Potential for cardiac toxicity with methylimidazolium ionic liquids.

Methylimidazolium ionic liquids (MILs) are solvent chemicals used in industry. Recent work suggests that MILs are beginning to contaminate the environment and lead to exposure in the general population. In this study, the potential for MILs to cause cardiac toxicity has been examined. The effects of 5 chloride MIL salts possessing increasing alkyl chain lengths (2 C, EMI; 4 C, BMI; 6 C; HMI, 8 C, M8OI; 10 C, DMI) on rat neonatal cardiomyocyte beat rate, beat amplitude and cell survival were initially examined. Increasing alkyl chain length resulted in increasing adverse effects, with effects seen at 10-5 M at all endpoints with M8OI and DMI, the lowest concentration tested. A limited sub-acute toxicity study in rats identified potential cardiotoxic effects with longer chain MILs (HMI, M8OI and DMI) based on clinical chemistry. A 5 month oral/drinking water study with these MILs confirmed cardiotoxicity based on histopathology and clinical chemistry endpoints. Since previous studies in mice did not identify the heart as a target organ, the likely cause of the species difference was investigated. qRT-PCR and Western blotting identified a marked higher expression of p-glycoprotein-3 (also known as ABCB4 or MDR2) and the breast cancer related protein transporter BCRP (also known as ABCG2) in mouse, compared to rat heart. Addition of the BCRP inhibitor Ko143 - but not the p-glycoproteins inhibitor cyclosporin A - increased mouse cardiomyocyte HL-1 cell sensitivity to longer chain MILs to a limited extent. MILs therefore have a potential for cardiotoxicity in rats. Mice may be less sensitive to cardiotoxicity from MILs due in part, to increased excretion via higher levels of cardiac BCRP expression and/or function. MILs alone, therefore may represent a hazard in man in the future, particularly if use levels increase. The impact that MILs exposure has on sensitivity to cardiotoxic drugs, heart disease and other chronic diseases is unknown.

Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction.

Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodelling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodelling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodelling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodelling by spreading senescence to other cell-types. Collectively this study presents the demonstration that senescent cardiomyocytes are major contributors to myocardial remodelling and dysfunction following a myocardial infarction. Therefore, to maximise the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimise senolytic strategies to target this cell lineage.

Baseline blood pressure and development of cardiotoxicity in patients treated with anthracyclines: A systematic review.

Aims: Anthracyclines, a mainstay of cancer treatment, are associated with significant life-threatening cardiotoxicity. As cancer survivorship improves, there is a growing need to identify patients most at risk and strategies to mitigate anthracycline-associated cardiotoxicity. Elevated baseline blood pressure (bBP) is a possible risk factor for cardiotoxicity. The aim of this systematic review was to summarise the literature and evaluate relationships between bBP and anthracycline-associated cardiotoxicity. Methods and results: Systematic searches were conducted, limited to English language but without restrictions on study type or country of origin. All studies fulfilled the PRISMA statement and relevant studies reviewed and narratively synthesised. A total of 1330 papers were screened, with 12 included in the qualitative synthesis. Eight papers indicated elevated bBP was associated with significantly higher risk of developing cardiotoxicity. Four papers noted significant relationships between left ventricular ejection fraction (LVEF) decline and elevated bBP. Of the four papers that failed to show an association, one noted increased risk of developing chronic heart failure. A relationship between baseline diastolic and systolic BP and anthracycline-associated cardiotoxicity is also noted. Conclusions: This study indicates adult patients with elevated bBP have increased vulnerability to anthracycline-associated cardiotoxicity, with those with pre-hypertension or raised systolic versus diastolic pressure potentially an overlooked population. Recommendations for inclusion of bBP, incorporating individual systolic versus diastolic pressures, in cardio-oncology risk prediction models to guide clinical decision-making are thus warranted.

Anthracycline-induced cardiotoxicity and senescence.

Cancer continues to place a heavy burden on healthcare systems around the world. Although cancer survivorship continues to improve, cardiotoxicity leading to cardiomyopathy and heart failure as a consequence of cancer therapy is rising, and yesterday's cancer survivors are fast becoming today's heart failure patients. Although the mechanisms driving cardiotoxicity are complex, cellular senescence is gaining attention as a major contributor to chemotherapy-induced cardiotoxicity and, therefore, may also represent a novel therapeutic target to prevent this disease. Cellular senescence is a well-recognized response to clinical doses of chemotherapies, including anthracyclines, and is defined by cell cycle exit, phenotypic alterations which include mitochondrial dysfunction, and the expression of the pro-senescent, pro-fibrotic, and pro-inflammatory senescence-associated phenotype. Senescence has an established involvement in promoting myocardial remodeling during aging, and studies have demonstrated that the elimination of senescence can attenuate the pathophysiology of several cardiovascular diseases. Most recently, pharmacology-mediated elimination of senescence, using a class of drugs termed senolytics, has been demonstrated to prevent myocardial dysfunction in preclinical models of chemotherapy-induced cardiotoxicity. In this review, we will discuss the evidence that anthracycline-induced senescence causes the long-term cardiotoxicity of anticancer chemotherapies, consider how the senescent phenotype may promote myocardial dysfunction, and examine the exciting possibility that targeting senescence may prove a therapeutic strategy to prevent or even reverse chemotherapy-induced cardiac dysfunction.

Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach.

Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection, particularly drug-resistant strains, are urgently required to tackle the global burden of this disease. Herein, we reported the synthesis of a novel series of N-substituted amino acid hydrazides, utilising a scaffold hopping approach within a library of anti-tubercular agents. Efficacy and selectivity were evaluated against three strains of Mtb (wild-type, isoniazid-resistant and rifampicin-resistant), and cytotoxicity against macrophages in vitro. The antibacterial activity and therapeutic index of these molecules were significantly affected by modifications with the N-substituents. Introduction of a 3,5-dinitroaryl moiety demonstrated enhanced antibacterial activity against all three strains of Mtb. In contrast, the inclusion of an imidazo [1,2-a]pyridine-3-carboxy moiety resulted in enhanced activity towards isoniazid mono-resistant Mtb relative to wild-type Mtb. Consequently, this scaffold hopping approach showed significant promise for exemplification of novel molecules with specific activity profiles against drug-resistant tuberculosis.

Trichostatin A blocks aldosterone-induced Na+ transport and control of serum- and glucocorticoid-inducible kinase 1 in cortical collecting duct cells.

BACKGROUND AND PURPOSE: Aldosterone stimulates epithelial Na+ channel (ENaC)-dependent Na+ retention in the cortical collecting duct (CCD) of the kidney by activating mineralocorticoid receptors that promote expression of serum and glucocorticoid-inducible kinase 1 (SGK1). This response is critical to BP homeostasis. It has previously been suggested that inhibiting lysine deacetylases (KDACs) can post-transcriptionally disrupt this response by promoting acetylation of the mineralocorticoid receptor. The present study critically evaluates this hypothesis. EXPERIMENTAL APPROACH: Electrometric and molecular methods were used to define the effects of a pan-KDAC inhibitor, trichostatin A, on the responses to a physiologically relevant concentration of aldosterone (3 nM) in murine mCCDcl1 cells. KEY RESULTS: Aldosterone augmented ENaC-induced Na+ absorption and increased SGK1 activity and abundance, as expected. In the presence of trichostatin A, these responses were suppressed. Trichostatin A-induced inhibition of KDAC was confirmed by increased acetylation of histone H3, H4, and α-tubulin. Trichostatin A did not block the electrometric response to insulin, a hormone that activates SGK1 independently of increased transcription, indicating that trichostatin A has no direct effect upon the SGK1/ENaC pathway. CONCLUSIONS AND IMPLICATIONS: Inhibition of lysine de-acetylation suppresses aldosterone-dependent control over the SGK1-ENaC pathway but does not perturb post-transcriptional signalling, providing a physiological basis for the anti-hypertensive action of KDAC inhibition seen in vivo.

Collaboration, competition and publication in toxicology: views of British Toxicology Society members.

To ascertain attitudes to resourcing, collaboration and publication in toxicology, a survey was developed and distributed to British Toxicology Society (BTS) members. The survey comprised 14 questions with 5 response options (strongly agree; agree; conflicted; disagree; strongly disagree) and a free text box. One hundred completed surveys were received by the cut-off date for data analysis. Unsurprisingly, 60% of participants disagreed or strongly disagreed that toxicology research is adequately funded in the UK; only 12% agreed with this statement. A similar proportion of participants (53%) disagreed with the statement that funding councils give equal opportunity to toxicology whereas 31% were conflicted on this point. An overwhelming 97% of respondents agreed that collaboration is important in driving toxicology research whereas only 38% agreed that competition is important. When this question was broadened out beyond the discipline of toxicology, a similar profile was seen suggesting that participants held similar views on toxicology versus other types of research. Many respondents were conflicted regarding the role of competition both in toxicology and in other research disciplines. Free text comments suggested that some competition is good to drive quality but can be counterproductive when competing for limited resources. Most participants were in favour of making toxicology research data openly available (86%) and in favour of open access publication (89%) although there were reservations about the cost of open access. Many (60%) thought the current system of peer review is fair but 65% also supported the idea of double-blind peer review (where both reviewer and author are anonymized). Others suggested a step in the opposite direction towards increased transparency (revealing and holding reviewers to account) would be preferable. Overall, there was a broad theme in free text responses that the need for experienced toxicologists has increased at a time when training and investment in the discipline has declined. However, not all respondents held that view with some noting that toxicology both as a research and as an applied discipline is strong within the UK scientific community.

Vascular Disrupting Agents in cancer treatment: Cardiovascular toxicity and implications for co-administration with other cancer chemotherapeutics.

Destruction of the established tumour vasculature by a class of compound termed Vascular Disrupting Agents (VDAs) is showing considerable promise as a viable approach for the management of solid tumours. VDAs induce a rapid shutdown and collapse of tumour blood vessels, leading to ischaemia and consequent necrosis of the tumour mass. Their efficacy is hindered by the persistence of a viable rim of tumour cells, supported by the peripheral normal vasculature, necessitating their co-administration with additional chemotherapeutics for maximal therapeutic benefit. However, a major limitation for the use of many cancer therapeutics is the development of life-threatening cardiovascular toxicities, with significant consequences for treatment response and the patient's quality of life. The aim of this review is to outline VDAs as a cancer therapeutic approach and define the mechanistic basis of cardiovascular toxicities of current chemotherapeutics, with the overall objective of discussing whether VDA combinations with specific chemotherapeutic classes would be good or bad in terms of cardiovascular toxicity.

Identification of Novel Benzoxa-[2,1,3]-diazole Substituted Amino Acid Hydrazides as Potential Anti-Tubercular Agents.

Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection are desperately needed to tackle the continuing global burden of this disease and the efficacy and cost limitations associated with current medicines. Herein, we report the synthesis of a series of novel benzoxa-[2,1,3]-diazole substituted amino acid hydrazides in a two-step synthesis and evaluate their inhibitory activity against Mtb and selected bacterial strains of clinical importance utilising an end point-determined REMA assay. Alongside this, their potential for undesired cytotoxicity against mammalian cells was assessed employing standard MTT assay methodologies. It has been demonstrated using modification at three sites (the hydrazine, amino acid, and the benzodiazole) it is possible to change both the antibacterial activity and cytotoxicity of these molecules whilst not affecting their microbial selectivity, making them attractive architectures for further exploitation as novel antibacterial agents.

Human Cardiac-Mesenchymal Stem Cell-Like Cells, a Novel Cell Population with Therapeutic Potential.

Cardiac stem/progenitors are being used in the clinic to treat patients with a range of cardiac pathologies. However, improvements in heart function following treatment have been reported to be variable, with some showing no response. This discrepancy in response remains unresolved. Mesenchymal stem cells (MSCs) have been highlighted as a regenerative tool as these cells display both immunomodulatory and proregenerative activities. The purpose of this study was to derive a cardiac MSC population to provide an alternative/support to current therapies. We derived human cardiac-mesenchymal stem cell-like cells (CMSCLC), so named as they share some MSC characteristics. However, CMSCLC lack the MSC trilineage differentiation capacity, being capable of only rare adipogenic differentiation and demonstrating low/no osteogenic or chondrogenic potential, a phenotype that may have advantages following transplantation. Furthermore, CMSCLC expressed low levels of p16, high levels of MHCI, and low levels of MHCII. A lack of senescent cells would also be advantageous for cells to be used therapeutically, as would the ability to modulate the immune response. Crucially, CMSCLC display a transcriptional profile that includes genes associated with cardioprotective/cardiobeneficial effects. CMSCLC are also secretory and multipotent, giving rise to cardiomyocytes and endothelial cells. Our findings support CMSCLC as a novel cell population suitable for use for transplantation.

Chronic cardiovascular toxicity in the older oncology patient population.

Survivorship statistics demonstrate that the incidence of cancer continues to rise worldwide, with a further 60% increase in diagnoses predicted by 2030 attributed to lifestyle risk factors, screening programmes resulting in earlier diagnosis but also the changing demographics of the population. More than a third of new cancer diagnoses and almost half of cancer survivors are now aged 70 years or older. Despite this increasing incidence, worldwide five-year cancer survival rates have improved significantly over the past two decades. After cancer, cardiovascular disease is the second most common cause of death in developed countries. With continued improvements in overall prognosis, patients with cancer have an increased exposure to cardiovascular risk factors resulting in higher cardiovascular morbidity and mortality, particularly in older patients. This relationship between cancer and cardiovascular disease is not surprising as they share the common risk factors of aging, smoking, obesity, and poor diet. In this review, we discuss the toxicity of cancer treatments on the cardiovascular system, particularly in older patients. We focus primarily on radiotherapy and anthracycline chemotherapy because of their chronic adverse effects and appraise approaches toward the detection and treatment of this toxicity to maximise survival and quality of life of older patients with cancer.

Rationalized Computer-Aided Design of Matrix-Metalloprotease-Selective Prodrugs.

Matrix metalloproteinases (MMPs) are central to cancer development and metastasis. They are highly active in the tumor environment and absent or inactive in normal tissues; therefore they represent viable targets for cancer drug discovery. In this study we evaluated in silico docking to develop MMP-subtype-selective tumor-activated prodrugs. Proof of principle for this therapeutic approach was demonstrated in vitro against an aggressive human glioma model, with involvement of MMPs confirmed using pharmacological inhibition.

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity.

For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping η(6)-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1 : 1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 µM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.

Anticancer RuII and RhIII Piano-Stool Complexes that are Histone Deacetylase Inhibitors.

The first examples of RuII and RhIII piano-stool complex histone deacetylase (HDAC) inhibitors are presented. The novel complexes have antiproliferative activity against H460 non-small-cell lung carcinoma cells that is comparable to the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Strong evidence for HDAC inhibition as a primary mechanism of action is provided. The complexes reported here represent an important step towards the design of highly active and selective HDAC inhibitors.

Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity.

Development of therapeutic strategies for tumor-selective delivery of therapeutics through exploitation of the proteolytic tumor phenotype has significant scope for improvement of cancer treatment. ICT2588 is a peptide-conjugated prodrug of the vascular disrupting agent (VDA) azademethylcolchicine developed to be selectively hydrolyzed by matrix metalloproteinase-14 (MMP-14) within the tumor. In this report, we extend our previous proof-of-concept studies and demonstrate the therapeutic potential of this agent against models of human colorectal, lung, breast, and prostate cancer. In all tumor types, ICT2588 was superior to azademethylcolchicine and was greater or comparable to standard clinically used agents for the respective tumor type. Prodrug activation in clinical human lung tumor homogenates relative to stability in human plasma and liver was observed, supporting clinical translation potential. A major limiting factor to the clinical value of VDAs is their inherent cardiovascular toxicity. No increase in plasma von Willebrand factor (vWF) levels, an indicator of systemic vascular dysfunction and acute cardiovascular toxicity, was detected with ICT2588, thereby supporting the tumor-selective activation and reduced potential of ICT2588 to cause cardiovascular toxicity. Our findings reinforce the improved therapeutic index and tumor-selective approach offered by ICT2588 and this nanotherapeutic approach.

Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy.

A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional "theranostic" nanoparticles (TNPs) is described for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death is observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.

Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder.

We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor α-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in γ-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.

Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192.

Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compound named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukaemic origin. When tested in culture against the acute myeloid leukaemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukaemia.

Development of a novel tumor-targeted vascular disrupting agent activated by membrane-type matrix metalloproteinases.

Vascular disrupting agents (VDA) offer a strategy to starve solid tumors of nutrients and oxygen concomitant with tumor shrinkage. Several VDAs have progressed into early clinical trials, but their therapeutic value seems to be compromised by systemic toxicity. In this report, we describe the design and characterization of a novel VDA, ICT2588, that is nontoxic until activated specifically in the tumor by membrane-type 1 matrix metalloproteinase (MT1-MMP). HT1080 cancer cells expressing MT1-MMP were selectively chemosensitive to ICT2588, whereas MCF7 cells that did not express MT1-MMP were nonresponsive. Preferential hydrolysis of ICT2588 to its active metabolite (ICT2552) was observed in tumor homogenates of HT1080 relative to MCF7 homogenates, mouse plasma, and liver homogenate. ICT2588 activation was inhibited by the MMP inhibitor ilomastat. In HT1080 tumor-bearing mice, ICT2588 administration resulted in the formation of the active metabolite, diminution of tumor vasculature, and hemorrhagic necrosis of the tumor. The antitumor activity of ICT2588 was superior to its active metabolite, exhibiting reduced toxicity, improved therapeutic index, enhanced pharmacodynamic effect, and greater efficacy. Coadministration of ICT2588 with doxorubicin resulted in a significant antitumor response (22.6 d growth delay), which was superior to the administration of ICT2588 or doxorubicin as a single agent, including complete tumor regressions. Our findings support the clinical development of ICT2588, which achieves selective VDA targeting based on MT-MMP activation in the tumor microenvironment.