Antivascular Cancer Therapy Research Articles

Cavitation in an antivascular cancer therapy setting

Focused ultrasound in combination with circulating microbubbles is being widely investigated as a means to promote spatially targeted drug delivery. This approach has considerable potential in oncology for a range of therapeutic agents. At sufficiently high pressures, above those typically employed in drug delivery, tumor microvessel damage can be induced to an extent that leads to perfusion shutdown and subsequent ischemic tissue necrosis. This approach is often referred to as antivascular ultrasound (AVUS), which has been shown in preclinical work to be capable of enhancing the effects of radiation therapy, antiangiogenic therapy, chemotherapy, and immunotherapy. At present, the mechanisms of AVUS are not well established. It is important to gain a more detailed understanding of the bubble–microvessel interactions that lead to perfusion shutdown, along with the cavitation signatures associated with these behaviors to enable the rational development of effective cavitation based control methods. This talk will provide a brief overview of AVUS therapy in oncology and highlight recent efforts employing two-photon microscopy, high speed optical imaging, and acoustic emission monitoring to gain insights into bubble behavior within small channels and in vivo microvessels under AVUS exposure conditions.

An erythrocyte membrane-modified biomimetic synergistic nanosystem for cancer anti-vascular therapy and initial efficacy monitoring.

Tumor vascular disruption has become a promising strategy for cancer therapy in recent decades. Nanocomposites loaded with therapeutic materials and drugs are expected to improve the accuracy of anti-vascular therapy and minimize side effects. However, how to prolong blood circulation of therapeutic nanocomposites for enhanced accumulation in tumor vasculature and how to monitor the initial efficacy of anti-vascular therapy for early evaluation of prognosis remain unsolved. Herein, a biomimetic nanosystem consisting of erythrocyte membrane modified nanocomposites (CMNCs) is developed for cooperation to achieve anti-vascular cancer therapy and initial efficacy monitoring. By utilizing poly(lactic-co-glycolic acid) (PLGA) as the interface material, functional nanomaterials and drug molecules are successfully integrated into CMNCs. The long circulation and immune escape features of the erythrocyte membrane facilitate CMNCs loaded with photothermal agents and chemodrugs to be delivered to the tumor region for anti-vascular treatment. Furthermore, the vascular damage-induced haemorrhage and the following coagulation process is labelled by near infrared emissive CMNCs to indicate the initial therapeutic efficacy of the treatment. This work not only points to a biomimetic strategy for conquering the challenges in anti-vascular cancer therapy, but also provides insights into the biological responses of erythrocyte membrane modified nanocomposites to exploit their biomedical applications.

Improved Evaluation of Antivascular Cancer Therapy Using Constrained Tracer-Kinetic Modeling for Multiagent Dynamic Contrast-Enhanced MRI.

Dynamic contrast-enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to antivascular therapies. Multiagent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we used multiagent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multiagent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 and 24 hours after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was used to estimate flow F, blood volume fraction vb, mean capillary transit time tc, bolus arrival time td, extracellular extravascular fraction ve, vascular heterogeneity index α-1 (all identical between agents) and extraction fraction E (reflective of permeability), and transfer constant Ktrans (both agent-specific) in perfused pixels. F, vb, and α-1 decreased at both time points after DMXAA, whereas tc increased. E (G2 and G5) showed an initial increase, after which, both parameters restored. Ktrans (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, tc, and Ktrans Gd-DOTA showed significant changes. Histologic perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multiagent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy by separating simultaneous changes in tumor hemodynamics and vascular permeability.Significance: These findings describe a new approach to measure separately the effects of antivascular therapy on tumor hemodynamics and vascular permeability, which could help more rapidly and accurately assess the efficacy of experimental therapy of this class. Cancer Res; 78(6); 1561-70. ©2018 AACR.

Tumor Stroma, Tumor Blood Vessels, and Antiangiogenesis Therapy

Solid tumors generally require a vascularized connective tissue stroma if they are to grow beyond minimal size. They generate that stroma in part by secreting vascular endothelial growth factor (VEGF), a potent vascular permeability and angiogenic factor. Increased vascular permeability leads to deposition of a provisional fibrin stroma, which supports tumor, connective tissue, and inflammatory cell migration and plays an active role in the formation of mature vascularized stroma. Vascular endothelial growth factor-induced tumor blood vessels are heterogeneous, of at least 6 distinct types, and develop linearly over time. They include both angiogenic (mother vessels, glomeruloid microvascular proliferations, vascular malformations, capillaries) and arteriovenogenic (feeding arteries, draining veins) blood vessels. Attacking the tumor vasculature with drugs that target VEGF or its receptors (VEGFR) has come into vogue but has been less effective than had been hope for. One reason for this is that anti-VEGF/VEGFR therapy attacks only a subset of tumor blood vessels, the earliest to form. New targets on late-forming blood vessels such as feeding arteries would be useful in helping antivascular cancer therapy fulfill its promise.

Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets

Therapies directed against VEGF-A and its receptors are effective in treating many mouse tumors but have been less so in treating human cancer patients. To elucidate the reasons that might be responsible for this difference in response, we investigated the nature of the blood vessels that appear in human and mouse cancers and the tumor “surrogate” blood vessels that develop in immunodeficient mice in response to an adenovirus expressing VEGF-A164. Both tumor and tumor surrogate blood vessels are heterogeneous and form by two distinct processes, angiogenesis and arterio-venogenesis. The first new angiogenic blood vessels to form are mother vessels (MV); MV arise from preexisting venules and capillaries and evolve over time into glomeruloid microvascular proliferations (GMP) and subsequently into capillaries and vascular malformations (VM). Arterio-venogenesis results from the remodeling and enlargement of preexisting arteries and veins, leading to the formation of feeder arteries (FA) and draining veins (DV) that supply and drain angiogenic vessels. Of these different blood vessel types, only the two that form first, MV and GMP, were highly responsive to anti-VEGF therapy, whereas “late”-formed capillaries, VM, FA and DV were relatively unresponsive. This finding may explain, at least in part, the relatively poor response of human cancers to anti-VEGF/VEGFR therapies, because human cancers, present for months or years prior to discovery, are expected to contain a large proportion of late-formed blood vessels. The future of anti-vascular cancer therapy may depend on finding new targets on “late” vessels, apart from those associated with the VEGF/VEGFR axis.

Functional Characterization of Filamin A Interacting Protein 1–Like, a Novel Candidate for Antivascular Cancer Therapy

Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify common intracellular mediators, we previously analyzed gene expression profiles of endothelial cells after treatment with angiogenesis inhibitors. Filamin A interacting protein 1-like (FILIP1L; previously known as down-regulated in ovarian cancer 1) was identified as one of the genes up-regulated in endothelial cells in response to these inhibitors. However, the expression and function of FILIP1L protein is uncharacterized. Here, we provide the first description of the expression and specific subcellular localization of FILIP1L protein in human tissue. Overexpression of FILIP1L resulted in inhibition of cell proliferation and migration and increased apoptosis. In addition, overexpression of FILIP1L truncation mutants showed differential antiproliferative activity. A COOH terminal truncation mutant (FILIP1LDeltaC103) was more potent than wild-type FILIP1L in mediating this activity. Targeted expression of FILIP1LDeltaC103 in tumor vasculature inhibited tumor growth in vivo. Overall, these findings suggest that the novel protein FILIP1L may be an important mediator of the effects of angiogenesis inhibitors and that FILIP1L has the potential to be an antivascular reagent for cancer therapy.

The Disruption of Murine Tumor Neovasculature by Low-intensity Ultrasound—Comparison Between 1- and 3-MHz Sonication Frequencies

The goal was to determine whether the tumor vascular disrupting actions of low-intensity ultrasound were frequency dependent. The effect of the frequency (1 MHz at 2.2 W/cm2 or 3 MHz at 2.4 W/cm2) of low-intensity ultrasound as a neovascular disrupting modality was investigated in 15 murine melanomas (K1735(22)) insonated for 3 minutes after the intravenous injection of a microbubble contrast agent (Definity). In contrast-enhanced power Doppler observations of each tumor (before and after treatment), measurements were made of the size of the area of the tumor that was perfused with blood containing the ultrasound contrast agent (percentage area of flow [PAF]), and the volume of contrast agent flowing through the unit volume of the tumor (color-weighted fractional area [CWFA]). During insonation of the tumor, the temperature was measured with a fine wire thermocouple in an additional eight mice. The antivascular action of low-intensity ultrasound was significantly enhanced (PAF by 64%; CWFA by 106%) when the tumor was treated with 3-MHz ultrasound rather than 1 MHz (analysis of variance: PAF, P=.02; CWFA, P=.04). The average rate of tumor temperature increase was 2.6+/-1.3 degrees C/min for 1 MHz and 5.0+/-1.7 degrees C/min for 3 MHz; these increases were significantly different (P=.04). Insonation of the tumor at a higher frequency amplified the heating of the neoplasm and led to greater disruption of the tumor vasculature; 3-MHz ultrasound was more efficacious than 1 MHz for antivascular cancer therapy.

An Organobismuth Compound that Exhibits Selective Cytotoxicity to Vascular Endothelial Cells in Vitro

Selective cytotoxicity of chemical compounds to vascular endothelial cells is often beneficial for clinical applications including antivascular cancer therapy. In this study, the cytotoxicity of 35 organic compounds containing bismuth or antimony was evaluated based on the leakage of lactate dehydrogenase and morphologic observations in cultured bovine aortic endothelial cells and other cell types. The results indicate that only tris[2-(N,N-dimethylaminomethyl)phenyl]-bismuthane (TDPBi) had potent cytotoxicity to bovine aortic endothelial cells but not to bovine aortic smooth muscle cells and porcine kidney epithelial LLC-PK1 cells; the compound exhibited moderate cytotoxicity to human fetal lung fibroblastic IMR-90 cells. Neither inorganic bismuth nor tris[2-(N,N-dimethylaminomethyl)phenyl]stibane, in which antimony substitutes for bismuth with the same organic structure as TDPBi, exhibited cytotoxicity to vascular endothelial cells, suggesting that the entire structure of TDPBi is required for selective cytotoxicity. The present data revealed that TDPBi has selective cytotoxicity to vascular endothelial cells, which may be applicable in antivascular cancer therapy.

Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI.

Antivascular photodynamic therapy (PDT) of tumors with palladium-bacteriopheophorbide (TOOKAD) relies on in situ photosensitization of the circulating drug by local generation of cytotoxic reactive oxygen species, which leads to rapid vascular occlusion, stasis, necrosis and tumor eradication. Intravascular production of reactive oxygen species is associated with photoconsumption of O(2) and consequent evolution of paramagnetic deoxyhemoglobin. In this study we evaluate the use of blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) for real-time monitoring of PDT efficacy. Using a solid tumor model, we show that TOOKAD-PDT generates appreciable attenuation (25-40%) of the magnetic resonance signal, solely at the illuminated tumor site. This phenomenon is independent of, though augmented by, ensuing changes in blood flow. These results were validated by immunohistochemistry and intravital microscopy. The concept of photosensitized BOLD-contrast MRI may have intraoperative applications in interactive guidance and monitoring of antivascular cancer therapy, PDT treatment of macular degeneration, interventional cardiology and possibly other biomedical disciplines.

TNF revisted: New perspectives for a successful antivascular cancer therapy

TNF revisted: New perspectives for a successful antivascular cancer therapy

Assessment of protamine-induced thrombosis of tumor vessels for cancer therapy using dynamic contrast-enhanced MRI.

Since the role of angiogenesis in cancer development has been recognized, the study of anti-angiogenic or anti-vascular therapeutic agents has become increasingly important for cancer treatment. Selective thrombosis is one approach towards this goal. Since many types of carcinoma accumulate large numbers of degranulating mast cells which will release heparin, intravenously injected protamine may bind to heparin, neutralize its anti-coagulant effect and induce thrombosis. In this work we studied the formation of thrombosis by using dynamic contrast enhanced MRI. The enhancement kinetics of the contrast medium measured before and after protamine treatment were compared to assess the thrombotic effect. The underlying concept was that if the vessels became clotted, the subsequently injected contrast medium could not be delivered into the tissue to cause enhancement. In addition to the tissue-specific changes, protamine may also induce systemic effect in the host. The therapy-induced changes measured in tumors were compared to changes in normal tissues: liver, kidney, and especially the muscle adjacent to tumor. The results showed that protamine induced pronounced changes in the tumor. However, the degree of change measured by MRI was not associated with the results of semiquantitative assessment of thrombosis assessed by histology, perhaps due to the heterogeneous nature of the tumor and the difficulty in sampling sufficient regions histologically. The protamine-induced temporal effects were also studied. We demonstrated that protamine could induce selective thrombosis in tumors, and that the effect could last for several hours. Dynamic contrast-enhanced MRI can serve as a suitable means to investigate the mechanism of this novel approach to induce selective thrombosis for anti-vascular cancer therapy.

Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105).

The use of adenoviruses for antivascular cancer gene therapy is limited by their low transduction efficiency for endothelial cells. We have developed a recombinant bispecific antibody as a molecular bridge, linking the adenovirus capsid to the endothelial cell surface protein endoglin, for vascular targeting of adenoviruses. Endoglin (CD105), a component of the transforming growth factor beta receptor complex, represents a promising target for antivascular cancer therapy. Endoglin is expressed predominantly on endothelial cells and is upregulated in angiogenic areas of tumors. We isolated single-chain Fv fragments directed against human endoglin from a human semisynthetic antibody library. One of the isolated scFv fragments (scFv C4) bound specifically to various proliferating primary endothelial cells or cell lines including HUVEC, HDMEC, HMVEC, and HMEC. ScFv C4 was therefore used to construct a bispecific single-chain diabody directed against endoglin and the adenovirus fiber knob domain (scDb EDG-Ad). This bispecific molecule mediated enhanced and selective adenovirus transduction of HUVECs, which was independent from binding to the coxsackievirus and adenovirus receptor (CAR) and alpha(v)-integrins. Thus, adenovirus infection was redirected to a new cellular receptor (CD105) and cell entry pathway. These results demonstrate the utility of bispecific single-chain diabodies, which can be produced in large quantities in bacteria, for the retargeting of adenoviruses in cancer gene therapy.