A GSH-Responsive Prodrug with Simultaneous Triple-Activation Capacity for Photodynamic/Sonodynamic Combination Therapy with Inhibited Skin Phototoxicity.

Herein, a dual-sensitizer prodrug, named pro-THPC, has been designed to function as both a photosensitizer and a sonosensitizer prodrug for precise antitumor combination therapy with minimized skin phototoxicity. Pro-THPC could be activated by glutathione (GSH) to release the dual-sensitizer, THPC, which simultaneously switches on fluorescence emission and combined capabilities of photodynamic therapy (PDT) and sonodynamic therapy (SDT). Pro-THPC is further formulated into nanoparticles (NPs) for water dispersity to enable in vivo applications. In vivo fluorescence imaging shows that the pro-THPC NPs group exhibits a significantly higher tumor-to-normal tissue ratio (T/N) (T/N = 5.2 ± 0.55) compared to the "always on" THPC NPs group (T/N = 2.9 ± 0.47) and the pro-THPC NPs group co-administrated with GSH synthesis inhibitor (buthionine sulfoximine, BSO) (T/N = 3.2 ± 0.63). In addition, the generation of the designed dual-sensitizer's reactive oxygen species (ROS) is effectively confined within the tumor tissues due to the relatively strong correlation between ROS generation and fluorescence emission. In vivo studies further demonstrate the remarkable efficacy of the designed pro-THPC NPs to eradicate tumors through the combination of PDT and SDT while significantly reducing skin phototoxicity.

Glutathione-depleting Liposome Adjuvant for Augmenting the Efficacy of a Glutathione Covalent Inhibitor Oridonin for Acute Myeloid Leukemia Therapy.

BACKGROUND: Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH. METHODS: We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets. RESULTS: We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells. CONCLUSION: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.

Small Molecule-Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs.

Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non-immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials.

GSH-activated Porphyrin Sonosensitizer Prodrug for Fluorescence Imaging-guided Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which uses ultrasound to trigger a sonosensitizer to generate reactive oxygen species (ROS), is a promising form of cancer therapy with outstanding tissue penetration depth. However, the sonosensitizer may inevitably spread to surrounding healthy tissue beyond the tumor, resulting in undesired side effects under an ultrasound stimulus. Herein, as glutathione (GSH) is overexpressed in the tumor microenvironment, a GSH-activatable sonosensitizer prodrug was designed by attaching a quencher to tetraphydroxy porphyrin for tumor therapy. The prodrug exhibited poor fluorescence and low ROS generation capacity under ultrasound irradiation but it can be activated by GSH to simultaneously switch on fluorescence emission and ROS generation in tumor site. Compared with the non-quenched sonosensitizer, the designed prodrug exhibited significantly higher tumor/healthy organ fluorescence ratios, due to the specific fluorescence and ROS activation by overexpressed GSH in the tumor. Finally, the prodrug exhibited efficient tumor growth inhibition under ultrasound irradiation, further demonstrating its promise as a GSH-activated sonosensitizer prodrug for highly effective cancer treatment.

A SPECT/NIR Fluorescence Dual-Modality Imaging Agent Composed of Drugs and Hospital Available Isotope for Preoperative Sentinel Lymph Node Mapping and Intraoperative Biopsy.

Background: Sentinel lymph node (SLN) mapping-guided biopsy is crucial for cancer staging and treatment. Optical/nuclide dual-modality imaging agents for mapping SLN are ideal for preoperative planning and intraoperative biopsy, which are enabled by penetration-depth unlimited nuclide imaging and dynamic real-time optical imaging, respectively. However, commonly reported dual-modality imaging agents are composed of novel but safety-unproven materials, making their quick clinical translation challenging. Herein, we report a novel nanoparticle composed of facile hospital-available drugs and isotope for single-photon emission computed tomography (SPECT)/near-infrared (NIR) fluorescence imaging to detect SLNs. Methods: Indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were synthesized by ICG-induced HSA self-assembly and further 99mTc-labeling via a one-step, facile hospital-available method. After injecting 99mTc-ICG-HSA into the rats' forepaw pads, the rats' draining axillary lymph nodes were visualized by preoperative mapping with SPECT/CT and intraoperative biopsy with NIR fluorescence. The axillary lymph nodes of rats were identified by pathology and fluorescent staining after execution. Additionally, its toxicity testing and comparison with 99mTc-sulfur colloid imaging were also explored. Results: The study reported a self-assembled 99mTc-ICG-HSA with a high radiochemical yield (85.6 ± 3.8%). Compared with conventional 99mTc-sulfur colloid, 99mTc-ICG-HSA NPs showed faster SLN identification, higher renal clearance, and lower hepatic retention. Furthermore, NIRF imaging allowed for the accurate visualization of the SLN and guided SLN biopsy intraoperatively. Notably, the 99mTc-ICG-HSA NPs were composed of hospital-available drugs and isotope, which are safe for acute toxicity evaluation by a certified institute. Conclusion: The proposed 99mTc-ICG-HSA NPs are safe and capable of noninvasive SLN identification and biopsy guidance with multi-modal imaging strategies and could be a promising tool for clinically assisted SLN biopsy.

A nanoparticle composed of totally hospital-available drugs and isotope for fluorescence/SPECT dual-modal imaging-guided photothermal therapy to inhibit tumor metastasis.

As primary sites of tumor metastasis, sentinel lymph nodes (SLNs) require a highly biocompatible theranostic platform for precise localization and treatment to inhibit tumor metastasis. Herein, indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were fabricated by ICG-induced self-assembly and radiolabeled with technetuim-99 m (99mTc). The fabricated NPs were composed of hospital-available drugs and isotopes, making them highly biocompatible for in vivo applications. In a mouse model of SLN metastasis, the prepared NPs exhibited excellent capacity for preoperative planning by single-photon emission computed tomography (SPECT) imaging-enabled SLN localization, near-infrared fluorescence (NIRF) imaging-enabled intraoperative real-time monitoring, and SLN photothermal treatment. Photothermal treatment with SLN enhanced the inhibition of lung metastasis and significantly increased the survival time of mice. The prepared NPs were highly biocompatible and exhibited efficient theranostic properties for inhibiting cancer metastasis, making them promising candidates for clinical translation.

Integrative analysis of metabolome and transcriptome reveals the mechanism of color formation in cassava (Manihot esculenta Crantz) leaves.

Cassava (Manihot esculenta Crantz) leaves are often used as vegetables in Africa. Anthocyanins possess antioxidant, anti-inflammatory, anti-cancer, and other biological activities. They are poor in green leaves but rich in the purple leaves of cassava. The mechanism of anthocyanin's accumulation in cassava is poorly understood. In this study, two cassava varieties, SC9 with green leaves and Ziyehuangxin with purple leaves (PL), were selected to perform an integrative analysis using metabolomics and transcriptomics. The metabolomic analysis indicated that the most significantly differential metabolites (SDMs) belong to anthocyanins and are highly accumulated in PL. The transcriptomic analysis revealed that differentially expressed genes (DEGs) are enriched in secondary metabolites biosynthesis. The analysis of the combination of metabolomics and transcriptomics showed that metabolite changes are associated with the gene expressions in the anthocyanin biosynthesis pathway. In addition, some transcription factors (TFs) may be involved in anthocyanin biosynthesis. To further investigate the correlation between anthocyanin accumulation and color formation in cassava leaves, the virus-induced gene silencing (VIGS) system was used. VIGS-MeANR silenced plant showed the altered phenotypes of cassava leaves, partially from green to purple color, resulting in a significant increase of the total anthocyanin content and reduction in the expression of MeANR. These results provide a theoretical basis for breeding cassava varieties with anthocyanin-rich leaves.

Correction: Facile synthesis of near-infrared bodipy by donor engineering for in vivo tumor targeted dual-modal imaging.

Correction for 'Facile synthesis of near-infrared bodipy by donor engineering for in vivo tumor targeted dual-modal imaging' by Feifei An et al., J. Mater. Chem. B, 2021, 9, 9308-9315, DOI: 10.1039/D1TB01883C.

19 F MRI Nanotheranostics for Cancer Management: Progress and Prospects.

Fluorine magnetic resonance imaging (19 F MRI) is a promising imaging technique for cancer diagnosis because of its excellent soft tissue resolution and deep tissue penetration, as well as the inherent high natural abundance, almost no endogenous interference, quantitative analysis, and wide chemical shift range of the 19 F nucleus. In recent years, scientists have synthesized various 19 F MRI contrast agents. By further integrating a wide variety of nanomaterials and cutting-edge construction strategies, magnetically equivalent 19 F atoms are super-loaded and maintain satisfactory relaxation efficiency to obtain high-intensity 19 F MRI signals. In this review, the nuclear magnetic resonance principle underlying 19 F MRI is first described. Then, the construction and performance of various fluorinated contrast agents are summarized. Finally, challenges and future prospects regarding the clinical translation of 19 F MRI nanoprobes are considered. This review will provide strategic guidance and panoramic expectations for designing new cancer theranostic regimens and realizing their clinical translation.

Facile synthesis of near-infrared bodipy by donor engineering for in vivo tumor targeted dual-modal imaging.

Bodipy is one of the most popular dyes for bioimaging, however, a complicated synthetic protocol is needed to create and isolate ideal near-infrared (NIR) emissive Bodipy derivatives for optical bioimaging. It is noticed that the donor species impact the wavelength when the π-conjugation system of green light emissive Bodipy is elongated via a one-step reaction. Herein, several Bodipy dyes bearing different common donors are synthesized. Their optical properties confirm that both absorption and emission peaks of the synthesized Bodipy could be tuned to NIR wavelength by using stronger donors via a facile reaction. The synthesized monocarboxyl Bodipy could conjugate with aminated PEG to yield an amphiphilic polymer, which further self-assembles into a NIR nanoparticle (NP). The NIR NP exhibits preferential tumor accumulation via the enhanced permeation and retention (EPR) effect, making it useful for tumor diagnosis by both fluorescence imaging and photoacoustic tomography.

Combining histone deacetylase inhibitors (HDACis) with other therapies for cancer therapy.

Histone deacetylases (HDACs) play an important role in regulating the expression of genes involved in tumorigenesis and tumor maintenance, and hence they have been considered as key targets in cancer therapy. As a novel category of antitumor agents, histone deacetylase inhibitors (HDACis) can induce cell cycle arrest, apoptosis, and differentiation in cancer cells, ultimately combating cancer. Although in the United States, the use of HDACis for the treatment of certain cancers has been approved, the therapeutic efficacy of HDACis as a single therapeutic agent in solid tumorshas been unsatisfactory and drug resistance may yet occur. To enhance therapeutic efficacy and limit drug resistance, numerous combination therapies involving HDACis in synergy with other antitumor therapies have been studied. In this review, we describe the classification of HDACs. Moreover, we summarize the antitumor mechanism of the HDACis for targeting key cellular processes of cancers (cell cycle, apoptosis, angiogenesis, DNA repair, and immune response). In addition, we outline the major developments of other antitumor therapies in combination with HDACis, including chemotherapy, radiotherapy, phototherapy, targeted therapy, and immunotherapy. Finally, we discuss the current state and challenges of HDACis-drugs combinations in future clinical studies, with the aim of optimizing the antitumor effect of such combinations.

Protease-triggered bioresponsive drug delivery for the targeted theranostics of malignancy.

Proteases have a fundamental role in maintaining physiological homeostasis, but their dysregulation results in severe activity imbalance and pathological conditions, including cancer onset, progression, invasion, and metastasis. This striking importance plus superior biological recognition and catalytic performance of proteases, combining with the excellent physicochemical characteristics of nanomaterials, results in enzyme-activated nano-drug delivery systems (nanoDDS) that perform theranostic functions in highly specific response to the tumor phenotype stimulus. In the tutorial review, the key advances of protease-responsive nanoDDS in the specific diagnosis and targeted treatment for malignancies are emphatically classified according to the effector biomolecule types, on the premise of summarizing the structure and function of each protease. Subsequently, the incomplete matching and recognition between enzyme and substrate, structural design complexity, volume production, and toxicological issues related to the nanocomposites are highlighted to clarify the direction of efforts in nanotheranostics. This will facilitate the promotion of nanotechnology in the management of malignant tumors.

Self-Assembly of an Antitumor Dipeptide Induced Near-Infrared Fluorescence and Improved Stability for Theranostic Applications.

It has been found that the self-assembly of nonfluorescent peptides can generate fluorescent peptide nanoparticles (f-PNPs) to perform multiple functions, including drug delivery and imaging and tracking therapeutic agents. Both pharmacologically inactive peptides and tumor-targeting peptides have been explored to construct biocompatible f-PNPs; however, the application of this technology in delivering antitumor peptides has never been reported. Herein, the self-assembly of an antitumor dipeptide, carnosine, into fluorescent carnosine nanoparticles (f-Car NPs) in the presence of zinc ions is demonstrated. The generated f-Car NPs exhibit fluorescence in the visible and near-infrared (NIR) ranges for fluorescence tracing in vitro and in vivo. On the other hand, the f-Car NPs minimize the contact between the dipeptide and the serum, which overcomes the dipeptide instability resulted from inefficient antitumor activity. In addition, the preparation of f-Car NPs does not introduce extra carrier materials, so the f-Car NPs exhibit biocompatibility to normal fibroblast cells in vitro and negligible toxicity against major organs in vivo. This study provides a new peptide drug delivery strategy with NIR fluorescence tracing ability.

Chemodynamic nanomaterials for cancer theranostics.

It is of utmost urgency to achieve effective and safe anticancer treatment with the increasing mortality rate of cancer. Novel anticancer drugs and strategies need to be designed for enhanced therapeutic efficacy. Fenton- and Fenton-like reaction-based chemodynamic therapy (CDT) are new strategies to enhance anticancer efficacy due to their capacity to generate reactive oxygen species (ROS) and oxygen (O2). On the one hand, the generated ROS can damage the cancer cells directly. On the other hand, the generated O2 can relieve the hypoxic condition in the tumor microenvironment (TME) which hinders efficient photodynamic therapy, radiotherapy, etc. Therefore, CDT can be used together with many other therapeutic strategies for synergistically enhanced combination therapy. The antitumor applications of Fenton- and Fenton-like reaction-based nanomaterials will be discussed in this review, including: (iþ) producing abundant ROS in-situ to kill cancer cells directly, (ii) enhancing therapeutic efficiency indirectly by Fenton reaction-mediated combination therapy, (iii) diagnosis and monitoring of cancer therapy. These strategies exhibit the potential of CDT-based nanomaterials for efficient cancer therapy.

Recent Advances in Paclitaxel-based Self-Delivery Nanomedicine for Cancer Therapy.

Paclitaxel (PTX) is the first natural plant-derived chemotherapeutic drug approved by the Food and Drug Administration. However, the clinical applications of PTX are limited by some drawbacks, such as poor water solubility, rapid blood clearance, nonspecific distribution, and adverse side effects. Nanocarriers have made important contributions to drug delivery and cancer therapy in recent years. However, low drug loading capacity, nanocarrier excipients-induced toxicity or immunogenicity, and complicated synthesis technologies pose a challenge for the clinical application of nanocarriers. To address these issues, the self-delivery nanomedicine (SDNs), in which pure drug molecules directly self-assemble into nanomedicine, have been developed for drug delivery and enhancing antitumor efficacy. In this review, we comprehensively summarize the recent advances in PTX-based SDNs for cancer therapy. First, the self-assembly strategies to develop pure PTX nanodrugs are discussed. Then, the emerging strategies of co-assembly PTX and other therapeutic agents for effective combination therapy are presented, composing of combination chemotherapy, chemo-photothermal therapy, chemo-photodynamic therapy, chemo-immunotherapy, and chemo-gene therapy. Finally, the limitations and future outlook of SDNs are discussed. The rational design of these unique nanoplatforms may make a new direction to develop highly efficient drug delivery systems for cancer therapy.

One-Step, Rapid, 18F-19F Isotopic Exchange Radiolabeling of Difluoro-dioxaborinins: Substituent Effect on Stability and In Vivo Applications.

The ß-diketone moiety is commonly present in many anticancer drugs, antibiotics, and natural products. We describe a general method for radiolabeling ß-diketone-bearing molecules with fluoride-18. Radiolabeling was carried out via 18F-19F isotopic exchange on nonradioactive difluoro-dioxaborinins, which were generated by minimally modifying the ß-diketone as a difluoroborate. Radiochemistry was one-step, rapid (<10 min), and high-yielding (>80%) and proceeded at room temperature to accommodate the half-life of F-18 (t1/2 = 110 min). High molar activities (7.4 Ci/µmol) were achieved with relatively low starting activities (16.4 mCi). It was found that substituents affected both the solvolytic stability and fluorescence properties of difluoro-dioxaborinins. An F-18 radiolabeled difluoro-dioxaborinin probe that was simultaneously fluorescent showed sufficient stability for in vivo positron emission tomography (PET)/fluorescence imaging in mice, rabbits, and patients. These findings will guide the design of probes with specific PET/fluorescence properties; the development of new PET/fluorescence dual-modality reporters; and accurate in vivo tracking of ß-diketone molecules.

Magnetic resonance imaging-guided and targeted theranostics of colorectal cancer.

Colorectal cancer (CRC) is the most common gastrointestinal tract cancer worldwide and is associated with high morbidity and mortality. The development of nanosized drug delivery systems has provided a new direction in CRC treatment. Among these systems, magnetic nanoparticle (MNP)-based multifunctional platforms provide a novel strategy for magnetic resonance imaging (MRI)-related cancer theranostics. At the beginning of this original review, the carcinogenesis and treatment status of CRC are summarized. Then, diversified preparation and functionalization methods of MNPs are systematically analyzed, followed by MRI-involved theranostic strategies. The latest progress in MRI-mediated multimode diagnosis and image-guided targeted therapy in CRC management is the main focus. Finally, the major challenges in promoting MRI-induced precise theranostics of CRC in clinical practice are discussed.

Hypoxia-activated nanomedicines for effective cancer therapy.

Hypoxia, a common characteristic in solid tumors, is found in phenotypically aggressive cancers that display resistance to typical cancer interventions. Due to its important role in tumor progression, tumor hypoxia has been considered as a primary target for cancer diagnosis and treatment. An advantage of hypoxia-activated nanomedicines is that they are inactive in normoxic cells. In hypoxic tumor tissues and cells, these nanomedicines undergo reduction by activated enzymes (usually through 1 or 2 electron oxidoreductases) to produce cytotoxic substances. In this review, we will focus on approaches to design nanomedicines that take advantage of tumor hypoxia. These approaches include: i) inhibitors of hypoxia-associated signaling pathways; ii) prodrugs activated by hypoxia; iii) nanocarriers responsive to hypoxia, and iv) bacteria mediated hypoxia targeting therapy. These strategies have guided and will continue to guide nanoparticle design in the near future. These strategies have the potential to overcome tumor heterogeneity to improve the efficiency of radiotherapy, chemotherapy and diagnosis.

A lysosome specific, acidic-pH activated, near-infrared Bodipy fluorescent probe for noninvasive, long-term, in vivo tumor imaging.

Long-term, in vivo, fluorescent cell tracking probes are useful for understanding complex cellular processes including tissue regeneration, communication, development, invasion, and cancer metastasis. A near-infrared fluorescent, water-soluble probe is particularly important for studying these biological events and processes. Herein, a lysosome specific, near-infrared Bodipy probe with increased fluorescent intensity in the acidic, lysosome environment is reported. This Bodipy probe is packaged in a nanoparticle using DSPE-PEG2000. The resulting nanoparticle is intravenously delivered to a tumor xenograft, where the fluorescent Bodipy becomes useful for non-invasive, long-term, in vivo fluorescent tumor imaging for periods greater than 36 days. These long-term, in vitro and in vitro tracking data indicate that the described Bodipy nanoparticles hold great potential for monitoring biological processes.