Abstract
IntroductionAcoustic cluster therapy (ACT) comprises co-administration of a formulation containing microbubble/microdroplet clusters (PS101), together with a regular medicinal drug (e.g., a chemotherapeutic) and local ultrasound (US) insonation of the targeted pathological tissue (e.g., the tumor). PS101 is confined to the vascular compartment and, when the clusters are exposed to regular diagnostic imaging US fields, the microdroplets undergo a phase-shift to produce bubbles with a median diameter of 22 µm when unconstrained by the capillary wall. In vivo these bubbles transiently lodge in the tumor’s microvasculature. Low frequency ultrasound (300 kHz) at a low mechanical index (MI = 0.15) is then applied to drive oscillations of the deposited ACT bubbles to induce a range of biomechanical effects that locally enhance extravasation, distribution, and uptake of the co-administered drug, significantly increasing its therapeutic efficacy.MethodsIn this study we investigated the therapeutic efficacy of ACT with liposomal doxorubicin for the treatment of triple negative breast cancer using orthotopic human tumor xenografts (MDA-MB-231-H.luc) in athymic mice (ICR-NCr-Foxn1nu). Doxil® (6 mg/kg, i.v.) was administered at days 0 and 21, each time immediately followed by three sequential ACT (20 ml/kg PS101) treatment procedures (n = 7–10). B-mode and nonlinear ultrasound images acquired during the activation phase were correlated to the therapeutic efficacy.ResultsResults show that combination with ACT induces a strong increase in the therapeutic efficacy of Doxil®, with 63% of animals in complete, stable remission at end of study, vs. 10% for Doxil® alone (p < 0.02). A significant positive correlation (p < 0.004) was found between B-mode contrast enhancement during ACT activation and therapy response. These observations indicate that ACT may also be used as a theranostic agent and that ultrasound contrast enhancement during or before ACT treatment may be employed as a biomarker of therapeutic response during clinical use.
Highlights
Acoustic cluster therapy (ACT) comprises co-administration of a formulation containing microbubble/microdroplet clusters (PS101), together with a regular medicinal drug and local ultrasound (US) insonation of the targeted pathological tissue
triple negative breast cancer (TNBC) is a cancer that lacks the expression of estrogen, progesterone, and human epidermal growth factor 2 receptors and is strongly correlated with a poorer outcome when compared to other breast cancer subtypes (Bianchini et al, 2016)
In our work here we investigate the treatment of TNBC with liposomal doxorubicin (Doxil®) using two treatments of ACT
Summary
Acoustic cluster therapy (ACT) comprises co-administration of a formulation containing microbubble/microdroplet clusters (PS101), together with a regular medicinal drug (e.g., a chemotherapeutic) and local ultrasound (US) insonation of the targeted pathological tissue (e.g., the tumor). The outcome is palliative benefit or life prolongation instead of a cure In conditions such as triple negative breast cancer (TNBC) treated with standard of care chemotherapy, this is the case. TNBC is a cancer that lacks the expression of estrogen, progesterone, and human epidermal growth factor 2 receptors and is strongly correlated with a poorer outcome when compared to other breast cancer subtypes (Bianchini et al, 2016). This is primarily due to the inherently aggressive clinical behavior, lack of recognized molecular targets for therapy, and heterogenous response to therapy. Patients diagnosed with TBNC have a mortality incidence from 40 to 50% (Foulkes et al, 2010; Gonçalves et al, 2018) This clearly indicates an important need to improve the therapeutic efficacy for the treatment of breast cancer and even more so of TNBC
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