Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer

Yingjie Sheng,Estelle Beguin,Heather Nesbitt,Sukanta Kamila,Joshua Owen,Lester C Barnsley,Bridgeen Callan,Christopher O'Kane,Nikolitsa Nomikou,Rifat Hamoudi,Mark A Taylor,Mark Love,Paul Kelly,Declan O'Rourke,Eleanor Stride,Anthony P Mchale,John F Callan

doi:10.1016/j.jconrel.2017.07.040

Abstract

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.

Highlights

Pancreatic cancer has the lowest survival rate among the 21 most common forms of cancer with only 3% of patients surviving five years after their initial diagnosis [1]
The use of lipid conjugated Superparamagnetic iron oxide nanoparticles (SPION) in this study was preferred over the use of previously reported isoparaffin stabilised SPION as the addition of lipids to lipid-shelled microbubbles is likely to be less disruptive to the acoustic response of the system compared to the addition of isoparaffin [19]
Rose Bengal sodium salt, NHS-biotin, MTT assay kit, avidin, chloroacetic acid, 4-dimethylaminopyridine (DMAP), hydroxybenzotriazole (HOBt), N,N′-dicyclohexylcarbodiimide (DCC), anhydrous dimethylformamide (DMF), and ethanol were purchased from Sigma Aldrich (UK) at the highest grade possible

Summary

Introduction

Pancreatic cancer has the lowest survival rate among the 21 most common forms of cancer with only 3% of patients surviving five years after their initial diagnosis [1]. Late presentation of patients due to the vague symptoms associated with the disease means only ~20% are eligible for potentially curative resection at the time of initial diagnosis [2]. Several studies have investigated the potential of neo-adjuvant chemo- and/or radio-therapy to downstage tumours and increase the number of patients eligible for resection [3,4,5]. Such treatments are often associated with significant off-target effects due to the non-specific nature of the chemotherapy regimen. The development of targeted treatments that reduce side-effects related to systemic chemotherapy have enormous potential as neo-adjuvant and palliative pancreatic cancer treatments by reducing tumour burden to either enable surgery or to provide symptom relief

Methods

Results

Conclusion