Pulsed Ultrasound Enhances Nanoparticle Penetration into Breast Cancer Spheroids

Abstract

Effective treatment of solid tumors requires homogenous distribution of anticancer drugs within the entire tumor volume to deliver lethal concentrations to resistant cancer cells and tumorinitiating cancer stem cells. However, penetration of small molecular weight chemotherapeutic agents and drug-loaded polymeric and lipid particles into the hypoxic and necrotic regions of solid tumors remains a significant challenge. This article reports the results of pulsed ultrasound enhanced penetration of nano-sized fluorescent particles into MCF-7 breast cancer spheroids (300-350 μm diameter) as a function of particle size and charge. With pulsed ultrasound application in the presence of microbubbles, small (20 nm) particles achieve 6-20 folds higher penetration and concentration in the spheroid's core compared to those not exposed to ultrasound. Increase in particle size to 40 nm and 100 nm results in their effective penetration into the spheroid's core to 9 and 3 folds, respectively. In addition, anionic carboxylate particles achieved higher penetration (2.3, 3.7, and 4.7 folds) into the core (0.25r) of MCF-7 breast cancer spheroids compared to neutral (2.2, 1.9, and 2.4 folds) and cationic particles (1.5, 1.4 and 1.9 folds) upon US exposure for 30, 60, and 90 seconds under the same experimental conditions. These results demonstrate the feasibility of utilizing pulsed ultrasound to increase the penetration of nano-sized particles into MCF-7 spheroids mimicking tumor tissue. The effects of particle properties on the penetration enhancement were also illustrated.

Cancer Cell Spheroids for Screening of Chemotherapeutics and drug-delivery Systems

“…MCF-7 breast cancer spheroids were treated with nanosized fluorescent particles with and without the application of pulsed ultrasound. It was found that the particles achieved sixfold to 20-fold higher penetration with the application of ultrasound [76]. In this study, the penetration was also found to be size and charge dependent.…”

Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo

“…Since multicellular spheroids (MCs) represent more closely the heterogeneity of the tumour microenvironment with a hypoxic core and normoxic surface 32,33 compared with traditional monolayer cell cultures, we incubated SH-SY5Y MCs with Ir-PVP. The strong phosphorescence signal of Ir-PVP was observed in the core of spheroids, while almost no signal was detected on the surface of spheroids (Fig.…”

Active Targeting of Nano-Photosensitizer Delivery Systems for Photodynamic Therapy of Cancer Stem Cells

“…The conjugate was ten-fold more selective for HER2-positive cells compared with soluble pyropheophorbide-a. Vrouenraets et al 95 directly used mAbs against tumor-associated antigens for the targeting of photosensitizers to improve the selectivity of PDT and found that AlPc(SO 3 H) 4 showed promising potential for use in PDT when coupled to internalizing tumor-selective mAbs.…”