Pulsed high intensity focused ultrasound increases penetration and therapeutic efficacy of monoclonal antibodies in murine xenograft tumors

Abstract

The success of radioimmunotherapy for solid tumors remains elusive due to poor biodistribution and insufficient tumor accumulation, in part, due to the unique tumor microenvironment resulting in heterogeneous tumor antibody distribution. Pulsed high intensity focused ultrasound (pulsed-HIFU) has previously been shown to increase the accumulation of 111In labeled B3 antibody (recognizes Lewisy antigen). The objective of this study was to investigate the tumor penetration and therapeutic efficacy of pulsed-HIFU exposures combined with 90Y labeled B3 mAb in an A431 solid tumor model. The ability of pulsed-HIFU (1 MHz, spatial averaged temporal peak intensity = 2685 Wcm−2; pulse repetition frequency = 1 Hz; duty cycle = 5%) to improve the tumor penetration and therapeutic efficacy of 90Y labeled B3 mAb (90Y-B3) was evaluated in Ley-positive A431 tumors. Antibody penetration from the tumor surface and blood vessel surface was evaluated with fluorescently labeled B3, epi-fluorescent microscopy, and custom image analysis. Tumor size was monitored to determine treatment efficacy, indicated by survival, following various treatments with pulsed-HIFU and/or 90Y-B3. The pulsed-HIFU exposures did not affect the vascular parameters including microvascular density, vascular size, and vascular architecture; although 1.6-fold more antibody was delivered to the solid tumors when combined with pulsed-HIFU. The distribution and penetration of the antibodies were significantly improved (p-value < 0.05) when combined with pulsed-HIFU, only in the tumor periphery. Pretreatment with pulsed-HIFU significantly improved (p-value < 0.05) survival over control treatments.

Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

“…A myriad of molecular approaches have been used to improve the tumor distribution of macromolecular therapeutics including: tumor penetrating peptides [6–8], hyperthermia [9,10], degradable nanoparticles [11], enzymes and small molecules that modify the tumor ECM [12–16], vascular priming [17], and vascular normalization [18,19]. The effectiveness of these approaches depends on the pharmacology of the drug and the biology of the tumor.…”

Direct brain infusion can be enhanced with focused ultrasound and microbubbles

“…12 In brain applications, however, the presence of the skull has to be taken into consideration. Different from soft tissues, the impedance mismatch between bone and soft tissue limits the propagation of acoustic energy.…”

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

“…Thermal injury can also reduce interstitial fluid pressure (23), which has been shown to enhance accumulation of nanoparticles in cancer (21), and modulate immune cell migration and oxygen tension (24)(25)(26). Unlike other modes of thermal therapy, ultrasound also induces mechanical tissue effects (27), which enhance local accumulation of drugs, antibodies, and nanoparticles (28)(29)(30). Mechanisms for these changes include radiation force, microstreaming, and oscillating gas bubbles within tissue and vasculature (31).…”