Photoacoustic-guided photothermal therapy by mapping of tumor microvasculature and nanoparticle

Although photothermal therapy (PTT) has demonstrated its clinical value and adaptability, it still requires imaging guidance to motivate the development of precise and effective treatment. For PTT, high-resolution visualization of tumor microvasculature and accurate location of nanoparticles distribution are crucial for the therapeutic outcome. Here, a wavelength-switchable photoacoustic microscopy (PAM) was developed to noninvasively investigate the tumor microvasculature and the accumulation of nanoparticles for accurately guiding PTT and evaluating the therapeutic effect. In a tumor model, PAM was used to continuously monitor the tumor microenvironment in vivo, and the proportion of microvessels in tumor site was found increased by 10%, and the diameters of the draining veins were doubled on day 7. In addition, quantitative parameters such as tumor volume and vascular density can also be demonstrated by the PAM. Meanwhile, the concentration of Den-RGD/Cy7 at the tumor site reached its maximum at 8 h by PA mapping after intravenous injection, which was used to determine the optimal irradiation timing. After treatment, photoacoustic monitoring showed that PTT can precisely kill the tumors and minimize damage to surrounding normal tissues, which was consistent with the pathological slides. The experimental results proved that PAM can provide an auxiliary means for precision PTT.

A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis

Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC). During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).

Normalization of tumor microvasculature basing on targeting and modulation of tumor microenvironment

Angiogenesis is an essential process for tumor development. Owing to imbalance of pro- and anti-angiogenic factors, the tumor vasculature possesses the characteristics of tortuous, hyperpermeable vessels and compressive force, resulting...

Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors

Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target. We discuss the development and testing of a bispecific LTT targeting EGFR and urokinase-type plasminogen activator receptor (uPAR) as two attractive targets implicated in tumor growth and in the regulation of the tumor microvasculature in solid tumors. In vitro and mouse xenograft studies have shown that EGFR-targeted bispecific angiotoxin (eBAT) is effective against human solid tumors. Canine studies have shown that eBAT is both safe and effective against canine hemangiosarcoma, which is physiologically similar to human angiosarcoma. Finding the appropriate dosing strategy and sequencing of eBAT administration, in combination with other therapeutics, are among important factors for future directions. Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may have a role in reducing toxicity in comparative oncologic trials in dogs.