Gemcitabine loaded microbubbles for targeted chemo-sonodynamic therapy of pancreatic cancer

Abstract

Pancreatic cancer remains one of the most lethal forms of cancer with a 10-year survival of <1%. With little improvement in survival rates observed in the past 40 years, there is a significant need for new treatments or more effective strategies to deliver existing treatments. The antimetabolite gemcitabine (Gem) is the most widely used form of chemotherapy for pancreatic cancer treatment, but is known to produce significant side effects when administered systemically. We have previously demonstrated the benefit of combined chemo-sonodynamic therapy (SDT), delivered using oxygen carrying microbubbles (OMB), as a targeted treatment for pancreatic cancer in a murine model of the disease. In this manuscript, we report the preparation of a biotin functionalised Gem ligand for attachment to OMBs (OMB-Gem). We demonstrate the effectiveness of chemo-sonodynamic therapy following ultrasound-targeted-microbubble-destruction (UTMD) of the OMB-Gem and a Rose Bengal loaded OMB (OMB-RB) as a targeted treatment for pancreatic cancer. Specifically, UTMD using the OMB-Gem and OMB-RB conjugates reduced the viability of MIA PaCa-2, PANC-1, BxPC3 and T110299 pancreatic cancer cells by >60% (p < 0.001) and provided significant tumour growth delay (>80%, p < 0.001) compared to untreated animals when human xenograft MIA PaCa-2 tumours were treated in SCID mice. The toxicity of the OMB-Gem conjugate was also determined in healthy non-tumour bearing MF1 mice and revealed no evidence of renal or hepatic damage. Therefore, the results presented in this manuscript suggest that chemo-sonodynamic therapy using the OMB-Gem and OMB-RB conjugates, is potentially an effective targeted and safe treatment modality for pancreatic cancer.

Ultrasound‐Activated Sensitizers and Applications

“…Nesbitt et al. developed microbubble‐loaded biotin‐functionalized gemcitabine (O 2 MB‐Gem) for the targeted chemo‐sonodynamic therapy of pancreatic cancer cells . The efficacy of chemo‐sonodynamic therapy was significantly increased, thereby indicating a potential new strategy for treating pancreatic cancer.…”

Microbubble-Mediated Delivery for Cancer Therapy

“…The combination of ultrasound and microbubbles has considerable potential as such a technique. In addition to coadministration, cavitation agents can be modified to load the drug of interest [124][125][126][127] or nanoparticle forms of the therapeutic (extensively reviewed in the literature [128][129][130]). In general, as permeability is only temporarily altered, colocalising the drug or nanocarrier to the site of microbubble activity promotes the delivery [131], effect [132], and release [133,134].…”

Ultrasound‐mediated therapies for the treatment of biofilms in chronic wounds: a review of present knowledge

“…Though high molecular weight gases are most commonly used as the MB core constituent, it is also possible to generate MBs that possess a biologically active gaseous core. Recent research has already highlighted the advantages of using MBs with an oxygen core, to increase the therapeutic efficacy of chemo-sonodynamic therapy (SDT) in the targeted treatment of solid malignant tumours (McEwan et al, 2015;Nesbitt et al, 2018). Bioactive gases such as NO have significant therapeutic potential, as they mediate a number of important biological signal pathways (Basudhar et al, 2016).…”