Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address ...these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
The Hippo tumor suppressor pathway is critical for balancing cellular differentiation and proliferation in response to cell-cell contact, mechanical signals and diffusible signals such as ...lysophosphatidic acid. Hippo pathway signaling is frequently dysregulated in gastric cancer (GC), as well as many other kinds of solid tumors, contributing to multiple aspects of malignant progression including unchecked cell division and metastasis. Considering the importance of this Hippo pathway in cancer, its pharmacological disruption may be of huge benefit in the fight against this disease. In this review, we summarize the components of the Hippo pathway, its crosstalk with other major oncogenic signaling pathways, common mechanisms of its dysregulation, as well as potential therapeutic approaches of targeting this pathway for cancer treatment, specifically in a GC context.
•This review highlighted the clinical significance of Hippo pathway in gastric cancer from the aspects of functions and mechanisms of dysregulation.•This review summarized the interplay between Hippo pathway and H. pylori infection, one of the strongest risk factors for gastric cancer.•This review conducted a comprehensive discussion regarding advances for targeting Hippo pathway for the treatment of cancer, including gastric cancer.
Ruthenium complexes have attracted a surge of interest as anticancer drug candidates because of their low toxicity, diversity in mode-of-actions and non-cross drug resistance with conventional ...platinum-based agents. Despite remarkable advances, only a limited number of ruthenium complexes have been demonstrated to kill cancer cells and suppress metastasis simultaneously. Here, two organometallic tetranuclear Ru(II) arene complexes (Ru-1 and Ru-2) have been synthesized and evaluated for their in vitro activity against a panel of human cancer cell lines, including a cisplatin-resistant human lung cancer A549 cell line. A superior cytotoxic activity of the ruthenium complexes compared to cisplatin across distinct cell lines was observed. Further examination of the mechanism indicated that anticancer activity was accomplished by inducing apoptosis in cancer cells. In addition, we found that such compounds exhibited promising antimetastatic activity and reduced the invasiveness of cancer cells. Importantly, choosing Ru-1 as a target compound, a significantly enhanced safety profile relative to cisplatin in animals was validated, suggesting that these complexes can be used as promising candidates for cancer therapy and deserve further investigation.
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•Tetranuclear Ru(II) arene complexes coordinating hydrazone groups were synthesized and characterized by spectral and analytical techniques.•The Ru-1 and Ru-2 complexes displayed higher cytotoxicity than cisplatin in human cancer cell lines.•The complexes showed antimetastatic activity, reducing the invasiveness of cancer cells.•Remarkable alleviation of systemic toxicity using the complex Ru-1 was validated, displaying an enhancement of drug tolerability relative to cisplatin in animals.
Cancer remains one of the world's leading causes of death. However, most conventional chemotherapeutic drugs only show a narrow therapeutic window in patients because of their inability to ...discriminate cancer cells from healthy cells. Nanoparticle‐based therapeutics (termed nanotherapeutics) have emerged as potential solutions to mitigate many obstacles posed by these free drugs. Deep insights into knowledge of the tumor microenvironment and materials science make it possible to construct nanotherapeutics that are able to release cargoes in response to a variety of internal stimuli and external triggers. Therefore, such highly sophisticated nanosystems could help impede the premature release of toxic drugs in the blood circulation or healthy tissues, thus enhancing the safety profiles of encapsulated drugs. In this context, this review offers a comprehensive overview of several specific stimuli, including internal stimuli (e.g., pH, temperature, enzyme, redox, and H2O2) and external stimuli (e.g., magnetic, photo, and ultrasound). We envision that applications of these smart nanotherapeutics can benefit cancer patients and provide a good chance for clinical translation of many nanoparticle formulas.
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Diagnostic Tools > Diagnostic Nanodevices
Diagnostic Tools > in vitro Nanoparticle‐Based Sensing
Nanotherapeutics have emerged as potential solutions to fulfill the promise of Paul Ehrlich's magic bullet concept. This review offers a comprehensive overview of the construction of nanotherapeutics that are able to precisely release drug cargoes in response to a variety of internal stimuli and external triggers. The applications of these smart systems can benefit cancer patients and provide a good chance for clinical translation of many nanoparticle formulas.
The often immune-suppressive tumor microenvironment (TME) may hinder immune evasion and response to checkpoint blockade therapies. Pharmacological activation of the STING pathway does create an ...immunologically hot TME, however, systemic delivery might lead to undesired off-target inflammatory responses. Here, we generate a small panel of esterase-activatable pro-drugs based on the structure of the non-nucleotide STING agonist MSA-2 that are subsequently stably incorporated into a liposomal vesicle for intravenous administration. The pharmacokinetic properties and immune stimulatory capacity of pro-drugs delivered via liposomes (SAProsomes) are enhanced compared to the free drug form. By performing efficacy screening among the SAProsomes incorporating different pro-drugs in syngeneic mouse tumor models, we find that superior therapeutic performance relies on improved delivery to the desired tumor and lymphoid compartments. The best candidate, SAProsome-3, highly stimulates secretion of inflammatory cytokines and creates a tumoricidal immune landscape. Notably, upon application to breast cancer or melanoma mouse models, SAProsome-3 elicits durable remission of established tumors and postsurgical tumor-free survival while decreasing metastatic burden without significant systemic toxicity. In summary, our work establishes the proof of principle for a better targeted and more efficient and safe STING agonist therapy.
Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2H-1,4-oxazines are obtained in moderate yields probably involving ...generation of α-imino rhodium(II) carbene species.
There is an urgent need for more effective, less toxic cancer therapy agents. Motivated by this need, we synthesized a small panel of N-heterocyclic carbene (NHC)-coordinated ruthenium(II) arene ...complexes Ru1–Ru6 with the formula Ru(p-cymene)(L)ClPF6 (L = NHC ligand with varying substituents). Cell-based in vitro studies revealed that despite the structural similarity, Ru1–Ru6 exhibited distinct cytotoxic activities against cancer cells. In particular, Ru4 and Ru6, which bear n-octyl and pentamethylbenzyl motifs, respectively, were the most active at inducing apoptosis. In human ovarian A2780 cancer cells, Ru4 and Ru6 showed the highest cytotoxicities with IC50 values of 2.74 ± 0.15 μM and 1.98 ± 0.10 μM, respectively, and they were approximately 2-fold more potent than cisplatin (IC50 = 5.55 ± 0.37 μM). In addition to the cell killing capacity, inhibition of cell migration was validated by using these two optimized complexes. Mechanistic studies revealed that Ru4 and Ru6 complexes induced apoptosis in a caspase-dependent manner, primarily through intracellular reactive oxygen species (ROS) overproduction and cell cycle arrest at G1 phase. Furthermore, in a preclinical metastatic model of A2780 tumor xenograft, administration of Ru4 and Ru6 (20 μmol/kg) resulted in a marked inhibition of tumor progression and metastasis. Finally, a substantially alleviated systemic toxicity was observed for both complexes in comparison with cisplatin in animals. Overall, this study greatly increases our understanding of NHC-coordinated Ru(II) arene metallodrugs, aiding further investigation of their therapeutic potential in the treatment of metastatic cancers.
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•New ruthenium(II) arene complexes bearing N-heterocyclic carbene ligands were synthesized.•Ru4 with n-octyl and Ru6 with pentamethylbenzyl were identified to be the most active at inducing apoptosis.•Treatment with Ru4 and Ru6 reduced tumor progression and metastasis in a preclinical mouse model.•The toxicity of Ru4 and Ru6 was alleviated relative to the same doses of cisplatin in animals.
The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing ...this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound
retained high antiproliferative activity. SNM assembled with compound
displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared with free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacologic efficacy while improving its safety profile.
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Intramolecular sp(3) C-H insertion reaction of α-imino rhodium carbene generated from N-sulfonyl-1,2,3-triazoles has been described. A number of 2,3-dihydrobenzofuran and benzofuran derivatives have ...been obtained in good to excellent yields.
Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous ...administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic.
