Cancer Targeted Enzymatic Theranostic Prodrug: Precise Diagnosis and Chemotherapy.

UNLABELLED: The development of targeted and effective theranostic (therapeutic and diagnostic) chemotherapeutic agents is highly desirable for precise diagnosis and treatment of cancer. To realize this goal, we developed a cancer-targeting and enzyme-triggered theranostic prodrug 1, containing 7-ethyl-10-hydroxycamptothecin (SN-38), a well-known anticancer drug, which inhibits topoisomerase I in the cell nucleus; hydroquinone as an enzyme-triggered moiety; and biotin as a cancer targeting unit. Enzyme-triggered theranostic prodrug 1 selectively targets cancer cells and is subsequently activated in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), a cytosolic flavoprotein that catalyzes the two-electron reduction of quinone moieties with the concomitant consumption of NADH or NADPH as electron donors. High levels of NQO1 were found in a variety of cancer cell lines compared to healthy cells, and therefore, it is an excellent target for the development of cancer targeted drug delivery systems. Upon preferential cancer cell delivery and uptake, aided by biotin, the enzyme-triggered theranostic prodrug 1 is cleaved by NQO1, with the subsequent release of SN-38, inhibiting topoisomerase I, leading to apoptosis. The drug release and induced apoptosis of cancer cells expressing both biotin receptors and high levels of NQO1 was simultaneously monitored via the innate fluorescence of the released SN-38 by confocal microscopy. In vitro and in vivo studies showed an effective inhibition of cancer growth by the enzyme-triggered theranostic prodrug 1. Thus, this type of enzyme-triggered targeted prodrug therapy is an interesting and promising approach for future cancer treatment.

Small conjugate-based theranostic agents: an encouraging approach for cancer therapy.

The advances in genomics, proteomics, and bioinformatics have directed the development of new anticancer agents to reduce drug abuse and increase safe and specific drug treatment. Theranostics, combining therapy and diagnosis, is an appealing approach for chemotherapy in medicine which exhibits improved biodistribution, selective cancer targeting ability, reduced toxicity, masked drug efficacy, and minimum side effects. The role of diagnosis tools in theranostics is to collect the information of the diseased state before and after specific treatment. Magnetic particle-, mesoporous silica-, various carbon allotrope-, and polymer nanoparticle-based theranostic systems are well accepted and clinically significant. Currently, small conjugate-based systems have received much attention for cancer treatment and diagnosis. The structural architecture of these systems is relatively simple, compact, biocompatible, and unidirectional. In this tutorial review, we summarize the latest developments on small conjugate based theranostic agents for tumor treatment and diagnosis using fluorescence and magnetic resonance imaging (MRI).

Targeted combinational therapy inducing mitochondrial dysfunction.

We report on a mitochondria-specific combinational theranostic agent, 1. This system contains a chlorambucil prodrug and an aggregation induced emission dye. In addition, compound 1 bears both an intracellular thiol-triggered moiety and a mitochondria targeting unit (triphenylphosphonium). Glutathione (GSH) is the most abundant thiol and its concentrations are significantly higher in a great number of cancer cell lines, compared to normal cells. The GSH-induced prodrug 1 upon activation releases chlorambucil and exhibits mitochondria targeted aggregation induced emission (AIE) fluorescence, resulting in cell apoptosis via the caspase pathway due to mitochondrial dysfunction.

Selective molecular recognition on calixarene-functionalized 3D surfaces.

Host-guest recognition plays an important role in biological analysis and biosensing. Accordingly, great efforts have been devoted to the development of sensors using versatile 3D surface materials. These functionalized nanomaterials possess the advantages of high selectivity and visual signals, enabling the selective detection of ions, amino acids, proteins, and other biological molecules. Therefore, in this feature article, we present some significant and representative examples of molecular recognition on calixarene functionalized 3D surface nanomaterials. By virtue of host-guest interactions, the functional interfaces displaying high selectivity and featuring a reversible switch response towards the environmental stimuli with various signal output (electrochemical and optical signals) are herein introduced. Furthermore, various 3D surface materials with unique signal amplification in molecular recognition are presented, including quantum dots (QDs), metal nanoparticles (NPs), nanotubes, and mesoporous silica. These excellent properties enable calixarene-functionalized 3D materials to become an outstanding platform for molecular recognition, offering convenient approaches for sensing and separation.

Mitochondria-targeted aggregation induced emission theranostics: crucial importance of in situ activation.

Tissue selective targeting and specific suborganellular localization combined with an efficient pathology associated enzymatic activation of drugs in drug delivery systems may exhibit a clear advantage over conventional cancer treatment. Here, a mitochondria targeted aggregation induced emission (AIE) fluorophore further conjugated with an NAD(P)H:quinone oxidoreductase-1 (NQO1) cleavable masking unit showed preferential uptake in cancer cells and was selectively activated, resulting in bright AIE fluorescence and apoptosis via the caspase pathway, triggered by mitochondrial dysfunction. In vivo experimental data further support the conclusions from in vitro experiments, clearly showing the dependence of the therapy's success on both the suborganelle localization and specific in situ activation. And the site specific and enzyme dependent activation and aggregation was further supported by in vivo and ex vivo imaging. As a whole, the data comprised in this work represent a strong argument for the further development of this type of novel anticancer drugs.

Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor.

We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro and in vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic ("phototheranostic").

In Vivo Tracking of Phagocytic Immune Cells Using a Dual Imaging Probe with Gadolinium-Enhanced MRI and Near-Infrared Fluorescence.

A novel dual imaging probe for in vivo magnetic resonance imaging (MRI) and optical imaging was developed by combining gadolinium (Gd)-chelating MR probe and a near-infrared (NIR) fluorophore, aza-BODIPY (AB; BODIPY = boron-dipyrromethene). This aza-BODIPY-based bimodal contrast agent (AB-BCA) showed a significant fluorescence emission around the NIR range and an enhanced longitudinal relaxivity in MR modality. The probe was easily delivered to phagocytic cells of the innate immune system, together with macrophages and dendritic cells (DCs), and presented high-performance fluorescence and MR imaging without obvious cytotoxicity. For in vivo visualization of AB-BCA using MRI and optical imaging, bone marrow-derived DCs were labeled and injected into the footpad of mice, and labeled DCs were tracked in vivo. We observed the migration of AB-BCA-labeled DCs into the lymph nodes via lymphatic vessels using NIR fluorescence and T1-weighted MR images. This dual-modality imaging probe was used for noninvasive monitoring of DC migration into lymph nodes and could be useful for investigating advanced cellular immunotherapy.

Hypoxia-directed and activated theranostic agent: Imaging and treatment of solid tumor.

Hypoxia, a distinguished feature of various solid tumors, has been considered as a key marker for tumor progression. Inadequate vasculature and high interstitial pressures result in relatively poor drug delivery to these tumors. Herein, we developed an antitumor theranostic agent, 4, which is activated in hypoxic conditions and can be used for the diagnosis and treatment of solid tumors. Compound 4, bearing biotin, a tumor-targeting unit, and SN38, an anticancer drug, proved to be an effective theranostic agent for solid tumors. SN38 plays a dual role: as an anticancer drug for therapy and as a fluorophore for diagnosis, thus avoids an extra fluorophore and limits cytotoxicity. Compound 4, activated in the hypoxic environment, showed high therapeutic activity in A549 and HeLa cells and spheroids. In vivo imaging of solid tumors confirmed the tumor-specific localization, deep tissue penetration and activation of compound 4, as well as the production of a strong anticancer effect through the inhibition of tumor growth in a xenograft mouse model validating it as a promising strategy for the treatment of solid tumors.