the non-invasive nature of light (and X-rays), we have discussed external excitation prodrug strategies as well as examples of activatable photosensitizers that enhance the precision of photodynamic therapy/photothermal therapy. Activatable photosensitizers/photothermal agents can be seen as analogous to prodrugs, with their phototherapeutic properties at a specific wavelength activated in the presence of disease-related biomarkers. We discuss each design strategy and illustrate the importance of targeting biomarkers specific to the tumour microenvironment and biomarkers that are known to be overexpressed within cancer cells. Moreover, we discuss the advantages of each approach and highlight their inherent limitations. We hope in doing so, the reader will appreciate the current challenges and available opportunities in the field and inspire subsequent generations to pursue this crucial area of cancer research.

SIWV tetrapeptide and ROS-responsive prodrug conjugate for advanced glioblastoma therapy.

A new conjugate formulation, SIWV-PB-SN, based on glioblastoma (GBM)-homing SIWV tetrapeptide and an ROS-responsive prodrug is reported. SIWV-PB-SN selectively penetrates the GBM cells and releases anti-GBM drug (SN-38) via ROS-induced linker cleavage. This study presents a new insight for a more advanced therapeutic approach to overcoming GBM.

DNA-Damage-Response-Targeting Mitochondria-Activated Multifunctional Prodrug Strategy for Self-Defensive Tumor Therapy.

We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.

Overcoming barriers in photodynamic therapy harnessing nano-formulation strategies.

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.

Fluorescent Probe for Monitoring Hydrogen Peroxide in COX-2-Positive Cancer Cells.

Hydrogen peroxide (H2O2), an important marker for oxidative stress, plays a vital role in cellular biological functions. Overproduction of H2O2 causes oxidative damage to cellular functions and promotes cancer and other neurodegenerative diseases. Also, cyclooxygenase-2 (COX-2) enzyme is known to be expressed in several cancer types and exerts multifaceted roles in carcinogenesis and resistance to cancer treatment. Hence, it is important to monitor the H2O2 concentration changes in the COX-2-expressing cancer cells. Herein, we have developed a molecular fluorescent ratiometric H2O2-responsive probe (NPDIN) composed of indomethacin (COX-2 inhibitor) conjugated with 1,8-napthalimide boronate ester as fluorescent reporter through a chemical linker. The probe was capable of imaging the endogenous H2O2 in COX-2 overexpressing cancer cell lines (A549, LoVo, HT29, and Caco-2). Further studies revealed the critical role of the indomethacin moiety in the cellular uptake behavior of NPDIN in COX-2-overexpressing cancer cells. Collectively, our results demonstrated NPDIN as a COX-2-positive cancer-targeting sensitive ratiometric fluorescent probe (I554/I398) for H2O2 imaging and showed its promising biological applications in the future.

Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy.

Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500-600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (PTUBDP) for tyrosinase-positive melanoma-targeted PDT. In light of our results, it exhibited an enhanced cytotoxic efficacy compared to BDP, a parallel PDT agent that absence of phenylthiourea unit. PTUBDP shows outstanding effects of increased oxidative stress by an enhanced cellular uptake of the tyrosinase positive melanoma cell line (B16F10). This work presents increased therapeutic efficacy through the combined therapeutic approach, enabling enhanced reactive oxygen species (ROS) generation as well as overcoming the critical limitations of melanoma.

Fluorescent Diagnostic Probes in Neurodegenerative Diseases.

Neurodegenerative diseases are debilitating disorders that feature progressive and selective loss of function or structure of anatomically or physiologically associated neuronal systems. Both chronic and acute neurodegenerative diseases are associated with high morbidity and mortality along with the death of neurons in different areas of the brain; moreover, there are few or no effective curative therapy options for treating these disorders. There is an urgent need to diagnose neurodegenerative disease as early as possible, and to distinguish between different disorders with overlapping symptoms that will help to decide the best clinical treatment. Recently, in neurodegenerative disease research, fluorescent-probe-mediated biomarker visualization techniques have been gaining increasing attention for the early diagnosis of neurodegenerative diseases. A survey of fluorescent probes for sensing and imaging biomarkers of neurodegenerative diseases is provided. These imaging probes are categorized based on the different potential biomarkers of various neurodegenerative diseases, and their advantages and disadvantages are discussed. Guides to develop new sensing strategies, recognition mechanisms, as well as the ideal features to further improve neurodegenerative disease fluorescence imaging are also explored.

Cancer stem cell-targeted bio-imaging and chemotherapeutic perspective.

Cancer stem cells (CSCs), also called tumor-initiating cells (TICs), have been studied intensively due to their rapid proliferation, migration, and role in the recurrence of cancer. In general, CSC marker-positive cells [CD133, CD44, CD166, aldehyde dehydrogenase (ALDH), and epithelial cell adhesion molecule (EpCAM)] exhibit a 100-fold increased capacity to initiate cancer. Within a heterogeneous tumor mass, only approximately 0.05-3% of cells are suspected to be CSCs and able to proliferate under hypoxia. Interestingly, CSCs, cancer cells, and normal stem cells share many cytochemical properties, such as inhibition of the redox system for reactive oxygen species (ROS) production and high expression of drug resistance transporters. However, compared to normal stem cells, CSCs develop unique metabolic flexibility, which involves switching between oxidative phosphorylation (OXPHOS) and glycolysis as their main source of energy. Due to the similarities between CSCs and other cancer cells and normal stem cells, limited chemotherapeutic and bio-imaging reagents specific for CSCs have been developed. In this short review, we address the current knowledge regarding CSCs with a focus on designing chemotherapeutic and bio-imaging reagents that target CSCs.

Nanomaterial designing strategies related to cell lysosome and their biomedical applications: A review.

Lysosomes, an important organelle of eukaryotic cells, are covered with the cell membrane and contain an array of degradative enzymes. The disrupt in lysosomal functions may lead to the development of severe diseases. In nanotechnology, nanomaterials working mechanism and its biomedical output are highly dependent on the lysosomes as it plays a crucial role in intracellular transport. Several nanomaterials specifically designed for lysosome-related actions are highly advantageous in trafficking and delivering the loaded imaging/therapeutic agents. But for other applications, especially gene-based therapeutic delivery into the sub-organelles such as mitochondria and nucleus, lysosomal related degradation could be an obstacle to achieve a maximal therapeutic index. In order to understand the relationship between lysosomes and designed nanomaterials for kind of desired application in biomedical research, complete knowledge of their various designing strategies, size dependent or ligand supportive cellular uptake mechanisms, trafficking, and localizations in eukaryotic cells is highly desired. In this review, we intended to discuss various nanomaterial types that have been applied in biomedical applications based on lysosomal internalization and escape from endo/lysosomes and explored their related advantages/disadvantages. Additionally, we also deliberated nanomaterials direct translocation mechanism, their autophagic accumulation and the underlying mechanism to induced autophagy. Finally, some challenges and critical issues in current research from clinical application perspective has also been addressed. Great understanding of these factors will help in understanding and facilitating the development of safe and effective lysosomal related nanomaterial-based imaging/therapeutic systems for future applications.

Binary Drug Reinforced First Small-Molecule-Based Prodrug for Synergistic Anticancer Effects.

We developed a small-molecule-based binary drug delivery system (BDDS) with two anticancer drugs, SN-38 and 5'-DFUR. The drug release from the prodrug BDDS can be achieved upon its reaction with intracellular H2O2, overexpressed in cancer cells. The efficacy of BDDS was demonstrated by a comparative study along with that of a single drug conjugate (SDDS), bearing SN-38 alone.

Stereoselective total synthesis of a novel regiomer of herbarumin I and its cytotoxic and antimicrobial activities.

Stereoselective synthesis of a novel regiomer of the natural nonenolide, herbarumin I has been accomplished. The synthesis involves the coupling of the alcohol and acid fragments of the molecule using Yamaguchi protocol followed by intramolecular ring closing metathesis. The cytotoxic and antimicrobial properties of the synthetic regiomer have been studied.