Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors

Abstract

Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies.

A Novel Theranostic Strategy for MMP-14–Expressing Glioblastomas Impacts Survival

“…1d). The dose range of CLIO-ICT and ICT was chosen based on previous studies (29,33,34) and in the case of CLIO, was calculated on the basis of plasma concentrations of CLIO reached in patients after clinically applied doses (35-37). In apoptosis assays, GBM cells expressing high MMP-14 showed higher signal for both active caspase-3 fluorescence and Annexin-V/PI staining after incubation with CLIO-ICT and ICT (Fig.…”

Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models

“…One such treatment strategy is vascular normalization, a concept for treatment of cancer patients through enhanced delivery and efficacy of anticancer therapeutics . Indeed, normalization of the microenvironment can improve treatment outcomes in mice and patients with malignant and non‐malignant diseases without increased MVD . Although tumor vascular remodeling illustrated here is similar to vascular normalization in that both strategies alter the tumor microenvironment for enhanced pharmacological outcomes of anticancer agents, there are distinct functional differences between the vascular remodeling effect that is induced by eribulin and vascular normalization.…”

“…(11) In this study, eribulin-induced vascular remodeling also increased accumulation of a liposomal anticancer agent, Doxil, in contrast with vascular normalization induced by VEGF blockage that only increased tumor delivery of intermediate size (12 nm) but not larger nanoparticles. (28) Recently, Daldrup-Link et al (26) reported that inhibition of type I transforming growth factor beta (TGF-b) receptor increased the delivery of macromolecules by increased transendothelial permeability in the tumor. Eribulin reduced TGF-b1, a ligand of type I TGF-b receptor expression in both animal models and breast cancer patients, which suggested increased permeability to endothelial cells.…”

Next-generation superparamagnetic iron oxide nanoparticles for cancer theranostics

“…All of these chemotherapeutic drugs have in common low molecular weights, rapid biodistribution and elimination from the body. Attaching these small molecules to SPIO increases their blood circulation half-life, promotes their tumor retention through the EPR effect and enables real-time in vivo drug tracking with MRI [20]. Although SPIO nanoparticles are normally metabolized in the liver, they were also found to accumulate in other organs of the reticuloendothelial system (e.g., spleen) [21,22], where the drug conjugates can exert potential toxic effects especially after multiple dose administration.…”